Autoantibody Production Research Articles

Occupational dust and chemical exposures and the development of autoimmune rheumatic diseases.

Although the association between certain occupational exposures and the development of autoimmune rheumatic disease was first described over a century ago, this association has only become more widely recognized in the past 10 years because of the use of high-silica-content engineered stone in construction and home renovation. There is now a substantial and growing body of evidence that occupational dust and chemical exposure, be it through mining, stonemasonry, building or other trades, increases the risk of various systemic autoimmune rheumatic diseases (SARDs) including rheumatoid arthritis and systemic sclerosis. Although the pathogenic mechanisms of silica-induced autoimmunity are not fully elucidated, it is thought that alveolar macrophage ingestion of silica and the ensuing phagosomal damage is an initiating event that ultimately leads to production of autoantibodies and immune-mediated tissue injury. The purportedly causal association between occupational exposure to chemicals, such as organic solvents, and an increased risk of SARDs is less frequently recognized compared with silica dust, and its immunopathogenesis is less well understood. An appreciation of the importance of occupational dust and chemical exposures in the development of SARDs has implications for workplace health and safety regulations and offers a unique opportunity to better understand autoimmune disease pathogenesis and implement preventative strategies.

CAR-T cell targeting three receptors on autoreactive B cells for systemic lupus erythematosus therapy.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell activation, autoantibody production, and nephritis. B cell activating factor (BAFF) overexpression enhances autoreactive B-cell survival, driving autoimmunity. BAFF specific belimumab and CD20 specific rituximab antibodies are used for SLE therapy but are not curative, highlighting the need for alternative B cell depletion therapies. Here, we use BAFF ligand based chimeric antigen receptor T (CAR-T) cells targeting BAFFr, BCMA and TACI expressed on mature B cells and plasma cells. BAFF CAR-T cells efficiently killed B cells after co-culture with peripheral blood mononuclear cells (PBMCs) from SLE patients and in a patient derived SLE xenograft humanized mouse model developed by injecting patient PBMCs into immunocompromised mice. We also generated murine CD8+ T cells expressing human BAFF CAR to test their therapeutic efficacy in spontaneous (MRL/lpr) and pristane induced mouse models of SLE. In both models, BAFF CAR-T cells mediated persistent elimination of mature B cells, resulting in a decrease in the production of autoantibodies (IgM, IgG, Anti-ANA, and Anti-dsDNA IgG) and proteinuria along with prolonged survival. Adoptive transfer of B cells from control MRL/lpr lupus mice to previously BAFF CAR-T treated MRL/lpr lupus mice showed continued depletion of B cells and prolonged survival. Potential advantages of BAFF CAR-T therapy include avoiding B cell aplasia as BAFF receptors are not expressed by early B cells and preventing the escape of long-lived plasma cells post BAFF CAR-T therapy as they express receptors of BAFF. These data demonstrate the potential for a cellular immunotherapy based approach to induce remission of SLE pathogenesis using BAFF-CAR-T therapy.

TLR7 responses in glomerular macrophages accelerate the progression of glomerulonephritis in NZBWF1 mice.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies and damage to multiple organs. Glomerulonephritis, a manifestation involving glomerular deposition of immune complexes and complement components, significantly contributes to disease morbidity. Although the endosomal single-stranded RNA sensor TLR7 is known to drive glomerulonephritis by promoting autoantibody production in B cells, the contribution of macrophage TLR7 responses to glomerulonephritis remains poorly understood. Here, we have examined Tlr7‒/‒ NZBWF1 mice and found that TLR7-deficiency ameliorates lupus nephritis by abolishing autoantibody production against RNA-associated antigens, C3 deposition, and macrophage accumulation in glomeruli. Furthermore, TLR7 signaling increased CD31 expression on glomerular endothelial cells and Ly6Clow macrophages but not on T and B cells, suggesting that CD31 mediates TLR7-dependent migration of monocyte into glomeruli. Compared to their splenic counterparts, glomerular macrophages produced IL-1β in a TLR7-dependent manner. In addition, single cell RNA sequencing (scRNA-seq) of glomerular macrophages revealed that TLR7 signaling induced expression of lupus associated genes including those encoding Chitinase 3 like 1, ferritin heavy chain 1, IKKε, and complement factor B (CfB). Although serum CfB did not increase in NZBWF1 mice, TLR7-dependent CfB protein expression was detected in glomerular macrophages. In addition, TLR7 signaling promoted C3 cleavage and deposition predominantly on mesangial cells. These findings suggest that TLR7 responses in glomerular macrophages accelerates the progression of glomerulonephritis in NZBWF1 mice.

B-Cell-Depleting Immune Therapies as Potential New Treatment Options for Systemic Sclerosis

Background: Systemic sclerosis (SSc), also known as scleroderma, is a complex, chronic autoimmune disease characterized by fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The treatment of SSc has historically focused on symptom management and slowing down disease progression through conventional immune-suppressive agents. New therapeutic approaches have been emerging due to advances in understanding of the disease mechanisms, particularly in the areas of fibrosis, vascular involvement, and immune dysregulation. Methods: In this review of the literature, we discuss the current stage of development of B-cell-depleting immune therapies in SSc. Results: B-cell depletion therapy has become an area of growing interest in the treatment of SSc due to the role played by B cells in the pathogenesis of the disease. There is increasing evidence that B cells contribute to disease progression through multiple mechanisms. B cells in SSc are implicated in autoantibody production, cytokine production, and fibroblast activation. B cells are responsible for producing autoantibodies, such as anti-topoisomerase I (Scl-70) and anti-centromere antibodies, which are hallmarks of SSc. B cells release pro-inflammatory cytokines (such as interleukin-6 [IL-6] and transforming growth factor β [TGF-β]), which promote fibrosis and inflammation, they also contribute to the activation of fibroblasts, the cells responsible for excessive collagen production and fibrosis, a key feature of SSc. Conclusions: In light of these findings, therapies that target B cells are being investigated for their potential to modify the disease course in SSc, particularly by reducing autoantibody production, inflammation, and fibrosis.

Microbiota and immune dynamics in rheumatoid arthritis: Mechanisms and therapeutic potential.

Rheumatoid arthritis (RA) is a complex autoimmune disease with growing evidence implicating the microbiota as a critical contributor to its pathogenesis. This review explores the multifaceted roles of microbial dysbiosis in RA, emphasizing its impact on immune cell modulation, autoantibody production, gut barrier integrity, and joint inflammation. Animal models reveal how genetic predisposition and environmental factors interact with specific microbial taxa to influence disease susceptibility. Dysbiosis-driven metabolic disruptions, including alterations in short-chain fatty acids and bile acids, further exacerbate immune dysregulation and systemic inflammation. Emerging therapeutic strategies-probiotics, microbial metabolites, fecal microbiota transplantation, and antibiotics-offer innovative avenues for restoring microbial balance and mitigating disease progression. By integrating microbiota-targeted approaches with existing treatments, this review highlights the potential to revolutionize RA management through precision medicine and underscores the need for further research to harness the microbiota's therapeutic potential.

Associated factors related to production of autoantibodies and dermo-epidermal separation in bullous pemphigoid.

Bullous pemphigoid (BP) is a debilitating autoimmune skin blistering disease, characterized by the deposition of specific autoantibodies at the dermal-epidermal junction. This leads to an inflammatory cascade involving the activation of complement proteins, mast cell degranulation, immune cell recruitment, and the release of proteases by granulocytes. While several cytokines and signaling pathways have been implicated in the pathogenesis of BP, the precise mechanism behind autoantibody production remains unclear. A variety of factors, including natural aging, genetic polymorphisms, microbiota, medications, vaccinations, and infection, may contribute to disease onset. Recent evidence also suggests that both vaccination against severe acute respiratory syndrome coronavirus-2 and infection with severe acute respiratory syndrome coronavirus-2 may also play a role in BP's development. This review aims to elucidate the mechanism underlying the production of autoantibodies in BP, address gaps in understanding disease progression, and explore opportunities for improving diagnosis and prognosis to enhance patient care.

Gestational Pemphigoid: A Comprehensive Review of Clinical Features, Differential Diagnosis, and Management Strategies with Case Report

Gestational pemphigoid (GP) is a rare autoimmune blistering disorder that typically occurs in the second or third trimester of pregnancy. Characterized by pruritic, tense blisters primarily affecting the abdomen and extremities, GP can lead to significant discomfort and potential complications for both the mother and fetus. The condition is caused by the production of autoantibodies against basement membrane proteins, resulting in subepithelial blister formation. Differential diagnoses include other pregnancy-related dermatoses, such as pruritic urticarial papules and plaques of pregnancy (PUPPP) and drug-induced bullous eruptions. Histopathological findings typically reveal subepidermal vesicles and lympho-eosinophilic infiltrates, although direct immunofluorescence may be negative in some cases. Management primarily involves symptomatic treatment with corticosteroids and antihistamines, leading to favorable outcomes for most patients. This review highlights the clinical features, differential diagnoses, and management strategies for gestational pemphigoid, emphasizing the importance of early recognition and intervention to ensure maternal and fetal health

Targeting Nanotherapeutics for Highly Efficient Diagnosis and Treatment of Systemic Lupus Erythematosus through Regulation of Immune Response

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies, particularly antidouble‐stranded (ds) DNA antibodies, which contribute to multiorgan damage (lupus nephritis, LN). Hence, there is an urgent need to recognize and eliminate SLE‐specific anti‐ds DNA antibodies to enhance the SLE treatment. Herein, mesoporous silica (MSNs) loaded with SeC and surface‐modified ctDNA are constructed to effectively specific bind and eliminate pathogenic anti‐dsDNA antibodies for treatment SLE in 125 plasm and enabling swift LN diagnosis in 36 kidney tissue from SLE patients. As expected, the clearance ratio of anti‐dsDNA antibodies by nanotherapeutics is significantly greater compared to other products commonly used in clinical therapies and exhibits biocompatibility and safety in patients. Moreover, MSNs‐DNA can also help visualize the distribution of anti‐dsDNA antibodies in the lesions of the kidney. Importantly, the combination strategy (MSNs‐DNA@SeC) can effectively remove antibodies and reduce UP production by the regulation of B cells and T cells in female MRL/lpr SLE model mice to alleviate related symptoms. Collectively, the resultant data not only presents a straightforward method for the systematic design of nanomedicine targeting SLE to enhance the effects on diagnosis and treatment, but also elucidates the potential mechanisms involving anti‐dsDNA antibodies in the pathogenesis and progression of SLE.

Compromised B-cell homeostasis: Unraveling the link between major depression, infection and autoimmune disorders.

Major depression can increase susceptibility to viral infections and autoimmune diseases. B cell responses are crucial for immune defense against infections but can trigger autoimmunity when deregulated. However, it remains unclear whether compromised B-cell homeostasis in major depression contributes to an increased risk of infection and autoimmunity. Chronic unpredictable mild stress (CUMS) procedure was applied to adult C57BL/6 J mice to generate a reliable depression model. Mice were immunized with (4-hydroxy-3-nitrophenyl) acetyl (NP) keyhole limpet hemocyanin (NP-KLH) to elicit B-cell-mediated humoral immune responses. CUMS mice were subjected to a collagen-induced arthritis model or a Bm12-induced systemic lupus erythematosus model to assess the contribution of major depression to autoimmunity. RNA sequencing was performed to understand the effects of CUMS on B-cell homeostasis at the transcriptomic level. CUMS mice exhibited an impaired humoral immune response, as evidenced by reduced germinal centers (GCs), plasma cells, and antigen-specific antibodies. Unimmunized CUMS mice displayed aberrant spontaneous expansion of GC B cells, plasma cells, age-associated B cells and autoantibody production. CUMS mice also demonstrated a greater exacerbation of autoimmune manifestations. RNA sequencing revealed that genes involved in B-cell-mediated immune response were downregulated in B cells from CUMS mice, while the pathways related to autoimmunity seem to be upregulated. Further research is needed to understand the specific targets, mechanisms, and role of B cell dysfunction in major depression. Our results provide novel insights into B-cell-dependent mechanisms that involve the association of increased susceptibility to infections and autoimmunity in major depression.

Impact of Thrombopoietin Receptor Agonists on Pathophysiology of Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) in pediatric patients is a common cause of isolated thrombocytopenia. Various pathophysiological mechanisms are implicated in ITP pathogenesis, including the production of autoantibodies against components of platelets (PLTs) by B-cells, the activation of the complement system, phagocytosis by macrophages mediated by Fcγ receptors, the dysregulation of T cells, and reduced bone marrow megakaryopoiesis. ITP is commonly manifested with skin and mucosal bleeding, and it is a diagnosis of exclusion. In some ITP cases, the disease is self-limiting, and treatment is not required, but chronic-persistent disease can also be developed. In these cases, anti-CD20 monoclonal antibodies, such as rituximab and thrombopoietin (TPO) receptor agonists, can be used. TPO agonists have become standard of care today. It has been reported in the published literature that the efficacy of TPO-RAs can be up to 80% in the achievement of several end goals, such as PLT counts. In the current literature review, the data regarding the impact of TPO agonists in the pathogenesis of ITP and treatment outcomes of the patients are examined. In the era of precision medicine, targeted and individualized therapies are crucial to achieving better outcomes for pediatric patients with ITP, especially when chronic refractory disease is developed.

Anti-M2-pyruvate kinase autoantibodies are correlated with digestive damage in human Chagas disease.

Determining esophageal and colon involvement in patients with Chagas disease occurs through invasive and uncomfortable examinations, which in most cases are not performed. The objective of this study was to assess the involvement of anti-M2-pyruvate kinase (M2-PK) autoantibodies in the development of digestive alterations and/or in the diagnosis of the digestive form of human Chagas disease. The total IgG and isotype (IgG1, IgG2, IgG3, IgG4) production was quantified using the antigen of Trypanosoma cruzi and the human M2-PK recombinant protein via the ELISA technique. The tests were conducted with serum samples from patients with indeterminate, cardiac, digestive and cardiodigestive clinical forms of Chagas disease, and the results were correlated with the dilatation degree of the esophagus and colon. Patients with the digestive form of Chagas disease had higher IgG4 anti-M2-PK autoantibody production compared with patients with the indeterminate and cardiac forms and the healthy control group. Furthermore, a positive correlation was observed between sigmoid and rectum size with IgG4 anti-M2-PK autoantibody production. These results demonstrate that IgG4 anti-M2-PK autoantibodies correlate with digestive damage in human Chagas disease, and their presence may also be implicated in the development of digestive lesions.

Immune Aging in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a life-long autoimmune disease caused by the confluence of genetic and environmental variables that lead to loss of self-tolerance and persistent joint inflammation. RA occurs at the highest incidence in individuals >65 years old, implicating the aging process in disease susceptibility. Transformative approaches in molecular immunology and in functional genomics have paved the way for pathway paradigms underlying the replacement of immune homeostasis with auto-destructive immunity in affected patients, including the process of immune aging. Patients with RA have a signature of premature immune aging, best understood for CD4+ T cells which function as pathogenic effectors in this HLA class II-associated disease. Premature immune aging is present in healthy HLA-DRB1*04+ individuals, placing accelerated immune aging prior to joint inflammation. Aging-related molecular abnormalities directly implicated in turning RA CD4+ T cells into pro-inflammatory effector cells are linked to malfunction of subcellular organelles, such as mitochondria, lysosomes, lipid droplets and the endoplasmic reticulum. Resulting changes in T cell behavior include cellular hypermobility; tissue invasiveness; unopposed mTORC activation; excessive release of tumor necrosis factor α (TNF); lysosomal failure; clonal expansion and immunogenic cell death. Aged and metabolically reprogrammed T cells in RA patients are accompanied by age-associated B cells (ABC), which specialize in autoantibody production. Clonal hematopoiesis drives myeloid cell aging by producing aged monocytes and hypermetabolic macrophages (Mϕ) that sustain the process of inflammaging. Here, we synthesize insights into the relationship of RA risk and immune aging and discuss mechanisms through which immune aging can cause autoimmunity.

Development, Optimization, and Evaluation of Rutin-Loaded Liposomes in the Management of Rheumatoid Arthritis.

Rheumatoid arthritis is a chronic autoimmune disease, progressively distinctive via cartilage destruction, auto-antibody production, severe joint pain, and synovial inflammation. Nanotechnology represents one of the utmost promising scientific technologies of the 21st century. Nanocarriers could be the key to unlocking its potential by encapsulating Rutin in targeted drug delivery systems, potentially for targeted Rheumatoid arthritis therapy. The rationale of current research is to prepare liposomes loaded with a bioflavonoid drug rutin for effective management of rheumatoid arthritis. This study investigated the formulation of rutin liposomes using the thinfilm hydration technique, also known as the Bangham method. A Box-Behnken design was employed to optimize the formulation parameters. The LP2 batch was then characterized for its mean particle size, zeta potential, shape, diffraction pattern, and thermal properties. Finally, the in-vitro anti-oxidant and anti-inflammatory potential of the rutin liposomes were evaluated using appropriate assays. Out of thirteen batches, LP2 was found to be an optimized batch with a mean particle size of 167.1 nm, zeta potential -13.50 mV, and entrapment efficiency of 61.22%. The above results showed higher stability of rutin liposomes. Further characterization of LP2 for morphological assessment, XRD analysis, and DSC revealed its spherical shape less than 1 μm, polycrystalline nature, and thermographic peak at 139°C, respectively. Evaluation of the antioxidant properties and antiinflammatory potential of LP2 revealed its maximum therapeutic potential in the reduction of inflammation and protein denaturation when evaluated via in-vitro assays. Rutin liposomal formulation has tremendous potential for the management of Rheumatoid arthritis due to its enhanced bioavailability, anti-oxidant, and anti-inflammatory properties when compared to free rutin.

Activation of V-Domain Immunoglobulin Suppressor of T-Cell Activation by Baloxavir Marboxil Ameliorates Systemic Lupus Erythematosus through Inhibiting Lysophosphatidylcholine/CD40 Ligand.

Deficiency of the V-domain immunoglobulin suppressor of T-cell activation (VISTA) accelerates disease progression in lupus-prone mice, and activation of VISTA shows therapeutic effects in mouse models of a lupus-like disease. Metabolic reprogramming of T cells in systemic lupus erythematosus (SLE) patients is important in regulating T-cell function and disease progression. However, the mechanism by which VISTA affects the immunometabolism in SLE remains unclear. Here, we demonstrated that the deficiency of VISTA promoted the synthesis of the metabolite lysophosphatidylcholine (LPC) using untargeted metabolomics and increased the protein expression of the CD40 ligand (CD40L). Furthermore, baloxavir marboxil (BXM), a small molecule agonist of VISTA, significantly ameliorated autoantibody production, renal damage, and imbalance of immune cell subpopulations in the models of a lupus-like disease in mice (chronic graft-versus-host disease and MRL/MpJ-Faslpr/J mice) possibly by inhibiting LPC synthesis to downregulate CD40L protein expression and inhibiting aberrant activation of noncanonical nuclear factor-κB pathway. Our results indicated that BXM targeting VISTA ameliorated lupus-like symptoms by altering lipid metabolism and CD40L expression, which offers novel mechanisms and a promising therapy for SLE.

Autoantibodies in COVID-19: implications for disease severity and clinical outcomes.

Few pathogens have historically been subjected to as intense scientific and clinical scrutiny as SARS-CoV-2. The genetic, immunological, and environmental factors influencing disease severity and post-infection clinical outcomes, known as correlates of immunity, remain largely undefined. Clinical outcomes of SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to those with life-threatening COVID-19 symptoms. While most infected individuals return to their former health and fitness within a few weeks, some develop debilitating chronic symptoms, referred to as long-COVID. Autoimmune responses have been proposed as one of the factors influencing long-COVID and the severity of SARS-CoV-2 infection. The association between viral infections and autoimmune pathologies is not new. Viruses such as Epstein-Barr virus and cytomegalovirus, among others, have been shown to induce the production of autoantibodies and the onset of autoimmune conditions. Given the extensive literature on SARS-CoV-2, here we review current evidence on SARS-CoV-2-induced autoimmune pathologies, with a focus on autoantibodies. We closely examine mechanisms driving autoantibody production, particularly their connection with disease severity and long-COVID.

Fatal C-Reactive Protein-less Sepsis with Anti-IL-6 Autoantibody Production after Administration of Durvalumab

Durvalumab plus platinum-based chemotherapy is the first-line treatment for extensive-stage small-cell lung cancer. Immune checkpoint inhibitors (durvalumab) can cause immune-related adverse events (irAEs). We herein report the first case of fatal sepsis with anti-interleukin-6 autoantibody production following durvalumab administration. A 62-year-old woman with extensive-stage small-cell lung cancer received carboplatin-etoposide plus durvalumab chemotherapy. Serum C-reactive protein (CRP) levels decreased below the detection sensitivity post-treatment. She developed severe sepsis during maintenance durvalumab therapy; however, her serum CRP level did not increase. The serum tested positive for anti-interleukin-6 autoantibodies, which can cause CRP-less infections. Anti-interleukin-6 autoantibody production and subsequent sepsis without serum CRP elevation are possible irAEs.

Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by the production of autoantibodies, resulting in inflammation and organ damage. Although extensive research has been conducted on SLE pathogenesis, a comprehensive understanding of its molecular landscape in different cell types has not been achieved. This study uncovers the molecular mechanisms of the disease by thoroughly examining gene regulatory networks within neutrophils, dendritic cells, T cells, and B cells. Firstly, we identified genes and ncRNAs with differential expression in SLE patients compared to controls for different cell types. Furthermore, the derived differentially expressed genes were curated based on immune functions using functional enrichment analysis to create a protein-protein interaction network. Topological network analysis of the formed genes revealed key hub genes associated with each of the cell types. To understand the regulatory mechanism through which these hub genes function in the diseased state, their associations with transcription factors, and non-coding RNAs in different immune cell types were investigated through correlation analysis and regression models. Finally, by integrating these findings, distinct gene regulatory networks were constructed, which provide a novel perspective on the molecular, cellular, and immunological landscapes of SLE. Importantly, we reveal the crucial role of IRF3, IRF7, and STAT1 in neutrophils, dendritic cells, and T cells, where their aberrant upregulation in disease states might enhance the production of type I IFN. Furthermore, we found MYB to be a crucial regulator that might activate T cells toward autoimmune responses in SLE. Similarly, in B-cell lymphocytes, we found FOXO1 to be a key player in autophagy and chemokine regulation. These findings were also validated using single-cell RNASeq analysis using an independent dataset. Genotype variations of these genes were also explored using the GWAS central database to ensure their targetability. These findings indicate that IRF3, IRF7, STAT1, MYB, and FOXO1 are promising targets for therapeutic interventions for SLE.

Development and therapeutic assessment of bispecific nanobodies targeting B-cell activating factor and interleukin-17 for the neutralization of inflammatory mediators in autoimmune diseases.

Autoimmune diseases are characterized by dysregulated immune responses and chronic inflammation. B cell activating factor (BAFF) and interleukin-17 (IL-17) are key mediators in the pathogenesis of several autoimmune diseases, driving B cell hyperactivation, autoantibody production, and tissue damage. Simultaneous targeting of these pathways may provide a synergistic therapeutic approach. In this study, we developed a bispecific nanobody (BiNB) that simultaneously neutralizes BAFF and IL-17 through rational design and screening of a fully synthetic nanobody library. In vitro, BiNB effectively antagonized BAFF-induced B cell proliferation (IC50 = 0.38 nM) and IL-17-driven inflammatory responses (IC50 = 4.98 nM), without interference. In murine models, BiNB suppressed B cell-mediated immune responses and alleviated IL-17-induced systemic inflammation. Pharmacokinetic analysis showed a favorable half-life of ~6 days and high bioavailability (91 %) after subcutaneous administration. Molecular docking identified BiNB's binding epitopes on BAFF and IL-17, explaining its dual mechanism of action. BiNB demonstrated strong antagonistic activity in vitro and effective target engagement in vivo, highlighting its potential as a therapeutic candidate for autoimmune diseases.

Aire attenuate collagen-induced arthritis by suppressing T follicular helper cells through ICOSL

ObjectiveTo assess the expression levels of autoimmune regulator (Aire) and inducible costimulator molecule ligand (ICOSL), as well as T follicular helper (Tfh) cell numbers in rheumatoid arthritis (RA) patients, and to explore their relationship with RA severity. We also aimed to investigate the effect of Aire on arthritis and its underlying mechanisms. MethodsThe expression levels of Aire, ICOSL, and Tfh cell numbers were measured in RA patients. The relationship between these factors and the levels of anticyclic citrullinated peptide antibodies (Anti-CCP) as well as the Disease Activity Score in 28 joints (DAS28) was analyzed. To investigate the effect of Aire on arthritis, Aire-overexpressing bone marrow-derived dendritic cells (Aire-BMDCs) and recombinant ICOSL were transferred into collagen-induced arthritis (CIA) mice, the symptoms, clinical scores, anti-collagen type II antibodies (anti-CII Abs), rheumatoid factor (RF), proportions of Tfh cells, and percentages of germinal center (GC) B cells in CIA mice were examined. ResultsThe results showed that Aire levels were significantly decreased in CD14+ PBMCs from patients with RA, and there were negative correlations between ICOSL expression levels, Tfh cell numbers, and Aire expression. Additionally, these factors were correlated with Anti-CCP levels and DAS28. Aire-BMDCs could influence Tfh differentiation, GC B cell development, as well as the levels of anti-CII Abs and RF, which further alleviate the symptoms and reduce clinical scores partly through ICOSL in CIA mice. ConclusionsThe findings suggest that Aire may alleviate rheumatoid arthritis by inhibiting ICOSL, which further inhibits Tfh cell differentiation and autoantibody production.

Unveiling the link: anti-protein disulfide isomerase A3 autoantibody expression and polycystic ovary syndrome risk in euthyroid autoimmune thyroiditis women

BackgroundPolycystic ovary syndrome (PCOS) is a common complication of autoimmune thyroiditis (AIT) in women, but the underlying mechanism remains unclear. Protein disulfide isomerase A3 (PDIA3) is a ubiquitous protein. We have reported that PDIA3 autoantibody (PDIA3Ab) production results from autoimmune responses against thyrocytes, resulting in its high expression in euthyroid AIT patients. This study aimed to explore potential correlations between PDIA3Ab expression and concurrent PCOS in euthyroid AIT women.MethodsThis is a single-center cross-sectional study. All participants, who visited the First Hospital of China Medical University from April 2023 to May 2024, were assigned to four groups according to AIT and PCOS diagnostic criteria. The PDIA3Ab levels of total IgG and IgG subclasses were detected using ELISA.ResultsFrom highest to lowest, PDIA3Ab total serum IgG levels were categorized as follows: AIT-PCOS group > AIT-non-PCOS group > non-AIT-PCOS group > non-AIT-non-PCOS group Significant differences were observed between each pair of groups, except for the non-AIT-PCOS and non-AIT-non-PCOS groups. Further analysis of the subclasses of PDIA3Ab revealed that serum IgG1 levels in the AIT-PCOS and AIT-non-PCOS groups were significantly higher than those in the non-AIT-PCOS and non-AIT-non-PCOS groups. In addition, the AIT-PCOS group had significantly higher serum IgG3 levels than the other three groups. Binary logistic regression analysis revealed that the PDIA3Ab total IgG level was an independent risk factor for concurrent PCOS in euthyroid AIT women (Q4 vs. Q1: OR, 95%CI = 5.082, 1.348–19.16). Furthermore, a trend test demonstrated a titer-dependent increase in PCOS prevalence among AIT women as the PDIA3Ab total IgG level increased.ConclusionsThe expression of serum PDIA3Ab may indicate an increased risk of PCOS in euthyroid AIT women and could potentially serve as new targets for markers or immune intervention.