Medicine and Pharmacology

Abstract: Allergen-specific IgE multiplex serology enables the molecular characterization of sensitizations in large populations. This study analyzed results from 21,121 canine sera collected in the USA during 2024–2025 using the Pet Allergy Xplorer (PAX) 238-allergen platform to determine sensitization prevalence and profiles. Sensitization to at least one allergen and to at least one environmental allergen was detected in 90.7% and 86.2% of dogs, respectively. House dust mites (HDM) were the predominant allergens (79.5%), followed by Hymenoptera venoms (39.8%), meats (21.9%), weeds (21.5%), and tree pollens (18.6%). Sensitization to the Dermatophagoides farinae HDM was the most prevalent (76.7%). Unsupervised clustering of 16,366 sensitized dogs identified six biologically coherent profiles centered on flea saliva, mammalian serum albumins/IgGs, honeybee venom, HDM group-2 allergens, storage mites, and PR-10-family allergens. A second, pollen/plant-food-focused analysis found clusters associated with Parietaria Par j 2, ragweed, granule-bound starch synthases, and PR-10 allergens, as well as a minor Phl p 6-associated grass pollen profile. Altogether, these results define the molecular sensitization repertoire of allergic dogs in the US and provide the background for interpreting IgE serological results and optimizing allergen selection for immunotherapy.

Abstract: Lipedema affects an estimated 11 to 12% of women and is characterized by bilateral, symmetric, painful enlargement of the limb subcutaneous fat that resists dietary weight loss. Its primary substrate is increasingly understood to be adipo-vascular and connective: genome-wide association studies implicate adipose, vascular, and extracellular-matrix loci rather than immune genes, and the affected fat is metabolically healthier than its mass predicts. Inflammation is itself well documented in lipedema tissue, but its type 2, reparative character suggests that it amplifies this substrate rather than initiating the disease. Against this substrate, however, a focused neuroimmune cluster remains unexplained by purely structural models: a diagnostically accurate quantitative sensory testing pattern, elevated tissue histamine, frequent comorbid fibromyalgia, and disease that is more severe in limbs carrying an additional local vascular trigger. We hypothesize that altered tissue mechanics and adipo-vascular biology help trigger a localized immune cascade, so that these observations may define a clinically identifiable subgroup exhibiting a type 2 immune and mast cell-activation endotype, nested within the broader adipo-vascular disorder. The core framework is deliberately limited to this testable sequence: adipo-vascular susceptibility, per-cell mast cell/type 2 activation, histaminergic peripheral sensitization, the quantitative sensory testing signature, and pain generation in a clinically identifiable endotype. We argue that the endotype is best characterized by per-cell mast cell secretory activity rather than abundance, which is not consistently increased in lipedema tissue. It is defined a priori, before treatment exposure, by a composite of baseline features (affected-fat erythema or warmth, atopic or mast cell-activation features, and the characteristic quantitative sensory testing pattern), with response to mast cell-directed therapy reserved as its prospective test rather than a defining criterion. We present the framework as a graded synthesis, distinguishing evidence shown directly in lipedema from that inferred from related fields and from untested hypotheses. Broader adipogenic, gut-immune, HLA-associated, cancer-related, ADHD-related, and systemic immunomodulatory concepts are separated into a dedicated exploratory section; they are secondary hypotheses and are not required for the central mast cell-histamine-QST-pain claim. The framework identifies mast cell activation as a potential therapeutic target in this subgroup for future investigation, pending prospective validation.

Abstract: Background/Objectives: Chronic spontaneous urticaria (CSU) is a heterogeneous immune-mediated condition involving multiple inflammatory pathways. The clinical utility of platelet-activating factor (PAF) as a biomarker in CSU remains insufficiently defined. This study aimed to evaluate serum PAF levels in patients with CSU and to investigate their associations with clinical characteristics, disease activity, and laboratory and immunological parameters. Methods: This cross-sectional study included 205 adult patients diagnosed with CSU between January 2016 and May 2023. Clinical data, patient-reported outcome measures (PROMs), and extensive laboratory parameters were collected. Serum PAF levels were measured using ELISA in 171 patients. Associations were analyzed using appropriate statistical methods. Results: The cohort was predominantly female (77.6%), with a mean age of 42.6 ± 15.3 years. Most patients had uncontrolled disease (76.9%). The median UAS7 indicated moderate disease activity. PAF levels differed significantly across clinical subgroups. Higher PAF levels were observed in patients with angioedema (alone or in combination with urticaria) compared to those with urticaria alone (p = 0.002), and in patients with predominantly nocturnal and early morning symptoms (p = 0.018). No associations were found between PAF levels and disease activity scores or treatment response. PAF levels showed positive correlations with age, age at symptom onset, IgM, IgG anti-IgE, HSP70, and the CD4/CD8 ratio (all p < 0.05). Conclusions: Circulating PAF levels are associated with specific clinical phenotypes, circadian symptom patterns, and selected immunological markers in CSU, supporting a role for PAF in disease heterogeneity and immune activation. PAF may reflect underlying biological processes not captured by patient-reported disease severity.

Abstract: BCR-mediated antigen internalization is the most efficient pathway for MHC class II presentation to CD4+ T cells, surpassing fluid-phase uptake by up to 10,000‑fold. Using hen egg lysozyme (HEL) complexed with antibodies D1.3 and HyHEL‑10, we show that antibody binding amplifies intrinsic conformational dynamics precisely at the epitope interface. Comparative B‑factor analysis of unbound and antibody‑bound HEL structures, together with NMR order parameters, reveals four findings: (1) antibody epitopes—including the subdominant T cell epitope HEL 112‑129—show elevated B‑factors (+22‑35%) upon complex formation; (2) these regions correspond to pre‑existing dynamic elements (S² = 0.65‑0.72); (3) immune complex size inversely correlates with global HEL B‑factors (global stabilization with local flexibility amplification, termed "focused flexibility"); and (4) HEL 112‑129 serves as a dual B‑cell/T‑cell epitope. Functionally, focused flexibility couples to FcRn‑dependent endosomal sorting: after pH‑dependent dissociation, FcRn binds the antibody Fc and directs recycling, while the conformationally primed antigen is actively trafficked to lysosomal compartments optimized for epitope‑conserving proteolysis. FcRn knockout studies confirm this pathway is required for efficient MHC II loading and CD4+ T cell activation. We propose that antibody binding creates an "optimally unstable" processing intermediate—sterically protected, locally destabilized, and FcRn‑routed—providing a structural and cellular basis for the extraordinary efficiency of BCR‑mediated antigen presentation.

Abstract: Background and Hypothesis: Schizophrenia spectrum disorders (SSD) refer to a collection of conditions causing loss of functionality, disrupted thoughts and perceptions. While the causes of SSD are not fully clear, systemic inflammation has been considered in their pathophysiology. Our purpose was to analyze peripheral inflammation using lymphocyte- and lipoprotein-derived inflammatory ratios in SSD patients. Then it was analyzed the association among these biomarkers, gender, psychopathology, metabolic and clinical data and the possible predictive value to diagnose SSD. Study Design: Cross-sectional case-control study. Blood-derived inflammatory indices were compared between SSD patients (n=351) and healthy control individuals (n=76). Associations with age, gender, body mass index (BMI), and substance use (alcohol, tobacco, xanthine) were evaluated. Diagnostic predictive ability was tested using ROC curve analysis. Study Results: SSD individuals showed significantly higher levels of MLR, SIRI, MHR, LHR, and PHR, along with lower HDL cholesterol and platelet volume, suggesting increased peripheral inflammation. These differences remained significant after accounting for sex and tobacco use. Within the psychosis group, males exhibited higher MHR and LHR values, and tobacco users showed elevated MHR, LHR, and PHR levels. ROC analysis revealed limited diagnostic utility for all tested biomarkers (AUC< 0.7), though findings from previous studies suggest potential value in specific subtypes. Conclusions: Psychotic disorders are associated with subtle yet consistent alterations in inflammation-related blood markers. While demographic and metabolic factors partly influence these indices, their predictive value for psychosis remains limited. These findings support the development of integrative models that combine clinical, social, and biomarkers to improve early identification.

Abstract: Background: The mannan-conjugated birch pollen polymerised allergoid EP-088_T502 has previously been shown to reduce allergic symptoms and anti-allergic medication use during the birch pollen season. This confirmatory phase III trial aimed to evaluate the efficacy, safety, tolerability, and immunologic effects of six pre-seasonal subcutaneous injections.Methods: In this DBPC trial, 278 participants with birch pollen–induced allergic rhinoconjunctivitis (ARC) received either placebo or a cumulative dose of 28,000 mTU EP-088_T502. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season. Safety, tolerability, health-related quality of life (QoL), and immunologic parameters were also assessed.Results: EP-088_T502 significantly reduced the CSMS during the peak birch pollen season compared with placebo (mean absolute difference [MAD] −0.31; p=0.016, FAS). In the PP and Complete Cases sets, MAD were -0.36 (p=0.012) and -0.51 (p=0.013), respectively. Health-related QoL improved by 20% in the EP-088_T502 group compared with placebo during the peak season (p<0.005). EP-088_T502 increased Bet v1-specific IgG4 levels after treatment compared with placebo (6.4-fold; p<0.0001). The Bet v1-specific IgE/IgG4 ratio was reduced by 73% from baseline and by 69% compared with placebo (both p<0.0001). Thirteen systemic allergic reactions occurred, including one grade III systemic reaction considered related to EP-088_T502.Conclusions: EP-088_T502 significantly improved symptom and medication scores in participants with birch pollen–induced ARC and induced a substantial Bet v1-specific IgG4 response. The higher cumulative dose was associated with enhanced immunologic effects and an acceptable safety and tolerability profile.

Abstract: Pediatric autoimmune disorders are increasingly common, but outcomes are poor due to delayed diagnosis. Immune system dysfunctions typically cause these in the presence of essential micronutrient deficiencies, especially vitamin D. Besides, vitamin D deficiency contributes to both immune and endocrine imbalances that may trigger or exacerbate autoimmunity in children. This review highlights the role of micronutrients, cofactors, and mechanisms, especially vitamin D, in regulating immune responses, maintaining hormonal equilibrium, and disease progression. It explores the complex interactions between vitamin D, zinc, selenium, probiotics, and omega-3 fatty acids and the immune and endocrine systems in pediatric autoimmune pathophysiology. The article underscores the importance of early diagnosis, effective interventions, and targeted micro-nutritional strategies to reduce the incidence and severity of these disorders. Proactive supplementation—especially with vitamin D3 and complementary micronutrients—can strengthen immune function, reduce inflammation and oxidative stress, and mitigate the development of childhood autoimmune diseases. Understanding the interconnected roles of different micronutrients, gut microbiota, and immune dysregulation is essential to preventing and effectively managing these conditions. The review encourages pediatricians and other healthcare professionals to adopt integrative approaches, including holistic, orthomolecular, and personalized nutritional therapies, to prevent these disorders and associated complications. Such cost-effective approaches improve clinical outcomes and guide future research and public health strategies. Optimizing micronutrient levels may significantly enhance pediatric well-being and long-term quality of life.

Abstract: Adoptive cellular therapy has emerged as one of the most pivotal modalities in cancer immunotherapy. Although chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in hematological malignancies, its broad application is hampered by severe immune-related toxicities, autologous manufacturing limitations, and suboptimal efficacy against most solid tumors, highlighting an urgent unmet clinical need for safer and more versatile cellular therapeutics. As a promising alternative, CAR-NK cell therapy exhibits inherent advantages in safety profile, off-the-shelf accessibility, and multimodal antitumor mechanisms. NKG2D, a pivotal activating receptor broadly expressed on NK cells, specifically recognizes stress-inducible ligands such as MICA/B and ULBP family molecules. These ligands are abundantly overexpressed in various hematological and solid malignancies yet rarely detected in normal tissues, thereby rendering NKG2D an ideal candidate for universal targeted immunotherapy. In this review, we systematically examine the structural design and iterative optimization of NKG2D CAR constructs and elucidate the inherent advantages of CAR-NK over conventional CAR-T cells. We also comprehensively review recent research advances in NKG2D CAR-NK across multiple malignancies, and critically analyze three pivotal translational bottlenecks, including tumor antigen escape, the immunosuppressive tumor microenvironment, and inadequate in vivo persistence. Moreover, we highlight current genetic engineering and combinatorial strategies to overcome these limitations, and outline future research directions focusing on the development of universal off-the-shelf products, multifunctional cell engineering, and rational combination regimens. By integrating mechanistic advances, preclinical findings and early clinical evidence, this review provides a systematic theoretical basis and translational guidance for the structural optimization, clinical translation, and widespread clinical adoption of NKG2D CAR-NK therapy, laying a solid foundation for its future development as a standardized universal anticancer cellular therapeutic.

Abstract: Food-grade lactic acid bacteria are increasingly recognized as promising candidates for mucosal immunization and various health applications. However, plasmid-based expression systems often face challenges related to antibiotic-resistance markers and genetic instability. To address these limitations, we developed and microbiologically characterized a marker-free strain of Lactococcus lactis subsp. cremoris NZ9000. This strain carries a chromosomally integrated expression cassette for the Surface Immunogenic Protein (SIP) of Streptococcus agalactiae, commonly known as Group B Streptococcus (GBS). Using an adapted pMBSacB sucrose-counterselection strategy, we successfully replaced the native upp locus with a nisin-inducible PnisA-Usp45-sip cassette. Whole-genome sequencing confirmed that the sip cassette was integrated at the designated locus, with no additional mutations or residual antibiotic-resistance determinants detected during our analysis. Importantly, this chromosomal insertion did not affect in vitro growth. Western blotting and confocal microscopy confirmed that the expression of rSIP is dependent on nisin and that rSIP is localized on the cell surface. In a pilot study in mice, L. lactis-SIP showed no adverse effects, including weight loss or any noticeable clinical changes. Importantly, serum analysis detected the presence of SIP-specific IgG, particularly at the highest evaluated dose of 1 × 10¹⁴ CFU. These findings support the potential of L. lactis-SIP as a genetically stable, marker-free platform for mucosal antigen delivery. This research paves the way for future evaluations of probiotic-based functional foods or live biotherapeutic formulations aimed at GBS.

Abstract: Antibody-dependent enhancement (ADE) is a paradoxical immunological phenomenon in which pre-existing antibodies facilitate viral entry into host cells rather than conferring protection [1,2]. ADE has been extensively characterised in flaviviral systems, most notably dengue virus (DENV), and presents a significant challenge for vaccine development and antibody-based therapeutic design [1,3]. In coronavirus infections, ADE may operate through both classical Fc gamma receptor (FcγR)-mediated pathways and an intrinsic signalling mechanism involving inhibitory FcγRIIb-mediated suppression of the type I interferon (IFN-I) response [4,5]. Of critical translational relevance is the functionally demonstrated cooperative FcγR–ACE2 entry model for SARS-CoV-2, wherein virus–antibody immune complexes engage Fcγ receptors and require ACE2 interaction for efficient enhancement [6,7]. For SARS-CoV-2 specifically, ADE magnitude appears to be determined by an antibody’s capacity to block spike–ACE2 interaction rather than its neutralisation potency in vitro—a finding distinct from FIPV and other coronavirus ADE systems where classical FcγR-mediated mechanisms predominate without ACE2 co-receptor dependency [6,7]. Feline infectious peritonitis virus (FIPV) represents one of the most rigorously documented biological systems in which antibody-mediated macrophage infection directly determines systemic disease outcome [8,9]. This comprehensive review integrates current knowledge of FcγR biology, IgG subclass dynamics, antibody glycosylation, coronavirus cell entry mechanisms, intracellular signalling cascades, cytokine dysregulation, comparative veterinary immunopathology, and nano-engineered immunomodulatory platforms for ADE-safe vaccine development. No confirmed clinical ADE has been documented to date in mRNA-vaccinated populations, though theoretical risk windows and population-specific vulnerabilities are critically discussed [26,27].

Abstract: Background: Enhancing the binding affinity of monoclonal antibodies (mAbs) has the potential to improve their therapeutic efficacy. In this study, we generated a novel mAb, PB-223, through affinity maturation of the parental antibody NEO-102. NEO-102 (Ensituximab) is a chimeric human IgG1 mAb that targets a cancer-specific glycosylated variant of MUC5AC expressed on colorectal and pancreatic cancers, while sparing healthy tissues. In a Phase 2 clinical study, involving heavily pretreated patients with advanced, refractory colorectal cancer, NEO-102, as a monotherapy, exhibited modest efficacy. Methods: We engineered the VH and VL regions of NEO-102 through affinity maturation to enhance antigen binding while preserving target specificity. The optimized clone, PB-223, was evaluated for improved binding by ELISA, flow cytometry, immunohistochemistry (IHC). Specific PB-223 target antigen was discovered using O-glycan array. Internalization assay evaluated the ability of PB-223 to internalize human cancer cell lines expressing its target antigen. Results: PB-223 exhibits a 4.55-fold lower dissociation constant (KD) compared with NEO-102 by ELISA. PB-223 has enhanced binding to human cancer cell lines recognized by NEO-102 by flow cytometry. O-glycan array analysis identified core 2 O-glycans, expressed by human cancer cell lines reactive with PB-233 in flow cytometry, as the specific binding epitope of PB-223. IHC analysis of human tumor tissues showed that PB-223 does not bind to healthy tissues, displays superior binding to multiple malignant tissues previously recognized by NEO-102 and binds to tumor types not recognized by NEO-102. PB-223 internalizes human cancer cell lines expressing core 2 O-glycans. Conclusions: PB-223 can potentially be used as a targeting moiety for antibody-based therapeutics, including antibody–drug conjugates (ADCs), bispecific antibodies, immune-engaging constructs, and radiopharmaceuticals, for the treatment of human cancers expressing core 2 O-glycans.

Abstract: Background: Food allergy is a heterogeneous pediatric disease involving IgE-mediated, non-IgE-mediated, and mixed immune mechanisms, with manifestations ranging from mild symptoms to life-threatening anaphylaxis. Current diagnostic tools, including clinical history, skin prick testing, serum specific IgE measurement, and oral food challenge, have limitations in specificity, invasiveness, prognostic value, and ability to guide personalized management. Methods: This narrative review summarizes emerging biomarkers in pediatric food allergy and evaluates their diagnostic, prognostic, predictive, and therapeutic potential. A literature search was conducted in PubMed/MEDLINE and Cochrane Central for English-language studies published between December 2015 and March 2026. Eligible studies included original clinical or translational research involving children aged 0–18 years and assessing functional cellular assays, epithelial barrier markers, intestinal permeability, gut microbiota, metabolomics, transcriptomics, proteomics, epigenetics, and immune biomarkers. Findings were synthesized qualitatively according to biomarker category and biological function. Results: Functional cellular biomarkers, particularly the basophil activation test, show the greatest translational readiness, with high diagnostic specificity, utility in reaction threshold and severity assessment, and potential value for monitoring oral immunotherapy. Biomarkers of epithelial barrier dysfunction, including zonulin, tight junction proteins, epithelial injury markers, filaggrin variants, and epithelial-derived cytokines, provide mechanistic insight into allergic sensitization and gastrointestinal phenotypes but remain insufficiently validated. Microbiota-derived, metabolomic, transcriptomic, proteomic, epigenetic, and integrated multi-omics approaches offer promising tools for risk prediction, tolerance monitoring, endotype identification, and precision medicine. Conclusion: Emerging biomarkers may improve diagnosis, risk stratification, therapeutic monitoring, and personalized care in pediatric food allergy. However, standardized assays, large longitudinal pediatric studies, and external validation are required before routine clinical implementation.

Abstract: Rheumatoid arthritis (RA) is a disease of the immune system that leads to continuous synovial inflammation and the progressive breakdown of joints. As essential effector cells in innate immunity, macrophages can become either pro-inflammatory M1 or anti-inflammatory M2 phenotypes, playing a critical role in RA pathogenesis. A marked M1/M2 polarization imbalance exists in the synovial microenvironment of RA, in which excessive activation and accumulation of M1 macrophages serve as a key hub driving persistent inflammation, cartilage degradation, and bone erosion. This review systematically summarizes the polarization mechanisms of macrophages in RA, their core pathological functions, and recent advances in targeting these cells as therapeutic strategies, therefore delivering novel insights and references for RA treatment through targeted changes in macrophage polarization.

Abstract: Abstract Background: Food hypersensitivity is frequently associated with gastrointestinal and systemic manifestations. This study aimed to evaluate the clinical, nutritional, biochemical, lifestyle characteristics and stress levels of Lebanese adults with food hypersensitivity (cases) compared with controls (absence of food hypersensitivity). Methods: A case–control study was conducted among 775 Lebanese adults, including participants with self-reported food allergy and/or food intolerance and controls. Sociodemographic, clinical, and lifestyle data were collected. Dietary intake was assessed using validated dietary assessment tools. Biochemical parameters, stool analyses, and fecal calprotectin were evaluated when available Results: Overall, 379 participants (48.9%) were classified as having food hypersensitivity. Dermatological, nasal, respiratory, and gastro-intestinal symptoms were significantly more frequent among cases than controls (p< 0.05). Autoimmune diseases were more prevalent among cases. Daily energy and nutrient intake differed significantly between groups, with cases generally reporting lower intakes than controls. Cases exhibited substantially lower serum vitamin D, vitamin B12, and hematocrit levels. In binary logistic regression, fecal calprotectin positivity (OR = 3.385; 95% CI: 1.869–6.132), were independently associated with increased odds of food hypersensitivity, whereas higher serum levels of vitamin D intake (OR = 0.855; 95% CI: 0.740–0.989) was associated with lower odds. Conclusions: Biochemical differences were observed despite generally adequate dietary intake. Fecal calprotectin positivity, and lower vitamin D intake were the main predictors of food hypersensitivity, highlighting the role of intestinal inflammation, dietary exposures, and immune modulation. This underscores the im-portance of regular biochemical monitoring, and tailored nutritional interventions rather than relying solely on dietary elimination.

Abstract: Breast implant illness (BII) is an emerging clinical disorder characterized by systemic symptoms, such as fatigue, cognitive dysfunction, musculoskeletal pain, and autoimmune-like complications. Despite increasing patient awareness and improved clinical care, BII remains controversial due to the absence of standardized diagnostic criteria and accurate biomarkers. In this review, we address the current clinical and research gaps in symptoms, diagnosis, and treatment outcomes of BII by focusing on the underlying immunological mechanisms, aiming to identify potential biomarkers for improving these areas in the clinical care of BII. Through comprehensive literature analysis, it has been found that patient-reported data consistently indicate a high prevalence of systemic symptoms, with up to one-third of women reporting BII-related complaints. Outcomes following explantation are remarkably positive, with 57–96% of patients experiencing partial or complete symptom relief. Among many etiological factors, immunological mechanisms are identified to be more relevant to BII, including silicone-related autoimmune/inflammatory syndrome induced by adjuvants (ASIA), chronic inflammation induced by bacterial biofilms, immune responses to connective tissue remodeling, and genetic predisposition associated with different HLA alleles. Potential endocrine or neuroimmune responses to degraded silicone products also contribute to the development of BII symptoms. Immunological mechanisms related to BII clinical symptoms and their utility in the development of diagnostic and therapeutic strategies are also discussed.

Abstract: Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and fibrosis involving the skin and internal organs. Interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cardiac involvement remain major causes of morbidity and mortality, yet prediction of disease progression and therapeutic responsiveness remains difficult. Methods: This narrative review summarizes studies of circulating blood biomarkers in SSc, with emphasis on literature published since 2020 and on Japanese multicenter longitudinal cohort studies. Disease-specific autoantibodies were intentionally excluded from the main scope, and the review focuses on soluble biomarkers measurable in peripheral blood that reflect inflammation, endothelial injury, and fibrotic remodeling. Results: Multiple cytokines, chemokines, adhesion molecules, endothelial markers, extracellular vesicle-associated molecules, and extracellular matrix (ECM)-related molecules have been associated with disease activity, organ involvement, prognosis, and therapeutic response in SSc. Among emerging biomarkers, interleukin (IL)-6, CCL2, CXCL8, CXCL4, intercellular adhesion molecule-1 (ICAM-1), Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), CCL18, periostin, endostatin, endothelin-1, extracellular vesicle signatures, and ECM turnover markers have shown particular promise. In particular, Japanese multicenter longitudinal studies have demonstrated the prognostic significance of circulating chemokines and adhesion molecules in early SSc and, more recently, identified biomarker-based clusters associated with distinct pulmonary trajectories. Recent multidimensional proteomic and transcriptomic approaches further support biologically based patient stratification in SSc. Conclusions: Blood biomarkers may contribute to risk stratification, prediction of organ progression, and precision medicine in SSc. Integrated biomarker signatures may better capture the biological heterogeneity of SSc than single biomarkers alone.

Abstract: Objectives: Borrelia burgdorferi sensu lato, a spirochete bacterium responsible for Lyme borreliosis - the most common tick-borne infection in North America and Europe - can trigger the production of antiphospholipid antibodies. These antibodies target host lipids such as cardiolipin (CL), phosphatidic acid (PA), phosphatidylcholine (PC), and phosphatidylserine (PS), which the spirochete incorporates into its membrane from the surrounding environment. Although antiphospholipid antibodies are typically associated with antiphospholipid syndrome (APS), they may also arise during infections, including Lyme borreliosis. This study aimed to develop and optimize several enzyme-linked immunosorbent assays (ELISAs) for measuring various antiphospholipid antibodies in patients with Lyme borreliosis. Methods: Thirty patients diagnosed with Lyme borreliosis were enrolled: ten with solitary erythema migrans (EM), ten with multiple EM (MEM), and ten with late manifestations known as acrodermatitis chronica atrophicans (ACA). Forty healthy blood donors served as controls. Four distinct antiphospholipid antibody ELISAs were developed, each using a different phospholipid coating: CL, PA, PC, and PS. Serum of APS patient was used as a positive control and for standard curve generation. Results: All four ELISAs were successfully established and demonstrated good measurement precision. Significant differences in antiphospholipid antibody levels and positivity rates were observed between Lyme borreliosis patients and healthy blood donors. Notably, levels of antibodies directed against PA (aPA), PC (aPC), and PS (aPS), both IgG and IgM, were significantly higher in patients with late Lyme borreliosis, manifested as ACA, compared to healthy blood donors. In contrast, anti-CL (aCL) levels did not differ significantly between groups. Patients with ACA also showed the highest frequency of multiple antiphospholipid antibody positivity, with 7 of 10 patients testing positive for three or more antiphospholipid antibodies. Conclusions: Accurate and precise in-house ELISAs for the detection of aCL, aPA, aPC, and aPS using APS sera as standard material were developed and validated for the analysis of samples of patients with Lyme borreliosis. Our data suggest that antiphospholipid antibody levels—specifically aPA, aPC, and aPS—differ across clinical manifestations of Lyme borreliosis, with the greatest increases observed in patients with ACA.

Abstract: Inflammasomes arise from complex protein assembly mechanisms and play a fundamental role in managing inflammation and the innate immune response. The molecules that trigger inflammasome assembly and activation are molecules derived from pathogens or DNA fragments released following cellular damage. The phenomena resulting from inflammasome activation range from the activation of caspases, such as caspase-1, to the secretion of pro-inflammatory cytokines, to cellular death by apoptosis or pyroptosis. Various pathologies have been linked to aberrant inflammasome activation, including several autoimmune diseases, leading scientists to direct experiments toward identifying the mechanisms responsible for aberrant inflammasome activation to develop new therapeutic strategies. In this review, we summarize the assembly mechanisms and involvement of two specific inflammasomes, NLRP3 and AIM2, in the autoimmune disease Sjögren's syndrome (SjD); NLRP3 and AIM2 aberrant activations appear to be involved in the exacerbation of inflammation, which becomes chronic, leading to dry mouth and dry eye and to an increased risk of developing B-cell non-Hodgkin's lymphoma in these patients. Understanding how different inflammasomes contribute to the pathogenesis of SjD could be fundamental to understanding the complex molecular mechanisms underlying this disease.

Abstract: Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regi-men has not yet been investigated. This study aimed to compare the safety and tolera-bility of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Meth-ods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.:2022-004082-20), patients (N=109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10.000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and thus before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N=20). Those who performed the last treatment visit thereafter were assigned to the pre/co-seasonal group (N=83). Both groups were compared in terms of local and sys-temic immediate and late phase reactions and other EP-088-T502-related adverse events (AEs). Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N=3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions according to the German AWMF classification were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm, late phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm, late-phase reac-tions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N=89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs was comparable between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well tolerated even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.

Abstract: C-reactive protein (CRP) was discovered in 1930 by Tillett and Francis as a protein that reacts with C-polysaccharides to form precipitates in the serum of patients with pneumococcal infection. Subsequently, it was found to increase in the serum of patients with bacterial infections and rheumatic diseases, and it has since been widely recognized as a nonspecific biomarker of acute inflammation and utilized in clinical medicine. Meanwhile, CRP-like proteins are also present in the hemolymph of horseshoe crabs, and it has become clear that these proteins have long played a crucial role in the humoral innate immune response against foreign microorganisms. In recent years, advances in molecular analysis have revealed the details of the complex biological functions performed by CRP. Furthermore, with the development of highly sensitive CRP measurement methods, its importance as a biomarker is gaining attention not only in acute inflammatory diseases but also in chronic inflammatory diseases such as cardiovascular disease, diabetes, cancer and neurological disorders. New treatment strategies targeting CRP, based on recent findings, are also being explored.