Abstract:

An exhausted antiviral immune response is observed in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-SARS-CoV-2 syndrome also termed long COVID. In this study, potential mechanisms behind this exhaustion were investigated. First, the viral load of Epstein-Barr virus (EBV), human adenovirus (HAdV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was determined in sputum samples (n = 29) derived from ME/CFS patients (n = 13), healthy controls (n = 10), elderly healthy controls (n = 4), and immunosuppressed controls (n = 2). Secondly, autoantibodies (autoAbs) to type I interferon (IFN-I) in sputum were analyzed to possibly explain impaired viral immunity. We found that ME/CFS patients released EBV at a significantly higher level compared to controls (p = 0.0256). HHV6 was present in ~50% of all participants at the same level. HAdV was detected in two cases with immunosuppression and severe ME/CFS, respectively. HCMV and SARS-CoV-2 were found only in immunosuppressed controls. Notably, anti-IFN-I autoAbs in ME/CFS and controls did not differ, except in a severe ME/CFS case showing an increased level. We conclude that ME/CFS patients, compared to controls, have a significantly higher load of EBV. IFN-I autoAbs cannot explain IFN-I dysfunction, with the possible exception of severe cases, also reported in severe SARS-CoV-2. We forward that additional mechanisms, such as viral evasion of IFN-I effect via degradation of IFN-receptors; may be present in ME/CFS, which demands further studies.

Abstract: The chemokine receptors possess seven‐transmembrane helices connected by an extracellular N‐terminal region, three extracellular loops (ECL1‐3), three intracellular loops, and an intracellular C‐terminal region. We have developed specific monoclonal antibodies (mAbs) against chemokine receptors for flow cytometry using the Cell-Based Immunization and Screening (CBIS) and the N-terminal peptide immunization methods. However, there are few reports for establishing anti-chemokine receptor mAbs by immunization of ECL peptides. Here, we established an anti-mouse CCR7 (mCCR7) mAb, C7Mab-2 (rat IgG2b, kappa) by immunization of the ECL3 peptide. C7Mab-2 demonstrated the reactivity to mCCR7-overexpressed Chinese hamster ovary-K1 (CHO/mCCR7) cells in flow cytometry, which was blocked by the ECL3 peptide. C7Mab-2 did not show the cross-reactivity to other mouse CC, CXC, CX3C, and XC chemokine receptors. The dissociation constant (KD) value of C7Mab-2 was determined to be 2.8 ± 0.3 × 10⁻⁹ M for CHO/mCCR7 cells. Furthermore, C7Mab-2 detected mCCR7 in immunohistochemistry. The strategy could accelerate the development of novel chemokine receptor mAbs with high affinity and specificity.

Abstract: Background: Platelets (PLTs) from healthy donors (HD) modulate T lymphocyte respons-es but PLTs from rheumatoid arthritis (RA) patients contribute to persistent systemic in-flammation. This suggests that PLTs from RA patients and HD have different immuno-modulatory effects. Methods: Using cell culture, flow cytometry, proteomics, and ELISA, we compared PLTs from HD and RA patients and their effects on T lymphocyte activation and cytokine pro-duction. Results: HD PLTs suppressed T lymphocyte proliferation and IFNγ and TNF production, while RA PLTs exhibited reduced suppressive capacity. In the presence of RA PLTs, IFNγ levels correlated with T lymphocyte proliferation, greater disease activity and ACPA. Pro-teomic analysis revealed that RA PLTs show upregulation of proteins linked to acute-phase response and complement activation. RA PLTs secreted higher levels of solu-ble CD40L (sCD40L) and PDGF-BB that correlated with enhanced IFNγ production. Sero-positive RA patients had higher levels of sCD40L and these levels were predictive of dis-ease remission in RA patients treated with anti-IL6R. sCD40L was found to enhance T lymphocyte activation and to contribute to increased pro-inflammatory cytokine produc-tion. Conclusion: This study highlights the diminished ability of RA PLTs to suppress T lym-phocyte activation and that sCD40L can be a potential biomarker and therapeutic target in RA.

Abstract: Neutrophils are increasingly recognized as key contributors to the pathogenesis of Type 1 Diabetes (T1D), yet their precise mechanistic role in disease onset and progression remains incompletely understood. While these innate immune cells reside in pancreatic tissue and support tissue homeostasis under physiological conditions, they can also drive tissue damage by triggering innate immune responses and modulating inflammation. Within the inflammatory milieu, neutrophils establish complex, bidirectional interactions with various immune cells, including macrophages, dendritic cells, natural killer cells, and lymphocytes. Once activated, they may enhance the innate immune response through direct or indirect crosstalk with immune cells, antigen presentation, and β-cell destruction or dysfunction. These mechanisms underscore the multifaceted and dynamic role of neutrophils in T1D, shaped by their intricate immunological interactions. Further research into the diverse functional capabilities of neutrophils is crucial for uncovering novel aspects of their involvement in T1D, potentially revealing new therapeutic targets to modulate disease progression.

Abstract:

Orange allergy is estimated to account for 3% of food allergies. Cit s 1 (germin-like protein) and Cit s 2 (profilin) have been identified as major allergens. Also, Cyt s 3 (lipid transfer protein) and Cyt s 7 (gibberellin-regulated protein) have been described as orange allergens. This study focuses on the unusual occurrence of orange allergy in five patients. Materials and methods: We report five cases of patients with immediate allergic manifestations after ingestion of orange. Skin prick-tests to common aeroallergens, and different foods. Prick by prick with orange, lemon pulp mandarin (peel, pulp and seeds). Anaphylaxis score; Total IgE, Serum-specific IgE and food allergy quality of life questionnaire. Allergenic extracts were prepared from orange (Citrus sinensis), lemon (Citrus lemon) and mandarin (Citrus reticulata) peel and pulp. Protein characterization was determined by Bradford and SDS-PAGE and sera by immunoblot. Selected proteins were identified by peptide fingerprinting. Results: A 23 kD band was recognized by all 5 patients in orange (pulp and peel), lemon (peel) and mandarin (pulp and peel), having already been annotated in IUIS in the case of orange as germin (Cit s 1). To send the 23 kDa bands for peptide fingerprinting, SDS-PAGE of the 3 fruits was performed and as a positive control we used the 23 kDa band from orange. Together, the 23 kDa bands from orange, lemon and mandarin peel were cut out and sent for peptide fingerprint analysis, yielding the germin like protein sequence in all cases. Conclusions: A band of 23 kDa (germin-like protein) appears common in orange (annotated in IUIS as germin), lemon and tange-rine peel. Not previously described in IUIS in lemon and mandarin and confirmed as germin. Germin was in the peel of the 3 fruits and in the orange pulp, but not in lemon or mandarin.

Abstract: Osteoporosis, a condition characterized by reduced bone strength and increased fracture risk, frequently coexists with spondylarthritis (SpA), an inflammatory rheumatic disease. Dual-energy X-ray absorptiometry (DXA), the gold standard for diagnosing osteoporosis, faces limitations in SpA patients due to spinal deformities and calcifications. Radiofrequency Echographic Multispectrometry (REMS), a novel ultrasound-based diagnostic technology, overcomes many of these challenges by assessing bone quality and microarchitecture without interference from structural changes. This article explores the underlying mechanisms linking SpA and osteoporosis, reviews the utility of REMS in this context, evaluates the existing evidence supporting its clinical application, and provides additional findings promoting the use of REMS in individuals with SpA.

Abstract:

The occurrence of asthma combined with IBD has been found in clinical practice, but the pathogenesis is not fully understood，this study is to use the bioinformatics technology to explore the related genes of asthma associated with IBD and its potential biological function. Transcriptomes dataset for asthma and IBD were screened by GEO data base. Cases in the datasets are divided into the case group and the control group. Differentially expressed genes with P<0.05 and | log2FC |>2 were selected. The intersected genes were used for GO and KEGG analysis. Cibersortx was used to analyze the relationship between differentially expressed genes and immune cells.ANXA3, TNFRSF21 and ZDHHC19 were significant in both pathogenesis of asthma and IBD. It was found that TNFRSF21 was positively correlated with plasma cells in asthma, negatively correlated with neutrophil function, and negatively correlated with NK cell activation in IBD. In conclusion, ANXA3, TNFRSF21, and ZDHHC19 were selected as the intersected genes associated with asthma and IBD, which may contribute to the development of the disease via cell membrane function and S-palmitoylation. The low expression of TNFRSF21 may lead to the disorder of immune function and the morbidity of patients with asthma associated with IBD.

Abstract:

IgG4 is an unusual immunoglobulin (Ig) and is the least component of IgG in humans. It is often asymmetrical and heterobivalent with weak Fc (fragment crystallizable region)-dependent effector function and ineffective complement activation; thus playing an unclear role in immune functions. IgE is an uncommon Ig, being important mostly in allergy and type 2 immunity. There are 2 rare chronic Ig-related fibroinflammatory diseases, namely IgG4-related disease (IgG4RD) and Kimura disease (KD), characterized by IgG4- or IgE-positive plasma cells are prominent in the affected tissues, with or without tissue interstitial or plasma elevations of the same Ig. The etiology of these 2 Ig-related diseases is unclear, though it appears that the pathogenesis in both is related to polarized Ig heavy chain isotype switching, concomitant with other cellular, cytokine and chemotaxin interactions that culminates in the characteristic pathologic manifestations of inflammation and fibrosis. IgG4RD and KD, despite having overlapping and differing features, may be connected by the similar pathogenetic polarized Ig isotype switching.

Abstract: The development of the human immune system starts already during the fetal period in a largely, but probably not completely, sterile environment. During and after birth the immune system is exposed to an increasingly complex microbiota. The first microbiota encountered during passage through the birth canal colonize the infant gut and induce tolerance of the immune system. Transplacental derived maternal IgG as well as IgA from breast milk protect the infant from in-fections during the first 100 days, during which the immune system further matures, and im-munological memory is formed. Weaning and introduction of solid food expose the immune system to novel (food) antigens and allow for other microbiota to colonize. The cells and mole-cules involved in the mutual, intricate interaction between microbiota and developing immune system are now beginning to be recognized. These include bacterial components such as poly-saccharide A from Bacteroides fragilis, as well as bacterial metabolites such as the short chain fatty acid butyrate, indole-3-aldehyde, and indole-3-propionic acid. All these, and probably more, bacterial metabolites have specific immunoregulatory functions which shape the development of the human immune system during the first 1000 days of life.

Abstract: Oral Allergy Syndrome (OAS) and Pollen Food Allergy Syndrome (PFAS) represent significant challenges in allergy research. This review examines the epidemiology, pathogenesis, and diagnostic approaches of OAS and PFAS, with a focus on their prevalence and impact in the adult population in Southern Europe. Key panallergens such as profilins, PR-10 proteins, and lipid transfer proteins (LTPs) are highlighted for their role in mediating PFAS, and their regional variation. The review explores the differential prevalence of PFAS across Southen Europe countries, where multi-sensitization to pollen like Olive, Cypress, Parietaria, Mugwort, and Grass is common, and underscores unique en-vironmental and ecological factors contributing to this phenomenon. Cross-reactivity, a hallmark of PFAS, is explored with emphasis on the interactions between common Southern European pollens and foods, such as fruits, nuts, and vegetables. Diagnostic challenges, including symptom variability, underreporting, and the need for region-specific diagnostic algorithms, are discussed. This comprehensive review aims to deepen understanding of OAS and PFAS among adults in the Mediterranean region of Southern Europe, offering insights that can improve the diagnosis, management, and overall care for this population.

Abstract: The pediatric common variable immunodeficiency (CVID) is the most frequent symptomatic antibody production defect characterized by infectious and non-infectious autoimmune, inflammatory, and lymphoproliferative complications. The background for CVID-related organ-specific immunopathology is associated with immune dysregulation and immunophenotypic biomarkers with expansion of CD21low B cells, and dysfunctional memory B cell, follicular T cell, and regulatory T cell compartments. The complexity of clinical phenotypes reflects the heterogeneity of genetic background for CVID, which is monogenic in a small proportion of affected children. Multiple systemic modulatory pathways are predominantly determined by variants in TACI (Transmembrane Activator and CAML Interactor) or TNFRSF13B gene (Tumor Necrosis Factor Receptor Superfamily Member 13B) encoding for BAFF-R (B cell Activating Factor Receptor), CTLA-4 (Cytotoxic T Lymphocyte Antigen 4), LRBA (Lipopolysaccharide Responsive Beige-Like Anchor Protein), NFKB1 and NFKB2 (Nuclear Factor Kappa B 1 and 2) PIK3CD or PIK3R1 (Phosphatidylinositol-3 Kinase Catalytic Subunit Delta and Regulatory Subunit 1, respectively). The organ-specific immunopathology encompasses a spectrum of disorders associated with immune dysregulation, such as granulomatous interstitial lung disease, hepatocellular nodular regenerative hyperplasia, enteropathy, neuropathy, endocrinopathies, and dermatoses. The use of biological agents offering personalized targeted therapies opens a new curative perspective for patients with genetically defined CVID.

Abstract: Allergens from pollen, mites, and moulds often sensitize patients simultaneously, posing challenges for developing stable and effective combination vaccines. Alternaria alternata, a major source of indoor and outdoor allergens, is strongly linked to asthma development and contains proteolytic enzymes that can degrade other allergens, potentially reducing vaccine efficacy. This study aimed to evaluate the safety, efficacy, and stability of polymerized A. alternata extracts (allergoids) compared to native extracts and their compatibility with pollen extracts (Phleum pratense). Allergoids were prepared using glutaraldehyde and characterized through SDS-PAGE, LC-MS/MS, NMR, and gas chromatography. Their immunogenicity and IgE-binding properties were assessed via Western blot and ELISA competition assays, while enzymatic activity was analysed using ApiZym kits. Mice immunization experiments were conducted to evaluate antibody responses. Polymerized extracts exhibited reduced IgE-binding capacity while maintaining IgG-binding and immunogenicity. Mice immunized with allergoids generated antibodies that efficiently blocked IgE binding in allergic patients. Proteolytic activity was significantly reduced in allergoids, and pollen extracts remained stable when combined with them. These findings demonstrate that A. alternata allergoids are a safer, more stable alternative for immunotherapy, offering enhanced efficacy and reduced injections for polysensitized patients. This study provides critical insights for designing optimized combination vaccines.

Abstract: Background: To elucidate the mechanisms of resistance to treatment in patients with acute myeloid leukemia (AML) except for M3 so as to devise ways to overcome them and improve the treatment outcomes. Methods: For this study, we randomly selected 35 patients with AML who had received combined cytarabine plus idarubicin treatment for new-onset AML at our hospital. Expressions of 23 treatment-resistance-related proteins in the biopsy specimens were evaluated by immunohistochemical staining using the corresponding antibodies, followed by retrospective analysis of the correlations between the expression　of the resistance proteins and patient survival. Results: The following four proteins were identified as being particularly significant in relation to treatment resistance and patient prognosis. 1) p53, 2) Multidrug resistance-associated protein 1 (MRP1) (Idarubicin extracellular efflux pump) 3)Aldo-keto reductase family 1 member B10 (AKR1B10) (Idarubicin-inactivating enzyme), and 4)AKR1B1 (AKR1B10 competitive

Abstract:

(1) Background: Gut microbial dysbiosis, leaky gut and increased transepithelial translocation of commensal bacteria have been documented in multiple sclerosis (MS). Intrathecal IgGs specific for Akkermansia muciniphila, a gut bacterium, are increased in MS patients and associated with clinical disability. Our objective here was to explore the putative involvement of intrathecal anti-A. muciniphila IgG in MS pathogenesis by characterizing patients with different anti-A. muciniphila IgG indices. (2) Methods: Serum and intrathecal IgG specific for A. muciniphila and other gut bacteria as well as routine cerebrospinal fluid (CSF) parameters were measured in 61 MS patients. Examination of these patients included immunophenotyping of CSF-infiltrating and paired circulating lymphocytes, intrathecal markers of neurodegeneration and inflammation and a detailed characterization of demographic-, clinical-, and magnetic resonance imaging (MRI) features. (3) Results: MS patients with high anti-A. muciniphila IgG index also showed higher intrathecal IgG indices against other gut bacteria. Plasma blasts, B cells and Th2 cells that might be involved in antibody production were increased in the CSF of these patients as well as blood pro-inflammatory Th17 cells. Anti-A. muciniphila IgG indices were negatively associated with blood brain barrier (BBB) permeability and circulating monocytes and positively with brain lesion load. (4) Conclusions: The differences between patients with low and high anti-A. muciniphila IgG indexes regarding BBB permeability, CSF cell infiltrates, pro-inflammatory peripheral immune cells as well as imaging features, support a role of anti-A. muciniphila immune response in MS pathogenesis.

Abstract: Bovine viral diarrhea (BVD) is caused by bovine viral diarrhea virus (BVDV). The disease incurs $1.5-2.5 billion/year and $0.50 to $687.80/cow loss in beef and dairy farms respectively. This review aims to provide insights into the interaction of BVDV with host immunity, currently available vaccines, and strategies used to advance the vaccines. The virus causes immunosuppression by interfering with the innate and adaptive immune systems in a strain and biotypes-dependent manner. Interferon production, apoptosis, neutrophil activity, macrophages, and antigen-presenting cells are significantly affected during viral infection. Maternal antibodies (MatAb) are crucial to protect calves from early infection. However, the MatAb is counterproductive during vaccination against the virus. There are several types of licensed commercial inactivated or modified live vaccines, most of which are made of cytopathic BVDV 1 and 2 and the BVDV 1a subtype. Subunit and marker vaccines are made of E2, Erns, and NS3 proteins in combination with modern adjuvants, respectively. Such types of vaccines are not yet licensed and are in the experimental stage. The limitations of currently available conventional vaccines are minimal or lack of cross-protection, production costs, safety concerns, and inefficiency in provoking both humoral and cellular immune systems. To alleviate these limitations, the knowledge of developing next-generation vaccines using appropriate viral proteins and the use of modern adjuvants is promising.

Abstract: In this paper, an attempt is made to shed additional light on the role of infectious agents (bacteria, viruses, etc.) in autoimmune diseases. While the correlation between them is well established, many points remain obscure. To offer a concise framework for many of the relevant research findings, the following conceptual model is discussed: autoimmune diseases are due to alterations of cells, tissues or organs, which are caused by infectious agents. These alterations evolve with time. Initially they are small and hardly detectable. As they become more severe, though, they are traced, and the infected cells are subsequently attacked by the immune system. The aforementioned process allows for new explanations of the relationship between triggers of autoimmunity and infectious agents, of the time lag between infection and autoimmune response and of the progressive nature of autoimmune diseases. It can also offer a new point of view of molecular mimicry and of epitope spreading. The roles of genetic predisposition, stress, diet habits and lifestyle fit in its framework, as well. Side effects of malignancy treatments using immune checkpoint inhibitors can also be explained. A conclusion of the aforementioned reasoning is that treatments should aim to completely eliminate the cause of these evolving alterations, namely the infectious agents. Presumably, they could be based on antibiotics and antiviral drugs. Τo check the validity of the proposed conceptual model, research directions are suggested in the last section of the paper.

Abstract:

This study aimed to assess the acute effects of two isoenergetic but micronutrient-diverse meals—a Mediterranean-like meal (MdM) and a fast food-like meal (FFM)—on the autonomic nervous system (ANS), lung function, and airway inflammation response. Forty-six participants were enrolled in a randomized cross-over clinical trial, consuming two isoenergetic meals: FFM (burger, fries, and sugar-sweetened drink) and MdM (vegetable soup, whole wheat pasta, salad, olive oil, sardines, fruit, and water). Pupillometry assessed parasympathetic (MaxD, MinD, Con, ACV, MCV) and sympathetic (ADV, T75) nervous system outcomes. Lung function and airway inflammation were measured before and after each meal through spirometry and fractional exhaled nitric oxide (FeNO), respectively. Mixed-effects model analysis showed that MdM was associated with a hegemony of parasympathetic response, with a significant increase of MaxD associated with a faster constriction velocity (ACV and MCV); on the other side, the FFM associated with changes in the sympathetic response, showing a quicker redilation velocity (decreased of T75). After adjusting for confounders, mixed-effects models revealed that the FFM significantly decreased T75. Regarding lung function, a meal negatively impacted FVC (ae= -0.079, p<0.001) and FEV1 (ae= -0.04, p= 0.017); however, FeNO increased, although after adjusting, no difference between meals was seen. In conclusion, our study showed that FFM counteracted the parasympathetic activity of a meal, while a meal, irrespective of the type, decreased lung function and increased airway inflammation.

Abstract: Climate change is significantly altering the dynamics of airborne allergens, affecting their seasonality, allergenicity, and geographic distribution, which correlates with increasing rates of allergic diseases. This study investigates aeroallergen sensitization among populations from Tenerife, Spain, and Lima, Peru—two regions with similar climates but distinct socio-economic conditions. Our findings reveal that Spanish individuals, particularly those with asthma, demonstrate higher sensitization levels to a broader range of allergens, especially mites, with 85% of participants reacting to at least one mite allergen. In contrast, Peruvian patients exhibit a narrower spectrum of sensitization. These results highlight the influence of environmental factors, such as pollution and socioeconomic disparities, on allergen exposure and immune responses. Moreover, the study underscores the necessity for region-specific diagnostic and therapeutic strategies to effectively address these variations. By elucidating the intricate relationship between climate change, environmental factors, and allergen sensitization, this research offers insights into respiratory allergic conditions, advocating for tailored interventions to mitigate their impact across diverse populations.

Abstract: The lung is a vital organ for the body as the main source of oxygen input. Importantly, it is also an internal organ that has direct contact with the outside world. Innate immunity is a vital protective system in various organs, whereas in the case of the lung, it helps maintain a healthy, functioning cellular and molecular environment and prevent any overt damage caused by pathogens or other inflammatory processes. Disturbance in lung innate immunity properties and process, whether it be the over-responsiveness of the process triggered by innate immunity or the lack of responses due to dysfunctions in the immune cells that make up the innate immunity system of the lung, could be correlated to various pathological conditions. In this review, we discussed globally how the components of lung innate immunity are important not only for maintaining lung homeostasis but also during the pathophysiology of notable lung diseases beyond acute pulmonary infections、including chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.

Abstract: As people living with HIV (PLWH) are living longer, they face increased risks of chronic diseases and may require care in nursing homes (NH). Given the complexity of the general NH resident population, NH staff may lack specialized training to provide optimal HIV care, leading to care gaps. This report highlights six cases of PLWH hospitalized from NHs, illustrating these gaps and the need for systemic changes in education and protocols for HIV care in NHs. Addressing these gaps is crucial for improving outcomes for this aging and vulnerable population.