Background and Objectives: Thyroid disease has been associated with autoimmune disorders. As systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations spanning across all organ systems, the relationship of SLE with thyroid disorders needs investigation. In particular, the relationship of SLE with autoimmune thyroid disease has attracted the interest of the research community. The aim was to evaluate the relationship of SLE with autoimmune thyroid disease. Materials and Methods: A cohort of 45 consecutive patients, mean age 47,97 years (range 21-79 years) and 45 age and sex-matched controls were prospectively studied over a period of 12 months for the presence of thyroid disease and the prevalence of antithyroid antibodies. Results: Four patients (8.9%) were found to suffer from primary hypothyroidism, 5 (11.11%) from subclinical hypothyroidism and 1 (2.22%) from hyperthyroidism, whereas 1 (2.22%) of the controls had primary hypothyroidism and 1 (2.22%) had hyperthyroidism. Five patients (11.11%) had a thyroid hormone profile compatible with the presence of euthyroid sick syndrome. Thyroid peroxidase (TPOab) and thyroglobulin (Tgab) antibodies were detected in 20/45 and 15/45 of the SLE population and in 7/45 and 5/45 of the controls, respectively (p<0.05, chi square test). Conclusions: In conclusion, the incidence of clinical thyroid disease is greater amongst SLE patients than in a control population and in a significant number of these patients antithyroid antibodies are detectable. Thus, a subset of lupus patients appears to be predisposed to the development of thyroid disease and this should be considered when evaluating patients with SLE.

Background. Helicobacter pylori infection has long been suspected to increase the risk of thyroid diseases but evidence from literature is conflicting. In a cohort of patients from Northern Sardinia, Italy, who underwent upper endoscopy, we investigated the association between current and long-lasting Helicobacter pylori infection and thyroid disease, both autoimmune and non-autoimmune, by adjusting for potential confounds. Methods. By using multivariable logistic regression we analyzed a cohort of 8490 adults aged 6–93 years: 730 were diagnosed with autoimmune thyroid disease (AITD) and 448 with nonautoimmune thyroid diseases. Results. We found a significant association between H. pylori long-lasting infection and AITD independently of age, sex, body mass index, smoke, hypertension and dyslipidemia (OR 1.42; 95%CI 1.20‒1.66) while the opposite was found regarding current infection (OR 0.75; 95%CI 0.63‒0.89). Current infection was not significantly associated to non-autoimmune thyroiditis. Conclusions. H. pylori infection is an independent risk factor for AITD in the population of Northern Sardinia, therefore it is advisable to eradicate the pathogen in subjects at risk of AITD.

Critical and progressive cachexia may be observed in numerous medical disciplines, but in patients with various diseases several pathways overlap (endocrine, inflammatory and kidney diseases, heart failure, cancer). A case-control analysis is presented of patients with initial immune-mediated thyroiditis complicated with cachexia, pulmonary pa-thology coexisting with opportunistic infection, finally diagnosed cancer (thyroid cancer, misdiagnosed as NSCLC). Contrary to other patients with lung cancer the presented pa-tients were not active smokers, exclusively women who developed cachexia with existing autoimmune process in the first phase. Furthermore, coexistence of short overall survival without cancer progression in the most seriously ill patients, correlation with sex (con-trary to history of smoking) and predisposition to mycobacterial disease are very sug-gestive. The unique sequence shed light on immune-mediated thyroid disease as a sub-clinical paraneoplastic process modified by various therapeutic regimens, however, with systemic consequences and a sequel, requiring holistic approach. Differential diagnosis of severe cachexia, adenocarcinoma with pulmonary localization and tuberculosis reac-tivation require analysis of immunological and genetic background. Contrary to highly specialized teams (e.g. lung cancer units) the immunotherapy and general medicine in aging populations require multidisciplinary observation, holistic and inquiring approach. Lack of differentiation, confusing bias as well as discrepancy in literature are the main obstacles in statistical research, that indicate correlation of common factors only. Such time-lapse case studies may be first to build evidence of a pathway and association be-tween immune parameters, comorbidity and cancer.

Various autoimmune diseases, including autoimmune hypothyroidism (AHT), are associated with a higher risk of developing mood disorders throughout life. Depression is accompanied by the changes in the levels of inflammatory and trophic factors, including interleukines (IL-1beta, IL-2, IL-6), interferon alpha (IFN-alpha), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) and brain derived neurotrophic factor (BDNF). Similar disturbances in the cytokine profile are seen in AHT patients and their relatives. Disclosure of the relationship between the co-existence of depression and autoimmune subclinical thyroiditis indicates that the pathomecha-nism of depression may be related to the changes in the immune system, it is possible that both conditions may be caused by the same immune processes. The above hypothesis is indirectly sup-ported by the observations that the treatment with both antidepressants and levothyroxine leads to a decrease in the levels of proinflammatory cytokines with an increase in BDNF concentrations, simultaneously correlating with an improvement in the clinical parameters. However, so far there are no long-term studies determining the causal relationship between depression, thyroid auto-antibodies, and cytokine profile, which could bring us closer to understanding the interrelation-ships between them and facilitate the use of an adequate pharmacotherapy, not necessarily psy-chiatric. We consider the above issues insufficiently investigated but of great importance. This ar-ticle is an overview of the available literature as well as an introduction to our research project.

Although relatively rare, affecting 8% of the general population, autoimmune disorders are causative linked with chronic diseases and morbidity. Control of the course of the disease is closely dependent on the ability to monitor its onset as well as response to treatment. In the present report, we review the progress in the development of biosensor-based approaches and related tools for the Point-of-Care diagnosis and monitoring of biomarkers related to several autoimmune diseases, such as Myasthenia Gravis, Rheumatoid Arthritis, Multiple Sclerosis, Systemic Erythematosus Lupus, Crohn’s Disease, Diabetes Mellitus, Behcet’s disease, Psoriasis and Celiac Disease. Various biosensing technologies are discussed, including electrochemical, optical and mechanical ones, along with the use of advanced nanomaterials and immobilization techniques for the biorecognition elements. The need for innovative devices with unique features of rapid, low-cost, real-time detection is considered in the context of preventing permanent organ and tissue damage from chronic autoimmune diseases.

Background: Autoimmune inner ear disease (AIED) is a rare autoimmune condition characterized by progressive sensorineural hearing loss with hearing fluctuations over weeks to months, presenting significant challenges in both diagnosis and treatment. Due to its rarity, treatment responses and prognosis in AIED remain poorly understood. Methods: This study reviewed medical records from Taipei Medical University Hospital documented between August 2016 and August 2021. Among 67 patients experiencing fluctuating hearing loss, 11 met the diagnostic criteria for AIED and underwent regular follow-up assessments within a 5-year timeframe. ROC curve was used to discriminate the power of these prognostic parameters. Results: In this study, several factors including younger age, milder initial hearing loss, meeting criteria for bilateral Meniere's disease (MD), having an ascending audiogram pattern, longer time interval between hearing impairment attacks in contralateral ears and responding well to steroids were associated with better prognosis. ROC curve demonstrated the diagnostic value of specific parameters such as the presence of bilateral MD (AUC 0.825, 95% CI 0.640–1.000), pretreatment HI ≤ 45 dB HL (AUC 0.808, 95% CI 0.610–1.000), response to steroids (AUC 0.800, 95% CI 0.595–1.000), and ascending audiogram (AUC 0.858, 95% CI 0.683–0.858). Conclusions: This study identified key prognostic factors for AIED, providing valuable insights for predicting AIED prognosis and facilitating personalized patient management.

Evans' Syndrome (ES) is a rare autoimmune disorder characterized by the simultaneous occurrence of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Thrombotic complications in ES patients are uncommon, particularly involving Buerger's Disease (BD). We report a case of a 49-year-old male with ES and a history of diabetes and heavy smoking, presenting with a necrotic wound on his right great toe. Diagnostic evaluations revealed severe stenosis and thrombosis in the lower limb arteries, diagnosed as BD. The patient underwent successful popliteal-tibioperoneal artery bypass surgery and subsequent disarticulation and revision of the distal phalanx, followed by the application of an acellular dermal matrix (ADM) to promote healing. Post-surgery, the patient showed significant improvement in blood flow and complete epithelialization without complications. This case highlights the importance of a multidisciplinary approach in managing complex wounds in ES patients, suggesting potential treatment pathways for future cases involving BD

Abstract: Autoimmune encephalitis is a complex and multifaceted pathology that involves the immune-mediated inflammation of the brain. It is characterized by the body's immune system mistakenly attacking the brain tissue, leading to a cascade of inflammatory processes. What makes autoimmune encephalitis vast is the wide range of causes, mechanisms, clinical presentations, and diagnostic challenges associated with the condition. The clinical presentations of autoimmune encephalitis are broad and can mimic other neurological disorders, making it a challenging differential diagnosis. This diverse clinical presentation can overlap with other conditions, making it crucial for healthcare professionals to maintain a high level of suspicion for autoimmune encephalitis when evaluating patients. The diagnostic challenges associated with autoimmune encephalitis further contribute to its vastness. Due to the variable nature of the condition, there is no definitive diagnostic test that can confirm autoimmune encephalitis in all cases. In this context, personalized patient management is crucial for achieving favorable outcomes. Each patient's treatment plan should be tailored to their specific clinical presentation, underlying cause, and immune response. Our objective is to raise awareness about the frequent yet under-diagnosed nature of autoimmune encephalitis by sharing five cases we encountered, along with a brief literature review.

Incidence of autoimmune diseases increases. Antinuclear antibodies (ANA) testing is a critical tool for their diagnosis. However, ANA prevalence in health increased over last decades, especially among young people. ANA in health occur in low concentrations, with prevalence up to 50% in some populations, which demands a cutoff revision. The review deals with origin and probable physiological or compensatory function of ANA in health, according to the concept of immunological clearance, theory of autoimmune regulation of cell functions and the concept of functional autoantibodies. Considering ANA titers ≤1:320 as a serological marker of autoimmune diseases seems inappropriate. The role of anti-DFS70/LEDGFp75 autoantibodies is highlighted as possible anti-risk biomarker for autoimmune rheumatic disorders. ANA prevalence in health is different in various regions due to several underlying causes discussed in the review, all influencing in additive combinations according to the concept of the mosaic of autoimmunity. Not only titer, but the HEp-2 IFA staining patterns, like AC-2, is also important. Accepting autoantibodies as a kind of bioregulators, not only upper, but also lower borders of their normal range should be determined. Not only their excess, but also lack of them or “autoimmunodeficiency” could be a reason of disorders.

The blood-brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. In the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, inducing antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS by autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert-Eaton myasthenic syndrome and were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune condition, yet its alignment with a specific host immunological pathway remains unclear. The THαβ host immunological pathway, recognized for its defense against viruses and prions, has recently emerged as a response to DNA, RNA, and protein pathogens. SLE patients often produce anti-double strand DNA antibodies and anti-nuclear antibodies, suggesting a potential association with the THαβ host immune reaction. Throughout the course of SLE, elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 are commonly observed. These cytokines and antibody isotypes are indicative of the THαβ host immunological pathway. Similarly, Myasthenia gravis, Grave’s disease, Graft versus host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjogren’s syndrome are also linked to THαβ-related type 2 hypersensitivities. Considering the potential association of these diseases with dysregulated THαβ immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferons α/β could be explored to manage these disorders effectively.

Myopathies are characterized by a diverse clinical picture affecting the skeletal muscle which includes weakness, fatigue and pain. Acquired myopathies are given importance because treatment is readily available however, some inherited myopathies can be treated as well. These myopathies can be grouped by etiology into infectious myopathies, autoimmune myopathies, granulomatous myopathies, metabolic myopathies, skeletal muscle channelopathies and Duchenne muscular dystrophy. Infectious myopathies are caused by microbiological agents. Autoimmune myopathies result from immunologic disorders causing inflammatory changes in the muscle. Granulomatous myopathy is associated with non-caseating granulomatous inflammation. Metabolic myopathies are caused by abnormal metabolic processes in the myocytes. Drug-induced myopathies are acute or subacute onset of muscle weakness after intake of a certain medications even at therapeutic doses. Critical illness myopathy stem from sepsis syndrome with failure to wean from respirator. Rhabdomyolysis is an acute myopathy, which is an urgent complex condition that involves rapid dissolution of damaged skeletal muscle. Skeletal channel myopathies are due to dysfunctions in the ion channels of the muscle. Duchenne muscular dystrophy is a genetic condition characterized by mutations in the dystrophin gene, resulting in pathologic muscle wasting. Therapies abound in myopathies as these are targeted in Infectious, Granulomatous and Autoimmune Myositides. Included in treatable myopathies are certain metabolic myopathies, rhabdomyolysis, periodic paralysis, critical illness myopathy and drug-induced myopathies. Symptomatic therapies are applied in channelopathies of muscle and dystrophinopathies can be potentially treated nowadays. Complementary rehabilitation practices are part of the management regimen.

Although genome-wide association studies (GWAS) have identified several hundred loci associated with autoimmune diseases, their mechanistic insights are still poorly understood. The human genome is more complex than common single nucleotide polymorphisms (SNPs) that are interrogated by GWAS arrays. Some structural variants such as insertions-deletions, copy number variations, and minisatellites that are not very well tagged by SNPs cannot be fully explored by GWAS. Therefore, it is possible that some of these loci may have large effects on autoimmune disease risk. In addition, other layers of regulations such as gene-gene interactions, epigenetic-determinants, gene and environmental interactions also contribute to the heritability of autoimmune diseases. This review focuses on discussing why studying these elements may allow us to gain a more comprehensive understanding of the aetiology of complex autoimmune traits.

Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia less than 50% of patients remain in a long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder which requires therapy in majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first line as well as relapsed setting. Rituximab is the preferred therapy for steroid refractory wAIHA and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of the rituximab and current literature its role in management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease.

The diagnosis and treatment of autoimmune diseases are major challenges. Their signs, symptoms, and their clinical severity change throughout the course of the disease. The available treatments for these conditions do not result in complete remission, and their long-term use generates several side effects. The main challenges in this field are the development of more sensitive diagnostic tools, and effective treatments. Studies in patients and animal models reported alterations in monocyte phenotype, activation, and function. These cells play an essential role in the pathogenesis of chronic inflammatory states and have become a target for extracorporeal monitoring and specific intervention. Nanoparticles (NPs) are ultrafine particles that can be used as contrast agents in diagnostic imaging techniques to detect specific cells in inflammatory infiltrates in tissues that are not easily accessible by biopsy. In addition, NPs can be designed to deliver drugs to a cell population or tissue. This review describes several experimental pieces of evidence demonstrating that monocytes and macrophages can specifically uptake various types of NPs, thus becoming detectable in vivo by magnetic resonance imaging and susceptible to be modulated by therapeutic agents. Hence, nanoparticles targeting mononuclear phagocytes represent promising tools for diagnosing and treatment.

The review analyzes a possible role of autoimmune processes in the pathogenesis of schizophrenia and evolution of concepts on this issue from its origin to present. Risks of autoimmune processes causing schizophrenia are associated with several factors: an impaired functioning of dopaminergic and glutamatergic systems in the brain, kynurenine pathway disorder with overproduction of quinolinic, anthranilic and kynurenic acids (possibly altering both neurons and T-regulators), increased intestinal permeability, as well as food antigens’ effects, stress and infections with various pathogens at different stages of ontogenesis. An increase in the levels of proinflammatory cytokines and chemokines as well as a decrease in the levels of anti-inflammatory ones also may contribute to schizophrenia risks. Schizophrenia often occurs in those patients having various autoimmune diseases and their first-degree relatives. Cases of schizophrenia resulted from autoimmune pathogenesis (including autoimmune encephalitis caused by autoantibodies against various neuronal antigens) are characterized by quite severe cognitive and psychotic symptoms and less favorable prognosis. This severe course may result from the chronic immune damage of the neuronal receptors such as NMDA, GABA, and others and depend on hyperprolactinemia, induced by antipsychotics, but aggravating autoimmune processes [with 2 tables, 4 figures, bibliography: 99 references].

Immune disorders, characterized by dysregulation at cellular and inflammatory levels, result from a complex interplay of genetics and environmental factors that lead to an abnormal immune response against autoantigens, triggering tissue damage. Recent research highlights reactive antibodies as key players in autoimmune diseases and graft rejection, but the complexity of their determination limits their use in clinic. Hence, we studied the specific binding profile of serological antibodies against a panel of cellular membranes in order to determine whether this antigenic panel could be used to diagnose specific immune disorders in humans. For this purpose, cell membrane microarrays of spleen, liver, and kidney tissues of monkey, rat, and human were developed, and human sera were analyzed, including healthy controls, patients with autoimmune disorders, and kidney transplant patients. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and Human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in the serum of patients as potential biomarkers of immune disorders.

The inflammatory bowels diseases (IBD) are autoimmune diseases that deeply impact the patients’ quality of life. The IBD pathogenesis is not yet defined, but evidence demonstrated that the IBD chronic inflammation is related to an impaired intestinal barrier. Traditionally, two actors were considered for their contribution to this disfunction: the gut microbiota and intestinal epithelium. However, a third element, which is the intestinal mucus, should be considered as peer of the epithelium and microbiota. Indeed, mucus represents the biological interface between bacteria and cells, filtering molecules or toxins and preventing bacteria penetration exploiting both structural and compositional properties. The boosting effect of the mucus characterization towards IBD comprehension is far too underestimated, although some mucus-oriented studies are already reported in literature. This work reviews the intestinal barrier features, describing each component of the gut mucosa (i.e., epithelium, microbiota, and mucus) in a mucus-oriented perspective.

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body’s proteins, it leads to various autoimmune disorders. And when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.

Autoimmune hepatitis (AIH) is a chronic, relapsing and remitting, immune mediated liver disease which progresses to cirrhosis if left untreated. A significant number of patients may present with acute hepatitis or acute liver failure, which are often misdiagnosed as toxic liver injury. AIH shows a preponderance for young women but may be seen in children and elderly. Diagnosis requires integration of clinical, biochemical and serologic parameters along with supportive liver histology and exclusion of other causes of liver disease. Liver biopsy is a pre-requisite for diagnosis of AIH, to assess severity and stage of disease, exclude other entities and recognize any concurrent morbidities. No single biomarker or histologic feature is pathognomonic for AIH. The diagnostic and histologic criteria have undergone several modifications since the Original Scoring system proposed by the International Autoimmune Hepatitis Group (IAIHG) in 1993. Recently, IAIHG has proposed consensus recommendations for histologic criteria, relevant for both acute and chronic AIH. This review article will describe the evolving diagnostic criteria for AIH with their limitations and utility, with an emphasis on the role of liver histology in diagnosis and management of AIH.

Presenting a case report on the occurrence of IgA nephropathy with hepatitis B infection in a 32-year-old male patient with main complaints of generalized weakness, easy fatigue, and bilateral swelling of the lower extremities. IgA nephropathy (IgAN), or Berger’s disease, is the most common primary glomerulonephritis worldwide. It is characterized by the formation of IgA1-containing circulating immune complexes and their deposition in the glomerular mesangium. Its etiology remains multifactorial and often idiopathic. IgA nephropathy alone does not have an infectious etiology; instead, it usually develops in conjunction with an infectious condition that triggers a dysregulated immune response. There is no proof that any particular infectious agent is the secondary cause of IgA nephropathy. Hepatitis B virus (HBV) infection is an infectious agent associated with renal complications, including IgA nephropathy. Symptoms include gross haematuria and mild proteinuria indicative of renal involvement. Laboratory investigations and serological tests are followed by imaging studies such as ultrasound and renal biopsy to confirm the diagnosis. The challenges encountered during the diagnostic process included overlapping symptoms and limitations of available diagnostic tests, highlighting the need for comprehensive diagnostic evaluation and multidisciplinary management approaches in similar cases. This case underscores the importance of recognizing and managing both conditions simultaneously to prevent long-term complications such as end-stage renal disease.

Background: Myocarditis is commonly diagnosed in the intensive care cardiology unit (ICCU). No current recommendation nor guideline aids aetiological assessment. Methods: From September 2021 to October 2023, 84 patients with acute myocarditis underwent thorough and systematic serum and blood cell panel evaluations to determine the most common causes of the myocarditis. Results: Of the 84 patients (median age 34 years, range 22–41 years, 79% male), 16 presented with complicated myocarditis. The systematic aetiological assessment revealed that 36% of patients were positive for lupus anticoagulant, 12% for antinuclear antibodies, 8% for anti-heart antibodies, and 12% for anti-striated muscle antibodies. Viral serology did not yield any significant results. After the aetiological assessment, one patient was diagnosed with an autoimmune inflammatory disorder (Still’s disease). T-cell subset analyses indicated that myocarditis severity tended to increase with the T-cell lymphopenia status. Conclusions: A comprehensive, systematic aetiological assessment was of limited value in terms of predicting the clinical or therapeutic outcomes in myocarditis patients presenting to the ICCU.

Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed world, although currently there are no approved antifibrotic therapies. In recent years, high levels of interleukin-17 (IL-17) have been associated with chronic inflammatory diseases with fibrotic complications, that culminate in organ failure. In this review, we provide an update on the role of IL-17 in fibrotic diseases, with particular attention to the most recent lines of research in the therapeutic field represented by the epigenetic mechanisms that control IL-17 levels in fibrosis. A better knowledge of the IL-17 signalling pathway implications in fibrosis could design new strategies for therapeutic benefits.

cGAS is a cytosolic DNA sensor that activates innate immune responses through production of the second messenger 2’3’-cGAMP, which activates the adaptor STING. cGAS senses dsDNA in a length-dependent but sequence-independent manner, and it cannot discriminate self-DNA from foreign DNA. In normal physiological conditions, cellular DNA is sequestered in the nucleus by nuclear envelope and in mitochondria by mitochondrial membrane. When self-DNA leaks into the cytosol during cellular stress, or during mitosis, the cGAS can be exposed to self-DNA and be activated. Recently, many studies have investigated how cGAS keeps inactive and avoids to be aberrantly activated by self-DNA. Thus, the aim of this narrative review is to summarize the mechanisms by which cGAS avoids to sense self-DNA under normal physiological conditions.

The nutritional habits regulate the gut microbiota and may provoke and/or prevent autoimmune disease. Western diet is rich in sugars, meat and poly-unsaturated fatty acids, which lead to dysbiosis of intestinal microbiota, disruption of gut epithelial barrier and chronic mucosal inflammation. On the other hand, Mediterranean Diet (MedDiet) is rich in ω3 fatty acids, fruits and vegetables and has anti-inflammatory properties, which can restore gut eubiosis. The effect of MedDiet and its components in health and disease states have been thoroughly analyzed in several studies. Moreover, several studies have specifically investigated the association between MedDiet, microbiota and risk for autoimmune diseases. Furthermore, the MedDiet has been associated with lower risk of cardiovascular diseases, which plays a critical role in reducing mortality in patients suffering from autoimmune diseases with comorbidities. The aim of the present review is to specifically highlight current knowledge regarding possible interactions of MedDiet with the patterns of intestinal microbiota focusing on autoimmunity and a blueprint through dietary modulations for the prevention and management of diseases’s activity and progression.

The role of pregnancy in multiple sclerosis (MS) is of importance because many patients with MS are young women in the childbearing age who require information to inform their reproductive decisions. Pregnancy is now well-known to be associated with fewer relapses of MS and reduced activity of autoimmune encephalomyelitis (EAE). However, in women with multiple sclerosis, this benefit is not always sufficient to protect against a rebound of disease activity if disease modulating therapy is ceased for pregnancy. There is reason to be concerned that use of assisted reproductive therapies can be associated with relapses of MS. It is thought that the beneficial effects of pregnancy are due to the pregnancy-associated changes in the maternal immune system. There is some evidence of this in human studies and studies of EAE. There is also evidence that having been pregnant leads to better long-term outcome of MS. The mechanism for this is not fully understood but it could result from epigenetic changes resulting from pregnancy or parenthood. Further studies of the mechanisms of the beneficial effects of pregnancy could provide information that might be used to produce new therapies.

Trio-based exome sequencing and high-resolution HLA typing were employed to analyze three patients with autoimmune adrenal insufficiency (AAI), including those with autoimmune polyglandular syndrome (APS) type 2, as well as their parents. Benign or likely benign variants of the AIRE gene were identified in all participants of the study. These variants, coupled with clinical data and the results of antibody studies to type I interferons, helped to exclude APS-1. Patients with APS-2, in contrast to patient with AAI, inherited distinct variants of unknown significance in the CLEC16A gene, which is associated with autoimmune diseases including AAI. Various risk alleles in other genes associated with autoimmunity were identified in all patients. HLA typing of second class loci revealed alleles related to APS types 2, 3, and 4. Nevertheless, the frequencies of the haplotypes identified are substantial in the healthy Russian population, precluding from regarding these alleles as genetic determinants linked to APS development. Immunological examination can detect antibody carriers and predict the risk of autoimmune disease development. In the future, to identify genetic predictors of autoimmune endocrinopathies, it is recommended to analyze the whole genome of patients and their relatives, examining clinically relevant variants in non-coding regions.

Viral infections leading to inflammation have been implicated in several common diseases such as Alzheimer’s disease (AD) and type 1 diabetes (T1D). Of note, herpes simplex virus 1 (HSV-1) has been reported to be associated with AD. We sought to identify the transcriptomic changes due to HSV-1 infection and anti-viral drug (acyclovir, ACV) treatment of HSV-1 infection in dissoci-ated cells from human cerebral organoids (dcOrgs) versus stem cell-derived pancreatic islets (sc-islets) to gain potential biological insights into the relevance of HSV-1-induced inflammation in AD and T1D. We observed that differentially expressed genes (DEGs) in HSV-1-infected sc-islets were enriched for genes associated with several autoimmune diseases, most significantly T1D but also rheumatoid arthritis, psoriasis, Crohn’s disease, and multiple sclerosis, whereas DEGs in HSV-1-infected dcOrgs were exclusively enriched for genes associated with AD. ACV treatment of sc-islets did not rescue transcript expression of autoimmune disease-associated genes. Finally, we identified gene ontology categories that were enriched for DEGs that were in common across, or unique to, viral treatment of dcOrgs and sc-islets, such as categories involved in the transferase complex, mitochondrial and autophagy function. Collectively, this studies pro-vide insight to the molecular effects of inflammation in AD and T1D.

Advances in diagnostic procedures have led to an increasing rate of diagnosis of autoimmune encephalitis or paraneoplastic neurological syndrome (AE/PNS) among patients with progressive supranuclear palsy (PSP)-like manifestations. The antibodies involved in these conditions include anti-IgLON5, -Ma2, and -Ri antibodies, each of which has a characteristic clinical presentation. The steps in the diagnosis of AE/PNS in patients with PSP-like manifestations include (i) suspicion of AE/PNS based on clinical presentations atypical of PSP and (ii) antibody detection measures. Methods used to identify antibodies include a combination of tissue-based assays and confirmatory tests. The primary confirmatory tests include cell-based assays and immunoblotting (line or western blot). Treatments can be divided into immunotherapy and tumor therapies, the former of which includes acute and maintenance therapies comprising corticosteroids, intravenous immunoglobulins, plasmapheresis, rituximab, and cyclophosphamide. One of the major challenges of diagnosis is that existing reports on PSP-like patients with AE/PNS include only case reports, with the majority discussing antibodies other than anti-IgLON5 antibody. As such, more patients need to be evaluated to establish the relationship between antibodies and PSP-like manifestations.

Autoimmune polyglandular syndrome (APS) comprises a complex association of autoimmune pathological conditions. APS Type 1 originates from loss-of-function mutations in the autoimmune regulatory (AIRE) gene. APS2, APS3, and APS4 are linked to specific HLA alleles within the major histocompatibility complex, with single nucleotide polymorphisms (SNPs) in non-HLA genes also contributing to disease. In general, variability in the AIRE locus and the presence of heterozygous loss-of-function mutations can impact self-antigen presentation in the thymus. In this study, Whole Exome Sequencing (WES) was performed on a sixteen-year-old female APS3A/B patient to investigate the genetic basis of her complex phenotype. The analysis identified two variants (p.Arg111Trp and p.Thr101Ile) of the hepatitis A virus cell receptor 2 gene (HAVCR2) encoding for the TIM-3 (T cell immunoglobulin and mucin domain 3) protein. These variants were predicted, through in silico analysis, to impact protein structure and stability, potentially influencing the patient’s autoimmune phenotype. While Confocal Microscopy analysis revealed no alteration in TIM-3 distribution between PBMCs isolated from the patient and those of a healthy donor, RT-qPCR showed reduced TIM-3 expression in the patient’s cells. A screening conducted on a cohort of thirty APS patients indicated that the p.Thr101Ile and p.Arg111Trp mutations were unique for the proband. This study opens the pathway for the search of TIM-3 variants possibly linked to complex autoimmune phenotypes, highlighting the potential of novel variant discovery in contributing to APS classification and diagnosis.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is an extremely rare type of vasculitis characterized by inflammation within small blood vessels or tissues that may cause damage to the lungs, heart, kidneys, and other organs. Here, we present a rare case of EGPA with cardiac involvement that presented with acute heart failure. Clinical findings: A 44-year-old woman with a history of bronchial asthma and sinusitis pre-sented with fever, shortness of breath, fatigue, unintentional weight loss, and polyarthritis. Physical examination revealed a fine basal crepitation and mononeuritis multiplex. Diagnosis: The peripheral film revealed dimorphic features, an elevated eosinophil count, low hemoglobin (Hb), and abnormally high lactate dehydrogenase levels. The cardiac enzyme levels were elevated upon admission. Cardiac magnetic resonance imaging (CMR) revealed global hypokinesia and features suggestive of myocarditis. Echocardiography showed a low ejection fraction of 25%. Thus, the patient diagnosed with EPGA and myocarditis presented with acute heart failure. Interventions: The patient was administered high-dose corticosteroids (intravenous bolus methylprednisolone 500 mg for three days, followed by 1 mg/kg of prednisolone) and cyclo-phosphamide 750 mg intravenously. Outcome: After one months, the patient showed a marked improvement in clinical and labora-tory parameters. The ejection fraction improved to 30-40%, the eosinophil count returned to normal, and the hemolytic anemia resolved. The patient was sent home with mycophenolate mofetil 1 g twice a day as maintenance therapy. Conclusion: Patients with EGPA have a higher morbidity and mortality rate when they have cardiac in-volvement. The pathophysiological mechanism of cardiac involvement in EGPA warrants con-sideration of immunosuppressive therapy in addition to standard heart failure treatment.

A 68-year-old man with malignant metastatic melanoma in complete remission after Pembrolizumab treatment, developed 10 months after Pembrolizumab cessation due a grade 3 diarrhea, confusion, altered mental status, progressive memory loss, gait disturbance. He was admitted to the neurologic department and comprehensive neurological workup, brain magnetic resonance imaging, cerebral fluid analysis, EEG, blood test allowed the diagnosis of autoimmune encephalitis. The patient was treated with plasmapheresis, high dose of intravenous steroids and intravenous immunoglobulins. The patient improved and he is now well with a performance status 1. This case is interesting since the AE developed approximately 10 months after the cessation of immunotherapy, the underlying cancer was in complete remission and the AE showed a good response to the treatment done.

Autoimmune hemolytic anemias (AIHAs) are conditions whereby a person produces an antibody to their own red blood cells (RBCs). These conditions can be primary with unknown cause or secondary, associated with diseases or infections. There are seven different categories of AIHA, warm-antibody AIHA (wAIHA); cold-antibody AIHA that includes cold agglutinin syndrome (CAS) and cold agglutin disease (CAD); mixed AIHA, also called combined cold and warm AIHA; paroxysmal cold hemoglobinuria (PCH) also termed Donath-Lansteiner test-positive AIHA; direct antiglobulin test-negative AIHA (DAT-neg AIHA); drug-induced immune hemolytic anemia (DIIHA); and passenger lymphocyte syndrome. This review will discuss each of these AIHAs and provide information on diagnosis and treatment.

Idiosyncratic drug induced liver injury (DILI) is an unpredictable reaction of exposed individual on a certain drug, and the drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case of a 48-year-old male that was hospitalized due to severe hepatocellular liver injury two months after the self-treatment with the muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract. His immunology panel was positive with increased IgG levels, and the radiologic methods showed no signs of chronic liver disease. He underwent corticosteroid treatment with adequate response. After the therapy withdrawal, a clinical relapse occurred. Seven months after the initial presentation liver MR suggested the initial cirrhotic changes of the right liver lobe. Liver biopsy revealed abundant lymphoplasmacytic infiltrate with piecemeal necrosis and grade 2 fibrosis. He responded well on the corticosteroid treatment again, and was further treated with low dose prednisone without additional relapses. Several years later, further management confirmed presence of liver cirrhosis with no histological or biochemical signs of the disease activity. DIAIH is a DILI phenotype difficult to distinguish from idiopathic AIH despite a wide armamentarium of diagnostic methods. Regular patient monitoring and clinical open-mindedness with the adjustment of therapeutic approaches according to the disease course are more important than strict labelling of the disease.

Centella asiatica (Centella) is a traditional botanical medicine that shows promise in treating dementia based on behavioral alterations seen in animal models of aging and cognitive dysfunction. In order to determine if Centella could similarly improve cognitive function and reduce disease burden in multiple sclerosis (MS), we tested its effects in the neuroinflammatory experimental autoimmune encephalomyelitis (EAE) model of MS. In two independent experiments, C57BL/6J mice were treated following induction of EAE with either a standardized water extract of Centella (CAW) or placebo for 2 weeks. At the dosing schedule and concentrations tested, CAW did not improve behavioral performance, EAE motor disability, or degrees of demyelination. However, CAW-treated mice demonstrated increases in nuclear factor (erythroid-derived 2)-like 2 and other antioxidant response element genes, and increases in mitochondrial respiratory activity. Caw also decreased spinal cord inflammation. Our findings indicate that CAW can increase antioxidant gene expression and mitochondrial respiratory activity in mice with EAE, supporting investigation of the clinical effects of CAW in people with MS.

Penile squamous cell carcinoma (SCC) is a rare disease. Treatment options for advanced penile cancer are often limited and prognosis remains poor. We reported a 52-year-old male recurrent and metastatic penile SCC patient with high PD-L1 expression(90%) and TMB(14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection and excision of the abdominal wall mass during two surgeries. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin were then carried out, the carcinoma still had progressed. The patient then obtained progression free survival exceeding 32 months with continuous sintilimab, although new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He didn’t have positive type 1 diabetes associated autoantibodies, but had susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory penile SCC obtained remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is one of the most controversial diseases in pediatric rheumatology. Despite its first description being published more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine re-lease in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

Autoimmune Glomerulonephritis represents a homogeneous area of renal pathology with clinical relevance for either the numerical impact or difficulties in treatment. SLE and Lupus nephritis are the most frequent occurrences. They are characterized by glomerular deposition of circulating autoantibodies that recognize glomerular antigens Technologies for studying tissue and circulating antibodies have evolved over the years and culminated with the direct analysis of the antigen-antibody complex in renal bioptic fragments. Mass-spectrometry of immunoprecipitates from the renal tissue is, in fact, the most recent evolution that eliminates the need for tissue microdissection. The results obtained with this technique have led to the discovery of several new glomerular antigens in Membranous Nephropathy and in Lupus Nephritis, two conditions whose pathogenesis remained unknown for decades, Peptide and protein arrays (Immunopeptidomics and immunoproteomics, respectively) for the characterization of circulating autoantibodies represent the new frontier for identifying autoantibodies. Immunopeptidomics consists in 7.5 million aligned peptides of 16 amino acids each which cover the whole human proteome; immunoproteomics utilizes a chip containing structured proteins, 26.000 overall. Both are very sensitive techniques that allow the characterization of hundreds of new antibodies in circulation. The contribution of arrays to amplify the panel of potential autoantibodies involved in glomerulonephritis is expected to be relevant for improving our knowledge of the pathogenesis of several autoimmune conditions.

Arsenic trioxide (ATO) is now part of the standard regimen for the treatment of newly diagnosed and relapsed acute promyelocytic leukaemia. The availability of an oral form of ATO has greatly reduced the incidence of cardiotoxicity as compared to intravenous administration. Increasing evidence suggests that ATO has anti-inflammatory properties that may be useful for the treatment of autoimmune diseases. These include the modulation of Treg cell activation, Th1/Th2 and Th17/Treg balance, depletion of activated T cells and plasmacytoid dendritic cells, and influence of B cell differentiation, leading to reduced autoantibody and cytokine production. ATO has also been shown to induce apoptosis of activated fibroblast-like synoviocytes through generation of reactive oxygen species and alter the gut microbiota in collagen-induced arthritis. Despite the emergence of newer treatment modalities, the treatment of systemic lupus erythematosus (SLE), especially refractory manifestations, remains a challenge, owing to the paucity of effective biological and targeted therapies that are devoid of adverse effects. Oral ATO is an attractive option for the treatment of SLE because of the lower cost of production, convenience of administration and reduced cardiotoxicity. This article summarizes the anti-inflammatory mechanisms of ATO and its potential application in the treatment of SLE.

Autoimmune blistering diseases represent a group of chronic severe, disabling, potentially fatal disorders of the skin and/or mucous membranes primarily mediated by pathogenic auto-antibodies. Despite their rarity, these diseases are associated with significant morbidity and mortality, a profound negative impact on the patient’s quality of life and impose a considerable economic burden. Rituximab, an anti CD-20 monoclonal antibody represents the first line of therapy for pemphigus, regardless of its severity as it ensures high rates of rapid, long-lasting complete remission. Nevertheless, disease recurrence is the rule, all patients requiring maintenance therapy with rituximab sooner or later. While innate resistance to rituximab in pemphigus patients is exceptional, acquired resistance is frequent and may develop even in patients with initial complete response to rituximab, representing a real challenge for physicians. We discuss the various resistance mechanisms and their complex interplay, as well as the numerous therapeutic alternatives that may be used to circumvent rituximab resistance. As no therapeutic measure is universally efficient, individualization of rituximab treatment regimen and tailored adjuvant therapies in refractory pemphigus cases are mandatory.

It is challenging to differentiate central nervous system (CNS) virus infections and neurological autoimmune diseases in the emergency department. Considering their different pathogenesis, we assume they differ in neuropsychiatric symptoms and laboratory results. 80 patients were included, 50 with CNS virus infections and 30 with CNS autoimmune diseases, confirmed by polymerase chain reaction (PCR) of cerebrospinal fluid (CSF). A binary logistic regression model and receiver operating characteristic (ROC) curve were conducted to examine the discrimination between the two diseases based on neuropsychiatric symptoms and laboratory results. Compared to patients with neurological autoimmune diseases, patients with CNS virus infections had higher incidence of abnormal behavior (p=0.026) and abnormal sensation/thought (p=0.029), higher total (p = 0.005), direct (p = 0.004), and indirect bilirubin (p = 0.004), increased CSF cell (p = 0.01) and CSF white cell counts (p = 0.01). ROC analysis showed that patients with disturbance of consciousness and abnormal sensation/thought were 7.79-fold and 5.07-fold more likely to be diagnosed with CNS virus infections (OR = 7.79, p = 0.008; OR = 5.07, p = 0.032). Each unit increase in blood indirect bilirubin concentration and CSF white cell counts increased risk of developing CNS virus infections by 1.25-fold and 1.01-fold (OR = 1.25, p = 0.016; OR = 1.01, p = 0.011). Our study found that patients with CNS viral infections tend to have higher blood indirect bilirubin concentration, CSF leukocyte count, frequency of disorders of consciousness, and abnormal sensation and thought, which may help differentiate them from neurological autoimmune diseases.

Autoimmune diseases of the liver and biliary tract require timely and accurate diagnosis. This study evaluates the D-tek panel (D-Tek, Mons, Belgium) of 10 immunodot antigens for its effectiveness in diagnosing autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). We retrospectively analysed serum samples from 111 patients who had undergone routine testing, including indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISA), to confirm or exclude autoimmune liver or biliary tract disease. The panel tested for M2/nPDC, M2/OGDC-E2, M2/BCOADC-E2, M2/PDC-E2, gp210, sp100, LKM1, LC1, SLA, and F-actin antigens. Results showed that all positive IIF+ELISA results were confirmed by the immunodot panel, except for two samples from patients never diagnosed with AIH. The immunodot test identified over 20 additional autoantibodies in samples initially negative by IIF, corroborated by laboratory imaging and medical history. The immunodot technique proved to be a quick, sensitive, and specific method with high overall accuracy. This study suggests that the immunodot technique may be an effective screening and confirmatory method for autoimmune liver diseases, potentially improving diagnostic efficiency and accuracy in clinical practice.

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the white matter. Pathophysiology is thought to be immune mediated as in most cases the condition follows an infection or triggering incident. More recent literature has demonstrated that there may be a link between autoimmune conditions and ADEM. Here we present a case of ADEM in a middle-aged woman with systemic lupus erythematosus that recovered well after treatment with corticosteroids and Rituximab.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS) characterized by varying degrees of demyelination of uncertain etiology, and is associated with specific environmental and genetic factors. Upon recognition of CNS antigens, the immune cells initiate an inflammatory process which leads to destruction and deterioration of the neurons. Innate immune cells such as macrophages, dendritic cells and natural killer cells are known to play critical roles in the pathogenesis of MS. Also, the activation of peripheral CD4+ T cells by CNS antigens leads to their extravasation into the CNS causing damages that exacerbates the disease. This could be accompanied by dysregulation of T regulatory cells and other cell types functions. Experimental autoimmune encephalomyelitis (EAE) is a mouse model used to study the pathophysiology of MS disease. In this review, we highlight the roles of innate and adaptive immune players in the pathogenesis of MS and EAE.

Human intestinal flora refers to a large and diverse microbial population present in the digestive tract of the human body, which plays a significant role in the establishment of human immune homeostasis and the normal function of the immune system. Myasthenia Gravis is an autoimmune disease of the neuromuscular junction, mainly involved in the anti-acetylcholine receptor antibody, cellular immune dependence, and complement¹. At present, studies have found that the intestinal flora of Myasthenia Gravis is different from that of healthy people. Probiotic therapy has been shown effective in the experimental autoimmune Myasthenia Gravis animal models. This article reviews the relationship between intestinal flora and Myasthenia Gravis, to provide new ideas for further study of the pathogenesis and clinical treatment of Myasthenia Gravis.

Diagnosis of encephalitis is a challenging problem due to the heterogeneity of clinical presentations and the myriad of aetiology. The objective was to determine the aetiology, clinical features, laboratory parameters, radiological findings and in-hospital outcome of acute encephalitis syndrome (AES) cases in Myanmar. Methods: A prospective analytic study was conducted at Neuromedical Ward of Yangon General Hospital during March to August 2023. 81 AES cases were enrolled and cerebrospinal fluids (CSF) samples were collected. Qiastat ME Panelwas used to detect viral, bacterial and fungal pathogens. Results: 17 out of 81 (21%) cases were non-encephalitis with alternative definite diagnosis. Among the remaining 64 encephalitis cases, the exact infectious and immune aetiologies were identified in 31/64 (48.4%); 26/31 cases (83.9%) were infectious causes and 5/31 patients (16.1%) were immune encephalitis. Among the infection causes, six Herpes Simplex Virus-1, one bacteriologically confirmed and seven probable Mycobacterium tuberculosis, three Haemophilus influenzae, two Streptococcus pneumoniae, one Streptococcus pyogenes, one Varicella-Zoster Virus (Ramsay Hunt Syndrome with meningoencephalitis), two Cryptococcus neoformans infected patients and rare causes such as Listeria monocytogenes, Burkholdelria cepacia, Sphingomonas paucimobilis and Aspergillus were identified. One case was dual infection with Haemophilus influenzae and Cryptococcus neformans. Abnormal protein levels and CSF pleocytosis were significantly higher among bacterial causes (P<0.05). 6.45% (2/31) of encephalitis patients with identified causes and 12.12% (4/33) of those without organism identified had bad outcome. Conclusions: Herpes encephalitis and tuberculous meningoencepalitis were the commonest. This study highlighted that molecular testing with multidisciplinary approach is required to ensure the right treatment on time.

Systemic autoimmune diseases (SAIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and rheumatoid arthritis (RA) are fully related to the unregulated innate and adaptive immune systems involved in their pathogenesis. They have similar pathogenic characteristics including the interferon signature, loss of tolerance to self-nuclear antigens, and enhanced tissue damage like necrosis and fibrosis. Glucocorticoids and immunosuppressants, which have limited specificity and are prone to tolerance, are used as the first-line therapy. A plethora of novel immunotherapies have been developed including monoclonal and bispecific antibodies, and other biological agents to target cellular and soluble factors involved in disease pathogenesis such as B cells, co-stimulatory molecules, cytokines or their receptors, and signalling molecules. Many of these have shown encouraging results in clinical trials. CAR-T cell therapy is considered the most promising technique for curing autoimmune diseases, with recent successes in the treatment of SLE and SSc.

Polymyositis is a rare condition with an unknown etiology occurring more frequently in adult women. There is a lack of evidence on the coexistence of PM and CMV infection in a patient with Hashimoto Thyroiditis hypothyroidism. However, the increasing incidence of CMV infection and autoimmune diseases overlapping points out a relationship, while the association direction remains unclear. Case outline: A 32-year-old woman recently treated for HT hypothyroidism was admitted to the hospital two weeks after being treated for common flu by the family doctor, complaining about a worsening condition with muscle pain, weakness, frequent falls, and fatigue. The first tests showed a normalized thyroid function, with elevated values of troponin and serum creatinine kinase (KC). The immunological tests revealed the presence of a high titer of CMV IgG antibodies and raised levels of CMV DNA. Pelvis MRI images demonstrated markedly elevated signals on the STIR sequences in the pelvis, thighs, and calves, indicating active and severe multifocal myositis. The diagnosis of PM was confirmed with the muscle biopsy on day 7 of hospitalization. The patient showed significant improvements within two weeks after the medical therapy and physiotherapy.

The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO). Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

Schizophrenia is characterized by an interrelated activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in natural regulatory autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative specific epitopes (OSEs), nitroso (NO) and nitro (NO₂) adducts in schizophrenia remain unknown.This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl and NO₂-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls.Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO₂-tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 – 42.2 %) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO₂-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall.These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in lowered IgM responses to MDA and azelaic acid (part of the CIRS) attenuate the negative immune-regulatory feedback on the primary immune response and that this process may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia.

Chronic urticaria (CU) is a debilitating skin condition affecting up to 20% of the global popula-tion, characterized by erythematous, maculo-papular lesions and significant quality of life im-pairment. This study focused on the role of interleukin 33 (IL-33) and its polymorphisms, partic-ularly SNP rs1929992, in chronic spontaneous urticaria (CSU). Using demographic, clinical, and laboratory data from CU patients and controls, we aestimated allele and genotype frequencies, Hardy-Weinberg equilibrium condition, and serum IL-33 levels, using unconditional binomial logistic regression for association analysis. Results revealed that CU patients had significantly higher frequencies of the minor allele of IL33 rs1929992 compared to controls (31.25% vs. 17.35%, p = 0.024), and carriers of the AG genotype exhibited increased odds of CU (adjusted OR = 2.208, p ≤ 0.001). Additionally, serum IL-33 levels were markedly elevated in CU patients, par-ticularly those with the GA genotype. The findings suggest that the IL-33 SNP rs1929992 is asso-ciated with an increased susceptibility to CSU, emphasizing its potential as a diagnostic and therapeutic biomarker. This study underscores the genetic and immunological underpinnings of CSU, paving the way for personalized treatment approaches.

The case of a patient with autoimmune haemolytic anaemia and an anastomosing haemangioma, is presented. The main dilemma was whether the haemangioma was the cause or the consequence of the autoimmune haemolytic anaemia and how both processes should be management. The diagnostic methods used are analytical and imaging techniques, which have not been conclusive in the diagnosis of anastomosing haemangiomas. Preoperative corticosteroid treatment does not prevent the recurrence of autoimmune haemolytic anaemia in the postoperative period. Surgical indication is established by the progression of proliferative activity, tumor enlargement and compression of the vena cava over time. Surgical resection of the tumor is the procedure used. The indication for surgical treatment of the anastomosing haemangioma and the decrease in alpha- fetoprotein after tumor resection are the most relevant results, although it increases again after a few weeks. The development of an anastomotic haemangioma may be secondary to autoimmune haemolytic anaemia. Angiogenesis resulting from the formation of erythroblastic islands at the periphery of the tumor and clonal expansions may be a mechanism to compensate for the haemolysis caused by autoimmune haemolytic anaemia

The best form of prevention against human infection through bacteria, viruses and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. As a therapeutic measure, various preclinical studies showed promising results, which are being revisited and reconsidered in times of pandemics and led to interesting results in recent clinical trials and reports, as presented by the example of protective measures against covid-19 in particularly vulnerable clinical personnel. In patients with rheumatoid arthritis, repeated ozone treatments have led to new findings in the "immunomodulation" through ozone. The more effective immune response is discussed as the response of innate immune memory and opens interesting aspects for complementary treatment of autoimmune diseases.

Hashimoto’s thyroiditis (HT) is a common autoimmune disease, with its prevalence rapidly increasing. Both genetic and environmental risk factors contribute to the development of HT. Recently, viral infection has been suggested to act as a trigger of HT by eliciting the host immune response and subsequent autoreactivity. We analyzed features of HT through bioinformatics analysis so as to identify markers of HT development. We accessed public microarray data of HT patients from the Gene Expression Omnibus (GEO) and obtained differentially expressed genes (DEGs) under HT. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed for functional clustering of our protein-protein interaction (PPI) network. Utilizing ranked gene lists, we performed Gene Set Enrichment Analysis (GSEA) using the clusterprofiler R package. By comparing the expression signatures of the huge perturbation database with the queried rank-ordered gene list, connectivity map (CMap) analysis was performed to screen potential therapeutic targets and agents. The gene expression profile of the HT group was in line with general characteristics of HT. Biological processes related to the immune response and viral infection pathways were obtained for the upregulated DEGs. GSEA results revealed activation of autoimmune disease-related pathways and several viral infection pathways. Autoimmune disease and viral infection pathways were highly interconnected by common genes, while the HLA genes which are shared by both were significantly upregulated. CMap analysis suggested that perturbagens, including SRRM1, NLK, and CCDC92, have the potential to reverse the HT expression profile. Several lines of evidence suggested that viral infection and the host immune response are activated during HT. Viral infection is suspected to act as a key trigger of HT by causing autoimmunity. SRRM1, an alternative splicing factor, which responds to viral activity, might serve as potential marker of HT.

Multiple sclerosis (MS) is a demyelinating autoimmune disorder of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) has been widely used to determine the pathogenesis of the disease and evaluate new treatment strategies for MS. Therefore, we investigated the efficacy of oral administration of a Myelin Oligodendrocyte Glycoprotein (MOG) in the treatment of EAE. Female C57BL/6 mice were utilized in three groups (Control group: received PBS orally; prevention group: oral administration of MOG35-55 two weeks before EAE induction; treatment group: oral administration of MOG35-55 after EAE induction. MOG administration, both as prevention and treatment, significantly controlled clinical score, weight loss, CNS inflammation, and demyelination, mainly through the modulation of T cell proliferation, reduction of pro-inflammatory cytokines and transcription factors, including TNF-α, IFN-γ, IL-17, T-bet, and ROR-γt. MOG administration, both as prevention and treatment, also induced anti-inflammatory cytokines and transcription factors, including IL-4, TGF-β, GATA-3, and Foxp3. The results showed that oral administration of MOG, both as prevention and treatment, could efficiently control EAE development. Immunomodulatory mechanisms include the induction of Th2 and Treg cells and the suppression of pro-inflammatory Th1 and Th17 cells.

Multiple sclerosis (MS) is a demyelinating autoimmune disorder of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) has been widely used to determine the pathogenesis of the disease and evaluate new treatment strategies for MS. Therefore, we investigated the efficacy of oral administration of a Myelin Oligodendrocyte Glycoprotein (MOG) in the treatment of EAE. Female C57BL/6 mice were utilized in three groups (Control group: received PBS orally; prevention group: oral administration of MOG35-55 two weeks before EAE induction; treatment group: oral administration of MOG35-55 after EAE induction. MOG administration, both as prevention and treatment, significantly controlled clinical score, weight loss, CNS inflammation, and demyelination, mainly through the modulation of T cell proliferation, reduction of pro-inflammatory cytokines and transcription factors, including TNF-α, IFN-γ, IL-17, T-bet, and ROR-γt. MOG administration, both as prevention and treatment, also induced anti-inflammatory cytokines and transcription factors, including IL-4, TGF-β, GATA-3, and Foxp3. The results showed that oral administration of MOG, both as prevention and treatment, could efficiently control EAE development. Immunomodulatory mechanisms include the induction of Th2 and Treg cells and the suppression of pro-inflammatory Th1 and Th17 cells.

Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with novel, recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment that is undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show for the first time that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data also imply that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a broad array of clinical signs. In this study, we aimed to use intravenous immunoglobulins (IVIG), called intacglobin, as a monotherapy to manage SLE in three patients. Laboratory investigations for SLE diagnosis were performed, including the detection of anti-nuclear antibodies (ANA) and SLE confirmation by detecting high titers of anti-dsDNA antibodies. C3 and C4 serum levels were assessed, as well as the determination of immunoglobulins. The SLEDAI score was measured to determine whether a significant degree of disease activity existed and as a prognostic value. The evaluation of any chest infection was performed by chest-X-ray. The patients were treated with five–ten g/day of IVIG for six consecutive days, followed by five–ten g/month. Immunological evaluation demonstrated that patients presented with a flare of SLE with high titers of ANA and anti-dsDNA antibodies, low C3 and C4, and elevated immunoglobulin levels. The SLEDAI score falls from 10 to below 3, and chest infections in some patients are cleared up. The postulated mechanisms of action of IVIG demonstrated that it could be used as an immunosuppressor, immunomodulator, and antimicrobial agent in patients with SLE.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family has been recently associated with the development of autoimmune diseases, including SLE. IL-33 is an alarmin and a pleiotropic cytokine that affects various types of immune cells via binding to its receptor, ST2. In this study, we determine the impact of intraperitoneal IL-33 treatments in young lupus, NZB/W F1 mice. Mice were treated from the age of 6 to 11 weeks. We then assessed the proteinuria level, renal damage, survival rate, and anti-dsDNA antibodies. The induction of regulatory B (Breg) cells and changes in gene expression were also examined. In comparison to the control group, young NZB/W F1 mice administered with IL-33 had a better survival rate as well as reduced proteinuria level and lupus nephritis. IL-33 treatments significantly induced IgM anti-dsDNA antibody, IL-10 expressing Breg cells, and alternatively induced M2 macrophage gene signatures. These results imply that IL-33 exhibit regulatory roles during lupus onset via the expansion of protective IgM anti-dsDNA as well as regulatory cells such as Bregs and M2 macrophages.

Autoimmune bullous diseases (AIBDs) are a group of conditions marked by the formation of blisters and erosions on the skin and mucous membranes. Knowing that, most of the AIBDs are severe and resistant to treatment, we decided to look upon the nutritional aspect as a light for the future for both - patients and clinicians. In this review, we would like to summarize the evidence of the role of nutrition in pathogenesis and treatment of the following AIBDs: i) pemphigus, ii) bullous pemphigoid and mucous membrane pemphigoid, iii) dermatitis herpetiformis, and iv) epidermolysis bullosa aqusita.

HLA class I alleles constitute established risk factors for non-infectious uveitis and preemptive genotyping of HLA class I alleles is standard practice in the diagnostic work-up. The HLA-A29 serotype is indispensable to Birdshot Uveitis (BU) and renders this enigmatic eye condition a unique model to better understand how the antigen processing and presentation machinery contributes to non-infectious uveitis or chronic inflammatory conditions in general. This review will discuss salient points regarding the protein structure of HLA-A29 using and how key amino acid positions impact the peptide binding preference and interaction with T cells. We discuss to what extent the risk genes ERAP1 and ERAP2 uniquely affect HLA-A29 and how the discovery of a HLA-A29-specific submotif may impact autoantigen discovery. We further provide a compelling argument to solve the long-standing question why BU only affects HLA-A29-positive individuals from Western-European ancestry by exploiting data from the 1000 Genomes Project. We combine novel insights from structural and immunopeptidomic studies and discuss the functional implications of genetic associations across the HLA class I antigen presentation pathway to refine the etiological basis of Birdshot Uveitis.

Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc and by a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction and autoimmune imbalances have been suggested to play a role in the pathophysiology of normal tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to resent an overview on the inflammatory and prooxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.

We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an anti-rheumatic drug, for acute EAE treatment, we aimed to elucidate the effect of IGU on the SPMS animal model. We induced pEAE by immunizing Cx47 icKO mice with myelin oligodendrocyte glycoprotein peptide 35–55. IGU was orally administered from 17 to 50 days postimmunization. We also prepared primary mixed glial cell culture and measured cytokine levels in the culture supernatant after stimulation with designated cytokines (IL-1α, C1q, TNF-α) and lipopolysaccharide. A migration assay was performed to evaluate the effect of IGU on the migration ability of T cells toward mixed glial cell cultures. IGU treatment ameliorated the clinical signs of pEAE, decreased the demyelinated area, and attenuated glial inflammation on immunohistochemical analysis. Additionally, IGU decreased the intrathecal IL-6 level and infiltrating Th17 cells. The migration assay revealed reduced Th17 cell migration and IL-6 levels in the culture supernatant after IGU treatment. Collectively, IGU successfully mitigated the clinical signs of pEAE by suppressing Th17 migration through inhibition of IL-6 production by proinflammatory-activated glial cells.

The makeup of human microbiota has been linked to a number of autoimmune disorders. Recent developments in whole metagenome sequencing and 16S rRNA sequencing technology have considerably aided research into the microbiome and its relationship to disease. Due to the inherent high dimensionality and complexity of data generated by high-throughput platforms, conventional bioinformatics techniques could only provide an inadequate explanation for the most relevant changes and seldom provide correct predictions. Machine learning, on the other hand, is a subset of artificial intelligence applications that enable the untangling of high-dimensional systems and intricate knots in correlation by learning complex patterns and improving automatically from training data without being explicitly programmed. Machine learning is increasingly being utilized to research the influence of microbes on the onset of illness and other clinical features since computer power has increased dramatically in the last few decades. In this review paper, we focused on emerging methodological approaches of supervised machine learning algorithms for identification of autoimmune disorders utilizing metagenomics data, as well as the potential benefits and limitations of machine learning models in clinical applications.

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility often is associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, thus preventing ovum fertilization. Infertility diagnosis requires mandatory check for the ASAs. The concept of blood-testis barrier currently is re-formulated with emphasis of informational paracrine and juxtacrine effects, rather than simple anatomical separation. Aetiology of male infertility includes both autoimmune and non-autoimmune diseases, but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter blood-testis barrier facilitating ASAs production as well. There are contradictory data on the role of ASAs in pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to “danger concept” mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism and hypothyroidism also facilitate ASAs production. Diagnostic value of various ASAs was not yet clearly attributed, and their cut-levels not agreed neither in sera nor in ejaculate. The assessment of the autoimmunity role in pathogenesis of male infertility is ambiguous.

Recently, a breakdown of paracellular and vascular pathways and activated neuroimmune and oxidative pathways were established in (deficit) schizophrenia. The aim of the current study was to delineate a) the differences in these pathways between stable phase, first (FES) and multiple (MES) episode schizophrenia, and b) the pathways that determine the behavioral-cognitive-physical-psychosocial (BCPS)-worsening in FES/MES. This study included 21 FES and 58 FES patients and 40 healthy controls and measured indicants of serum IgA to C1q, and leaky gut, immune activation, and oxidative stress toxicity (OSTOX) biomarkers. We constructed a BCPS-worsening index by extracting a latent vector from symptomatic, neurocognitive, and quality of life data. FES patients showed significantly higher IgA to C1q, cadherin, catenin, plasmalemma vesicle-associated protein, and IgA/IgM to Gram-negative bacteria than FES patients and controls. In FES patients, the BCPS-worsening score was predicted (48.7%) by IgA to Klebsiella pneumoniae and lowered paraoxonase 1 activity. In MES patients, the BCPS-worsening score was explained (42.7%) by increased tumor necrosis factor-α, OSTOX, and number of episodes. In schizophrenia, 34.0% of the variance in the BCPS-worsening score was explained by IgA to K. pneumoniae, OSTOX, and number of episodes. Increased IgA to K. pneumoniae was the single best predictor of residual psychotic symptoms in FES and MES. This study delineated different mechanistic processes in FES, including breakdown of adherens junctions, bacterial translocation, and C1q circulating immune complexes; and FES, including immune and oxidative stress neurotoxic pathways. FES and MES comprise different staging subtypes, i.e., FES and MES with and without worsening.

Cortical theta burst stimulation (TBS) structured as intermittent (iTBS) and continuous (cTBS) could prevent the progression of the experimental autoimmune encephalomyelitis (EAE). The interplay of brain antioxidant defense systems against overproduction of reactive oxygen, nitrogen, and thiol species induced by EAE has not been entirely investigated, just as the effect of iTBS or cTBS on oxidative-nitrogen stress (ONS) in EAE rats. Dark Agouti strain female rats were tested for the effects of EAE and TBS. The rats were randomly divided into the following groups: C - control, EAE - rats immunized for EAE, CFA - rats immunized with Complete Freund's adjuvant; iTBS and cTBS groups, and EAE+iTBS and EAE+cTBS - health and EAE rats exposed to iTBS and cTBS, respectively; EAE+iTBSsh and EAE+cTBSsh - sham stimulated EAE rats with the same noise artifacts of iTBS and cTBS, respectively. Superoxide dismutase activity, levels of superoxide anion (O2•-), lipid peroxidation, glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR) activity were analyzed in rat spinal cords homogenates. The severity of EAE clinical coincided with the climax of ONS, based on the increase of superoxide anion and lipid peroxidation; depletion of total thiols, GSH and NADPH; and decrease of SOD activity. The TrxR imposed the most sensitive response against the applied central nervous system (CNS) stressors to rats. We concluded that the TrxR upregulation meritoriously compensates decreased ROS sequestrating and GSH systems in EAE. Both iTBS and cTBS modulate the biochemical environment at a distance from the area of stimulation against ONS, accomplish a similar effect on TrxR activity to EAE and healthy rats, and alleviate symptoms of EAE.

Immunomodulation as means of immunotherapy has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulator used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARγ ligands i.e thiazolidinedione (TZD) class of drugs on Foxp3 expression and possible crosstalk between PPARγ and nTreg cells of NOD and NOR mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARγ 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARγ inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARγ ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARγ-independant mechanism(s). These results demonstrate that both natural and synthetic PPARγ ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARγ ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies.

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autosomal recessive autoinflammatory disease with symptoms including but not limited to osteomyelitis, periostitis, and systemic inflammation. DIRA is developed from the loss-of-function mutations of IL1RN gene that encodes IL-1 receptor antagonist (IL-1RA), leading to the unchecked pro-inflammatory signaling and subsequent systemic inflammation. Thus, Anakinra as the recombinant IL-1RA has become the primary drug to treat DIRA. Although Anakinra has been effective for complete remission of DIRA, it also showed various side effects. To further address its efficacy and safety in treating DIRA, a review of literature was conducted in this study. We have identified 15 papers with 25 patients studied, making it possible to conduct reliable statistical analyses. The literature review found that continual treatment with Anakinra is effective to cause clinical remission of DIRA. Statistical analyses found that after the treatment with Anakinra, patients had improved Hemoglobin, Erythrocyte Sedimentation Rate, and C-reactive Protein levels. All known cytogenetic abnormalities were also analyzed to inform clinicians for genetic screening and rapid diagnosis of DIRA. The results from this study provide a comprehensive view for further improving the treatment of DIRA by Anakinra.

SARS-CoV-2 can trigger autoimmune central nervous system (CNS) diseases in genetically susceptible individuals, a mechanism poorly understood. Molecular mimicry (MM) has been identified in other viral diseases as potential triggers of autoimmune CNS events. This study investigated if MM is the process through which SARS-CoV-2 induce the breakdown of immune tolerance. The frequency of autoimmune CNS disorders was evaluated in a prospective cohort with patients admitted in the COVID-19 Intense Care Unity (ICU) in Rio de Janeiro. Then, an in silico analysis was performed to identify the conserved regions which share high identity between SARS-Cov-2 anti-gens and human proteins. The sequences with significant identity and antigenic properties were then assessed for their binding capacity to HLA subtypes. Of the 112 patients included, 3 were classified as having an autoimmune disorder. A total of eleven combinations had significant linear and three-dimensional overlap. NMDAR1, MOG and MPO were the self-antigens with more significant combinations, followed by GAD65. All sequences presented at least one epitope with strong or intermediate binding capacity to the HLA subtypes selected. This study underscores the possibility that CNS autoimmune attacks observed in COVID-19 patients, including those in our population, could be driven by MM in genetically predisposed individuals.

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of glutamate de-carboxylase autoantibodies (GADA). LADA has intermediate features between type 1 diabetes and type 2 diabetes. In addition, genetic risk factors for both types of diabetes are present in LADA. Nonetheless, evidence about the genetics of LADA in non-European populations is scarce. This study aims to perform a genome-wide association study with a phenome-wide association study of LADA in a southeastern Mexican population. We included 59 patients diagnosed with LADA from a previous study and 3121 individuals without diabetes from the MxGDAR/ENCODAT database. We utilized the GENESIS package in R to perform the GWAS of LADA and PLINK for the PheWAS of LADA features. Nine polymorphisms reach the nominal association level (1x10-5) in the GWAS. The PheWAS showed that rs7305229 is genome-wide associated with serum GADA levels in our sample (p=1.84x10-8). rs7305229 is located downstream FAIM2 gene; previous reports associate FAIM2 variants with childhood obesity, body mass index, body adiposity measures, lymphocyte CD8+ activity, and anti-thyroid peroxidase antibodies. Our findings reveal that rs7305229 affects the GADA levels in patients with LADA from southeastern Mexico. More studies are needed to determine if this risk genotype exists in other populations with LADA.

Omega-3 polyunsaturated fatty acids (PUFA) play a pivotal role in health, wellbeing, and inflammatory diseases in humans. Lack of omega-3 consumption is associated with diseases. Specialized Pro-resolving Mediators (SPM) are produced from Omega-3-PUFAs and accelerate resolution of inflammation. They are classified as resolvins, maresins, protectins, and lipoxins. SPMs actions in resolution consist in limiting neutrophilic infiltration, promote the clearance of apoptotic cell and cellular debris, enhancing efferocytosis and phagocytosis, counter regulate the production of pro-inflammatory mediators such as chemokines and cytokines, and promote pro-resolving macrophage phenotype. We identified temporal plasma and serum increases of SPMs after 6 g of oral supplementation of SPM-enriched emulsion in ten healthy subjects. We also described temporal increases of omega-3, as well as pharmacokinetics fundamentals in plasma and serum using LC-MS/MS lipid profiling. These results provide evidence of temporal increases of SPMs that together support the idea that given oral supplementation is a good source of essential bioactive SPMs.

Gene or genome editing (GE) revises, removes, or replaces a mutated gene at the DNA level; it is a tool. Gene therapy (GT) offsets mutations by introducing a "normal" version of the gene into the body while the diseased gene remains in the genome; it is a medicine. So far, no in vivo GE product has been approved, as opposed to 22 GT products approved by the FDA. However, several are under development, and the FDA anticipates their fast entry, as evidenced by the FDA's actions of issuing GE-specific guidelines. The potential of GE in treating diseases far supersedes any other modality due to the recognized role of genes in most human diseases. While GT products add missing genes, GE tools can overcome many aberrations. However, GE presents many safety challenges, including off-target impact, delivery consistency, and long-term effects of gene-fixing. However, most of these concerns will be resolved once the FDA begins approving them, leading to hundreds of products capable of treating untreatable diseases.

The article is devoted to the problem of autoimmune diseases provocation by coronavirus infection and the role of molecular mimicry in this phenomenon. SARS-CoV-2 can disguise its proteins as human ones in order to avoid immune attack. A bioinformatics analysis of the probable pentapeptide sharing between human autoantigens of endocrinocytes and SARS-CoV-2 spike protein, membrane protein and nucleocapsid protein was performed. Antigen mimicry between S-proteins of all other known human Coronaviruses and typical target autoantigens of endocrinocytes was also explored. Six human-identical regions were found in the SARS-CoV-2 membrane and nucleocapsid proteins, all of them in their immunodominant epitopes. All shared epitopes belong to antigens of endocrine cells commonly targeted during autoimmune endocrinopathies. Moreover, samples of the pituitary, adrenal and thyroid from patients who died from coronovirus infection (COVID-19) were studied morphologically using histochemical methods. A high frequency of SARS-CoV-2 caused inflammation of the studied endocrine organs was found in patients who died from severe COVID-19. At the same time, the abundant expression of virus antigens by the cells of the adenohypophysis was combined with the complete absence of its expression by the cells of the neurohypophysis. SARS-CoV-2 infected cells apparently perished by non-apoptotic pathway. The foci of lesions in endocrine organs contained abundant lymphocytic infiltrates which may witness for the impact of autoimmune processes. The facts revealed emphasize the need of endocrinological diagnostic alertness of a physician while observing patients with post-vaccination and post-COVID-19 health disorders. [3 figures, 6 tables, bibliography: 45 references].

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied methotrexate and tumor necrosis factor inhibitor (TNFi) effects on neutralization responses post-COVID vaccination, in immune-mediated inflammatory disease(IMID). Methods: Prospective data and sera on adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA) and systemic lupus (SLE) were collected at 6 academic centres in Alberta, Manitoba, Ontario, and Quebec between 2022-2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between 5 laboratories, and each lab’s results analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for methotrexate and TNFi effects were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID vaccinations (number/type), and infections in the 6 months prior to sample. Adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for ancestral, and Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) RA, and the remainder PsA, SpA and SLE. Mean age was 57 (62.2 % female). For both individual labs and the meta-analyses, adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval, CI 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

Gut luminal dysbiosis and pathobiosis result in compositional and biodiversify alterations in the microbial and host co-metabolites. The main mechanism of bacterial evolution is horizontal gene transfer (HGT) and acquisition of new traits can be achieved through mobile genetic element (MGEs) exchange. Introducing genetically engineered microbes (GEMs) might break the harmonized balance in the intestinal compartment. The present objectives are: 1. To reveal the role played by GEMs' horizontal gene transfers in changing the landscape of the enteric microbiome eubiosis 2. To expand on the potential detrimental effects of those changes on human genome and health. A search of articles published in PubMed/MEDLINE, EMBASE, and Scielo from 2000 to august 2023, using appropriate MeSH entry terms were performed. GEMs' horizontal gene exchanges might induce multiple human diseases. The new GEMs can change the long-term natural evolution of the enteric pro- or eukaryotic cells inhabitants. The worldwide regulatory authority's safety control of GEMs is not enough to protect public health. Viability and biocontainment and many other aspects are only partially controlled and harmful consequences for public health should be avoided. Always remember that prevention is the most cost- effective strategy and "primum non nocere" is the name of the game.

Background: The present work aimed to estimate the economic impact of PTSD following COVID-19 in a population of patients affected by systemic autoimmune disease (SAD) using a cost-of-illness approach and accounting for the perspective of society. Methods: Considering data collected from SAD patients enrolled in a specialized outpatient clinic in the Tuscany region, Italy, generalized-linear-models and LASSO logistic regression were used to evaluate the impact of PTSD on costs and its relevance as possible predictors of being a high-cost patient, respectively. Results: Considering 301 SAD patients, 161 (51.2%) of whom diagnosed with PTSD, the overall costs were 3,670 [890;40,529] Euro per patient/year among patients with PTSD and 2,736.7 [283;21,078] Euro per patient/year among those without PTSD (P-value<0.001), with differences mainly attributable to significantly greater direct non-healthcare and indirect costs. PTSD was estimated to increase overall costs (β=0.296 (0.140), P-value=0.035), direct non-healthcare (β =1.193 (0.392), P-value =0.002) and indirect costs (β =3.741 (1.136), P-value =0.001). PTSD diagnosis was also significantly associated with the likelihood of being a high-cost patient. Conclusions: Findings from the present study offer a novel perspective on the economic impact of COVID-19 and provide valuable data for policymakers to better understand demand for healthcare services and associated costs.

Anti-islet autoantibodies serve as key markers in immune-mediated type 1 diabetes (T1D) and slowly-progressive T1D (SPIDDM), also known as latent autoimmune diabetes in adults (LADA). Autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), tyrosine phosphatase-like protein IA-2 (IA-2A), and zinc transporter 8 (ZnT8A) are currently employed in the diagnosis, pathological analysis, and prediction of T1D. GADA can also be detected in non-diabetic patients with autoimmune diseases other than T1D and may not necessarily reflect insulitis. Conversely, IA-2A and ZnT8A serve as surrogate markers of pancreatic β-cell destruction. Combinatorial analysis of these four anti-islet autoantibodies demonstrated that 93-96% of acute-onset T1D and SPIDDM cases were diagnosed as immune-mediated T1D, while the majority of fulminant T1D cases were autoantibody-negative. Evaluating the epitopes and immunoglobulin subclasses of anti-islet autoantibodies help distinguish between diabetes-associated and non-diabetes-associated autoantibodies and is valuable for predicting future insulin deficiency in SPIDDM (LADA) patients. Additionally, GADA in T1D patients with autoimmune thyroid disease reveals the polyclonal expansion of autoantibody epitopes and immunoglobulin subclasses. Recent advancements in anti-islet autoantibody assays include nonradioactive fluid-phase assays and the simultaneous determination of multiple biochemically defined autoantibodies. Developing a high-throughput assay for detecting epitope-specific or immunoglobulin isotype-specific autoantibodies will facilitate more accurate diagnosis and prediction of autoimmune disorders.

Serum albumin (ALB), one of the most important proteins in human physiology, has the main functions of maintaining plasma oncotic pressure and plasma volume, transporting hormones, vitamins, oligominerals and drugs, and exerting a powerful antioxidant-antiinflammatory role. Its prognostic value in liver and malabsorption syndromes is well known. In this narrative review, an analysis of the most important studies evaluating the prognostic significance of low serum ALB levels in hospitalized patients was performed. Specifically, the risk in emergency medicine, cardiovascular diseases, COVID-19 infection, nephrology, oncology and autoimmune rheumatic diseases has been examined to fully explore its clinical value. ALB is a negative acute-phase reactant and the reduction of its serum levels represents a threatening parameter for long-term survival in several clinical settings, and a strong poor prognostic biomarker in most diseases. Therefore, clinicians should consider serum ALB as a valuable tool to assess the efficacy of specific therapies, both in hospitalized patients and in chronic follow-up.

Abstract: Autoimmune diseases (AIDs) are a group of disorders, in which the immune system attacks the body own tissues leading to chronic inflammation and organ damage. These diseases are difficult to treat due to variability in drug PK among individuals, patient responses to treatment, and the side effects of long-term immunosuppressive therapies. In recent years, pharmacometrics has emerged as a critical tool in Drug Discovery and Development (DDD) and precision medicine. The aim of this review is to explore the diverse roles that pharmacometrics has played in addressing the challenges associated with DDD and personalized therapies in the treatment of AIDs. Methods: The review synthesizes research from past two decades on pharmacometric methodologies, including Physiologically Based Pharmacokinetic (PBPK) modeling, Pharmaco-kinetic/Pharmacodynamic (PK/PD) modeling, Disease Progression (DisP) modeling, population modeling, and Quantitative Systems Pharmacology (QSP). The incorporation of Artificial Intelli-gence (AI) and Machine Learning (ML) into pharmacometrics is also discussed. Results: Pharmacometrics has demonstrated significant potential in optimizing dosing regimens, improving drug safety, and predicting patient-specific responses in AIDs. PBPK and PK/PD models have been instrumental in personalizing treatments, while DisP and QSP models provide insights into disease evolution and pathophysiological mechanisms in AIDs. AI/ML implementation has further enhanced precision of these models. Conclusions: Pharmacometrics plays a crucial role in bridging preclinical findings and clinical applications, driving more personalized and effective treatments for AIDs. Its integration into DDD and translational science in combination with AI and ML algorithms holds promise for advancing therapeutic strategies and improving autoimmune patient outcomes.

Diet is considered a possible cofactor that affects the immune system and potentially could cause dysregulation of intestinal homeostasis and inflammation. This study aimed to review the evidence on specific diet composition effects on some immune-mediated inflammatory diseases (IMID) -rheumatoid arthritis (RA), psoriatic arthritis, spondyloarthritis, multiple sclerosis (MS), Inflammatory bowel disease (IBD) [remission maintenance of Crohn´s disease and ulcerative colitis] and psoriasis- symptoms in adult patients. We conducted a rapid review of meta-analyses and Cochrane systematic reviews using PubMed, EMBASE, from inception to September 2024, and Google Scholar. The methodological quality of meta-analyses was assessed using AMSTAR 2 rating. Three COCHRANE systematic reviews and eight meta-analyses Some specific composition diets have been shown to reduce symptoms in RA, IBD, and MS; and improve some activity parameters in IBD and RA; with critically low, or low levels of evidence. The reduction in inflammatory biomarker levels is unclear. This review updates the global dietary evidence to improve IMID symptoms, discusses the influences of dietary mechanisms, clarifies the weaknesses of clinical trials and dietary meta-analyses, with critically low, or low levels of evidence, and shows the need to use indexes such as DII, that allow diets to be classified for their content of pro-inflammatory or anti-inflammatory foods, to better compare diet groups in clinical trials. The difficulty in obtaining high-level evidence in dietary studies is apparent, which may delay the application of the results.

Molecular mimicry between human and microbial/viral/parasite peptides is common and for a long time is associated with the etiology of autoimmune disorders provoked by exogenous pathogens. Increasing evidence accumulated from the past years suggests a strong correlation between the SARS-CoV-2 infection and autoimmunity. The article analyzes the immunogenic potential of the peptides shared between SARS-CoV-2 spike glycoprotein (S-protein and antigens of human endocrinocytes involved in most common autoimmune endocrinopathies. Totally the study revealed 14 pentapeptides shared by S-protein of SARS-CoV-2 and autoantigens of thyroid, pituitary, adrenal cortex and Langerhans’ islets beta-cells, 12 of them belong to immunoreactive epitopes of SARS-CoV-2. The discussion of the data links the results with clinical correlates of COVID-associated autoimmune endocrinopathies. Most common of them is an autoimmune thyroid disease, so the majority of shared pentapeptides belong to marker autoantigens of this disease. Most important in pathogenesis of severe COVID-19, according authors’ opinion, can be autoimmunity against adrenals, because their adequate response prevents from excessive systemic action of inflammatory mediators which cause cytokine storm and hemodynamic shock. The criticism of antigen mimicry concept is given with a statement that peptide sharing is not a guarantee, but just a prerequisite of autoimmunity excess provocation. The last event occurs in carriers of certain HLA haplotypes and in case when shared peptide is used in antigen processing only [1 figure, 5 tables, bibliography 38 references].

The association between autoimmune diseases, mostly rheumatoid arthritis, systemic lupus erythematous, celiac disease and Sjögren syndrome, and lymphoma has been widely demonstrated by several epidemiologic studies. By a not yet entirely elucidated mechanism, chronic activation/stimulation of the immune system, along with the administration of specific treatments, may lead to persistent stimulation of both of B- and T-cells, and to the onset of different types of lymphoma in such patients. Specifically, patients affected by may develop lymphomas may years after the original diagnosis. Several epidemiologic, hematologic and histological factors may anticipate the progression from Sjögren syndrome into lymphoma but, to the best of our knowledge, a definite pathogenetic mechanism for such progression is still missing. In fact, while the association between Sjögren syndrome and non-Hodgkin lymphoma, mostly diffuse large B-cell and extranodal marginal zone lymphomas is well established, many other variables, such as time of onset, gender predilection, sites of occurrence, subtype of lymphoma and predictive factors still remain unclear. We report on a rare case of primary breast lymphoma occurring three years after the diagnosis of Sjögren syndrome in a 57 y.o. patient. The diagnostic work-up, including radiograms, core needle biopsy and histological examination are discussed, along with emerging data from the recent literature, thus highlighting the usefulness of breast surveillance in Sjögren syndrome patients.

Recently, Mulroney,et.al., demonstrated that Pfizer’s ModRNA Covid vaccine, but not AstraZeneca Covid vaccine, produce aberrant foreign proteins in vivo due to reading frame shift in ribosomes. This phenomenon could elucidate the notable surge in autoimmune diseases following the administration of ModRNA vaccines compared to Influenza vaccines between 2020 and 2023, as found in the VAERS database. These findings bear significant implications for the future application of mRNA technology, emphasizing the necessity of modifying the design of the mRNA sequence to mitigate these defects. Remarkably, Mulroney and collaborators achieved a reduction in frame shift proteins by introducing additional edits to the mRNA sequences. This adjustment is pivotal for rectifying the flawed design of the ModRNA employed by Pfizer. In light of these findings, many advocate for the immediate recall and further investigation of these products. The notion of a "future mRNA-based therapy" should be postponed indefinitely.

Systemic Lupus Erythematosus (lupus) and B-cell lymphoma (lymphoma) are serious diseases. Lupus and lymphoma co-occur at higher-than-expected rates and primarily depend on B-cells for their pathology, implicating shared inflammation-related B-cell molecular mechanisms as a potential cause of co-occurrence. We consequently implemented a novel Immune Imbalance Transcriptomics (IIT) algorithm and applied IIT to lupus, lymphoma, and healthy B-cell RNA-seq data to find shared- and contrasting mechanisms potentially targetable for treatment. We observed 8,562 genes significantly dysregulated in both lupus and lymphoma. Of those genes, we found 5,335 to have a significant immune imbalance, defined as significant dysregulation by both diseases, as determined by IIT. Gene Ontology (GO) term and pathway enrichment of IIT genes yielded immune-related “Neutrophil Degranulation” and “Adaptive Immune System”, validating that the IIT algorithm isolates biologically relevant genes in immunity and inflammation. We found that 389 IIT gene products are drug-targetable with established or repurposed drugs. Among our results, we found 40 known and 349 novel lupus targets, along with 151 known and 238 novel lymphoma targets. Known disease drug targets in our IIT results further validate that IIT isolates genes with disease-relevant mechanisms. We anticipate the IIT algorithm and shared and contrasting gene mechanisms uncovered here will contribute to the development of immune-related therapeutic options for lupus and lymphoma patients.

Hashimoto's thyroiditis (HT) is essentially featured by self-tissue destruction by means of the adaptive immune responses that evade immune regulation. Vitamin D carries out an immunomodulatory role that appears to promote immune tolerance. The aim of this study is to elaborate a narrative review about the relationship between vitamin D status and HT and the role of vitamin D supplementation to reduce HT risk by modulating the immune system. There is an extensive literature confirming that vitamin D levels are significantly lower in HT patients compared to healthy people. On the other hand, after the supplementation with cholecalciferol in patients with HT and vitamin D deficiency, thyroid autoantibody titer decreased significantly, However, there are no conclusive results on the effect of vitamin D supplementation on the thyroid function. The confirmation of the beneficial effects of vitamin D in the prevention and treatment of autoimmune thyroid diseases require additional randomized, double-blind, placebo-controlled trials with longer follow-up.

Magnetic resonance elastography (MRE) has revealed sexual dimorphism in brain stiffness in healthy individuals and multiple sclerosis (MS) patients. In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we showed previously that inflammation-induced brain softening was associated with alterations of the extracellular matrix (ECM). However, it remained unclear whether the brain ECM presents sex-specific properties that can be visualized by MRE. Therefore, we aimed here at quantifying sexual dimorphism in brain viscoelasticity in association with ECM changes in healthy and inflamed brains. Multifrequency MRE was applied to the midbrain of healthy and EAE mice of both sexes to quantitatively map regional stiffness. To define differences in brain ECM composition, gene expression of the key basement membrane components laminin (Lama4, Lama5), collagen (Col4a1, Col1a1) and fibronectin (Fn1) was investigated by RT-qPCR. We showed that the healthy male cortex expressed less Lama4, Lama5, Col4a1 but more Fn1 (all p < 0.05) than the healthy female cortex, which was associated with 9% softer properties (p = 0.044) in that region. At peak EAE, cortical softening was similar in both sexes compared to healthy tissue, with an 8% difference remaining between males and females during EAE (p < 0.001). Cortical Lama4, Lama5 and Col4a1 expression increased 2 to 3-fold in EAE in both sexes while Fn1 decreased only in males (all p < 0.05). No significant sex differences in stiffness were detected in other brain regions. In conclusion, sexual dimorphism in the ECM composition of cortical tissue in the mouse brain is reflected by in vivo stiffness measured with MRE and should be considered in future studies by sex-specific reference values.

Encephalitis is a condition with a variety of etiologies, clinical presentations and degrees of severity. The causes of these disorders include both neuroinfections and autoimmune diseases in which host antibodies are pathologically directed against self antigens. In autoimmune encephalitis, autoantibodies are expressed in the central nervous system. The incidence of this disease is approximately 4% of all reported cases of encephalitis. Autoimmune encephalitis can be induced by antibodies against neuronal surface antigens such as N-methyl-D-aspartate-activated glutamate receptors (NMDAR), ⍺-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPAR) or gangliosides GQ1b, DPPX, CASPR2, LGI1, as well as by antibodies against neuronal intracellular antigens. The paper presents a number of both mental and neurological symptoms of autoimmune encephalitis. Moreover, the coexistence of psychoses, neoplastic diseases and the methods of diagnosing autoimmune encephalitis are discussed. Attention was also drawn to the fact that early diagnosis, as well as early initiation of targeted treatment, increases the chance of a successful course of the therapeutic process.

Aim: This study aims to analyze the collaborative networks and identify key players in autoimmune pancreatitis (AIP) research from 2000 to 2023. Using data from the Web of Science (WoS) Core Collection, I assess the structure and evolution of co-authorship networks to understand collaboration trends and influential researchers in the field.Method: I conducted a network analysis of co-authorship patterns in AIP research using Python (Version 3.10.5) in the PyCharm development environment (Software Version 2022.1.3). The analysis included macro-level indicators: network density, clustering coefficient, components, and average distance, as well as micro-level indicators: degree centrality, closeness centrality, and betweenness centrality. These metrics were used to evaluate the connectivity, clustering, and key nodes within the network across three distinct periods: 2000-2009, 2010-2019, and 2020-2023.Result: The analysis revealed that the co-authorship network in AIP research evolved from a fragmented structure with limited collaboration in the early 2000s to a more interconnected but still dispersed network in recent years. Despite an increase in network density and a decrease in the number of disconnected components over time, the overall structure remains highly clustered, with many researchers operating within isolated groups. Key figures, such as Kazuichi Okazaki, Terumi Kamisawa, and Shigeyuki Kawa from Japan, consistently ranked high in centrality measures, highlighting their significant influence and leadership in the field. The findings suggest that while local collaborations are strong, broader international connections are still developing.Conclusion: This study provides a comprehensive overview of the collaborative landscape in AIP research, identifying central researchers and highlighting persistent fragmentation within the network. The prominent role of Japanese researchers in shaping the field underscores the importance of fostering greater international collaboration to bridge gaps between research clusters. Enhancing global partnerships could lead to more integrated and impactful research outcomes, ultimately advancing the understanding and management of autoimmune pancreatitis.

A large body of evidence, replicated in many mouse models of Alzheimer Disease (AD), demonstrated the therapeutic efficacy of oral rapamycin. Administration of m-TOR inhibitors (mTOR-Is), early after the clinical onset, greatly diminished cognitive impairment, amyloid angiopathy, intracellular beta Amyloid and neurofibrillary tangles load. The daily intake of rapamycin has always been 2.24g/Kg/24h. In humans the maximal tolerated oral dose is a few milligrams/day, and at this dosage patients are severely immunosuppressed. Thanks to rapalogs’ scarce CNS-related side effects, we administered intracerebroventricularly (ICV) high doses of the mTOR-I everolimus in a mouse model of AD (3xTg-AD) without significant systemic effects. The instability of the liquid formulation at body temperature (BT) made the treatment very short. Nevertheless, the efficacy of the treatment was high and much longer lasting than expected. In order to set up a thermostable, translational liquid formulation of mTOR-Is, we loaded everolimus in distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) micelles by the thin layer method. The formulation we obtained maintained over 95% of activity after 14 days at BT. We can envision short, potentially periodic ICV treatments in AD patients which replicate results obtained on animal models. The treatment could benefit also Tuberous Sclerosis and Multiple Sclerosis patients.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hem-atopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflam-matory biomarkers, and reconstitution of various T cell populations. Of 35 patients, four devel-oped LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.

Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4⁺ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.

The literature on the causation of multiple sclerosis (MS), both genetic and environmental, extends over hundreds of years, with no firm conclusions on the exact role of autoimmunity and lifestyle. The epidemiology of MS was the basis for this review, but with a new, extensive examination of genes pertaining to each disorder, and disease of first, and second, degree relatives of those with MS. The author’s motivation was to discover some relationship between MS, and notable familial conditions, as the heredity of MS is concluded to be 30%, and the disorders had a chronic and/or idiopathic nature. This investigation hoped to further understand the randomness of MS- who acquires it, and what symptoms develop- after the author’s decades of observing several incidences of multiple members developing MS in a single family. Online databases for the human genome were used to link genes to MS, and symptoms, including excessive depression, fatigue and suicide rates, in coordination with linking genes for specific familial conditions including seizures, stroke, mental illness, bowel disorders, and thyroid conditions. Interesting associations were found, notably a cluster of Th2 cytokines, known to cure the animal model of MS, important receptors for neurotransmitters and hormones, a gene specific to Epstein Barr Virus, and potential genes for mitochondrial dysfunction. The results surprised the author, showing polygenic regions of chromosome 2 and 5, especially a cluster at loci 5q31-q33, may be dysregulated. The conclusion agrees with past hypotheses MS results not from a single gene, but from various genes, including those expressed in glial cells. The individual theories to the causation of MS, starting with Charcot may be explained by multiple pathways converging into a single disease outcome. In coordination with a sunlight factor, chromosome 2 appears to mediate the immune system, and inflammation, through ultraviolet radiation producing vitamin D3 in the skin, but additionally through peptides formed in the melanocyte stimulating and concentrating hormone class. The impact of stress in MS could be primary, given the loci of several stress-related and stress-modulated genes on these chromosomes, and calls for more appreciation of, and greater care for, the MS patients’ state of mind.

The article titled "Immunoglobulins and Its Applications" provides a comprehensive overview of the structure, function, and therapeutic significance of immunoglobulins, also known as antibodies. These vital proteins, produced by plasma cells in response to immunogens, are essential components of the immune system, playing a critical role in recognizing and neutralizing pathogens such as bacteria and viruses. The article elaborates on the five primary classes of immunoglobulins (IgA, IgD, IgE, IgG, and IgM), each distinguished by its unique structural and functional properties. It discusses the molecular composition of immunoglobulins, highlighting the significance of their variable and constant regions in antigen binding. The paper also explores the diverse immune functions mediated by these proteins, including precipitation, agglutination, and neutralization of antigens. Additionally, the article emphasizes the therapeutic applications of immunoglobulins, particularly in treating immune deficiencies and other diseases. Advances in monoclonal antibody technology have significantly expanded the utility of immunoglobulins in both research and medicine, leading to the development of innovative therapeutic approaches such as humanized monoclonal antibodies and bifunctional antibodies. This comprehensive analysis underscores the critical role of immunoglobulins in both natural immunity and therapeutic interventions.