IgG Autoantibodies Research Articles

Deciphering the IgG Idiotype Network Through Proteomic Analysis of Potential Targets in SARS-CoV-2-Induced Immune Responses.

The association between COVID-19 and autoimmune diseases has gained increasing recognition, yet the specific targets of SARS-CoV-2-induced IgG are currently in focus for several studies. This study aims to explore the proteomic targets of these antibodies and their potential role in autoimmunity. We utilised a human proteome microarray encompassing 23 736 unique proteins, including isoform variants and fragments, as catalogued by the Human Protein Atlas. Serum samples were analysed from four groups: healthy controls (N-exp HC), individuals vaccinated with protein-based vaccines (N-Cov Vac) and patients with moderate or severe COVID-19 (COVID-Mod and COVID-Sev). The evaluation of SARS-CoV-2-induced IgG antibodies revealed their potential to recognise multiple human proteins. Key targets included interferon alpha (IFN-α), tumour growth factor beta (TGF-β), interleukin 1 (IL-1), CXCL16, TGF-β receptors, CD34, CD47 and BCL2. The antibodies also targeted proteins from genes overexpressed in various immune cells, such as CD4+ and CD8+ T cells, γδ T cells, B cells, dendritic cells and NK cells. Reactivity was also observed with proteins specifically expressed in multiple organs, including the brain, liver, lungs and heart. Targeting patterns differed between COVID-19 patients and controls, with some proteins showing differential recognition in moderate versus severe cases. Furthermore, we evaluated the protein-protein interaction network (PPIN) of all targeted proteins and observed minimal structural homology and co-expression among the evaluated proteins, with almost no relation to the SARS-CoV-2 immune system reactome. The results suggest that the profile of SARS-CoV-2-induced IgG autoantibodies is associated with disease severity. In contrast, protein-vaccinated individuals exhibited a profile similar to non-exposed controls, suggesting that autoreactive IgG is specifically linked to active SARS-CoV-2 infection. These findings reveal a complex network of SARS-CoV-2-induced IgG idiotypes capable of targeting human proteins, not merely through simple cross-recognition of homologous proteins. This highlights the need for further investigations to determine whether they may influence COVID-19 pathophysiology and its clinical outcomes.

Research in practice: Immune checkpoint inhibitor related autoimmune bullous dermatosis.

Immune checkpoint receptors and ligands such as cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1) and ligand-1 (PD-L1) are widely expressed on immune and non-immune cells and fine tune the activation level of immune cells, thus, enabling, preventing, or terminating immune responses. Blockade of CTLA-4, PD-1 or PD-L1 by checkpoint inhibitors (CIs), unleashing immune responses, has become a mainstay in the treatment of diverse types of cancer. The induction of autoinflammatory, yet unspecific tissue damage in diverse organs is called an immune related adverse event (irAE), a class side-effect of CIs and may require the discontinuation of immunotherapy. Among frequent skin rashes, CIs targeting the PD-L1/PD-1 axis can elicit the IgG autoantibody- and granulocyte-driven bullous pemphigoid (BP) in about 0.3% to 0.6% of treated patients. Pathogenesis of BP requires a complex cellular inflammatory response after anti-BP180 autoantibody binding to the dermal epidermal junction. The prevalence of autoantibodies against BP180 in healthy blood donors of approximately 0.52% equals the prevalence of irBP among treated cancer patients, underlining the potential relevance of the PD-1 mediated regulation of tissue inflammation for spontaneous BP. If skin rashes appear during CI therapy, biopsies should be taken and examined by histopathological and direct immunofluorescence microscopy.

Anti-fibroblast and anti-endothelial cell autoantibodies in pulmonary arterial hypertension (PAH) in patients with connective tissue diseases (CTD).

Pulmonary arterial hypertension (PAH) is a rare disease that may be associated with connective tissue diseases (CTD). Anti-fibroblast (AFA) and anti-endothelial cell autoantibodies (AECA) have been identified in idiopathic and systemic sclerosis (SSc)-associated PAH. The aim was to identify autoantibodies discriminating for PAH associated with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) and primary Sjögren's syndrome (SS), and their target antigens. Sera were collected in the French multicentre Auto-HTAP study from 86 patients with CTD excluding SSc, including 32 with PAH (PAH+) and 54 without (PAH-). AFA and AECA were identified using one (1D) and two dimensions (2D) immunoblots and proteomics. ELISA tests using human recombinant proteins were used to confirm PAH-associated IgG reactivities. PAH+ patients had similar IgG AFA and AECA reactivities in 56.2% and 40.6% of the cases in 1D immunoblots, respectively. In 2D immunoblots, serum IgG pools from SLE patients (n = 14), MCTD (n = 10), SS (n = 9) and 14 healthy controls (n = 1) recognized respectively 273 ± 79, 205 ± 77, 109 ± 11 and 109 protein spots in fibroblasts and 189 ± 48, 146 ± 30, 88 ± 33 and 190 protein spots in endothelial cell extracts. Serum IgG from PAH+ patients recognized 39 fibroblast and 34 endothelial cell protein spots that were not recognized by IgG from PAH- patients, including Annexin A5 (ANXA5). Anti-ANXA5 IgG reactivity was significantly higher in PAH+ compared with PAH- patients with MCTD (73% vs 0%, p< 0.001) and SLE (33% vs 0%, p= 0.009). Anti-ANXA5 IgG autoantibody reactivity might represent a predictive biomarker for PAH associated with MCTD and SLE.

Association of combined pulmonary fibrosis and emphysema in rheumatoid arthritis with high titer of rheumatoid factor and autoimmunity to the lung.

Combined pulmonary fibrosis and emphysema (CPFE) commonly coexists with connective tissue diseases (CTD), such as rheumatoid arthritis (RA). However, the risk factors contributing to the development of CTD-CPFE remain largely unidentified. This study aimed to characterize CPFE using a large cohort of consecutive RA patients and to elucidate potential risk factors associated with RA- CPFE development. A total of 976 RA patients were enrolled in this cross-sectional study to characterize RA-CPFE. Multiple logistic analyses were conducted to identify potential risk factors for RA-CPFE development. Patient IgG and IgM autoantibodies to primary human bronchial epithelial cells (HBEC) from healthy donors were assessed using flow cytometry. Among the 976 RA patients, 414 (42.4%) developed interstitial lung disease (ILD), with 74 (7.6%) experiencing CPFE. In comparison to RA-CPFE patients with centrilobular or paraseptal emphysema, those with panacinar emphysema had higher emphysema scores and decreased pulmonary function parameters. Multiple logistic regression analysis revealed that male gender, cigarette smoking, occupational exposure to dust, high ILD score, high rheumatoid factor (RF) titers, and the presence of anti-SSA were associated with an increased risk for RA-CPFE. Additionally, levels of IgG and IgM autoantibodies to HBEC were elevated in RA-CPFE patients compared to healthy controls and positively correlated with RF levels. This study is the first to demonstrate the association of RA-CPFE with high titer of RF and the presence of autoantibodies against HBEC, suggesting a link between autoimmunity to the lung and RA-CPFE.

Autoantibodies in patients with fibromyalgia syndrome.

The objective of this study was to assess the frequency of IgG autoantibodies in patients with fibromyalgia syndrome (FMS), to characterize their binding to dorsal root ganglion (DRG) neurons and glial cells, and to assess whether specific DRG binding patterns correlate with clinical symptoms. Sera of a cohort of 184 patients with FMS and 55 control sera were used to test binding of patient IgG on rat DRG sections. ELISA, Western blot, and preadsorption tests were used to search for potential target antigens. We found binding to DRGs in 68 of 184 FMS sera and in none of the control sera. We could identify 9 binding clusters including binding to neurons and to cells labelled with the satellite glial cell marker fatty acid binding protein 7 (FABP7). Current pain intensity correlated positively with IgG binding to FABP7 immunoreactive structures, and burning pain was associated with binding to transient receptor potential vanilloid 1 immunoreactive neurons. Specific antibody detection revealed 13 of 68 sera positive for anti-citrullinated peptide antibodies, 9 of 68 positive for SOX1 antibodies, 7 of 68 positive for antibodies against the serotonin receptor 5HT1AR, and 3 of 68 positive for fibroblast growth factor 3 antibodies. Our findings support the notion of an immune activation in a subgroup of patients with FMS.

Identification of novel autoantibodies in Sjögren's disease.

The diagnosis of Sjögren's disease (SjD) in patients without autoantibodies against Ro/SSA is a major challenge. We aimed to identify novel autoantibodies in SjD that may facilitate the diagnostic procedure for Ro/SSA negative SjD. IgG and IgA autoantibody reactivity of 94 potential candidate autoantigens for SjD, selected from a discovery screen of 1,629 human antigens coupled to Luminex beads and prior knowledge about potential biological relevance, were examined in serum of SjD patients (n=347) using Luminex and ELISA technology. Healthy (HC, n=118) and non-Sjögren's sicca syndrome (NSS, n=44) individuals served as controls. To assess disease specificity, the novel autoantibodies were also measured in serum of patients with Rheumatoid Arthritis (RA, n=50), Systemic Lupus Erythematosus (SLE, n=49), and Systemic Sclerosis (SSc, n=37). 45 novel autoantibodies were significantly (p ≤ 0.05) more prevalent in SjD than in HC and were detected in up to 19% of the SjD cohort. The most common autoantibodies were against CCL4, M5, TMPO and OAS3. Some of the novel autoantibodies were associated with extraglandular disease manifestations, such as anti-TONSL or anti-IL6 with pulmonary involvement. We have developed a three and five marker panel for the detection of Ro/SSA negative patients, consisting of anti-FNBP4, anti-SNRPC, anti-CCL4, anti-M3 and anti-KDM6B, which had a sensitivity of up to 46% with a specificity of 95% (SjD vs. HC). Both panels discriminate these patients from HC, whereas the three-marker more effectively differentiates between Ro/SSA negative patients and NSS. Novel autoantibodies will facilitate the diagnosis of Ro/SSA negative patients with SjD, in particular our predictive panel will be useful in the diagnosis and differentiation of these patients from healthy and NSS individuals in a clinical context. In addition, the autoantibodies may also be useful for risk stratification of extraglandular manifestations.

FcRn inhibitors: Transformative advances and significant impacts on IgG-mediated autoimmune diseases.

FcRn inhibitors: Transformative advances and significant impacts on IgG-mediated autoimmune diseases.

Serum and tear autoantibodies from NOD and NOR mice as potential diagnostic indicators of local and systemic inflammation in Sjögren's disease.

Sjögren's Disease (SjD) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands (LG). The LG produces the protein-rich aqueous component of tears, and SjD-associated autoimmune dacryoadenitis (AD) may thus alter tear autoantibody composition. The presence of tertiary lymphoid structures (TLS) in LG from two murine models of SjD-associated AD, male non-obese diabetic (NOD) and male non-obese insulitis resistant (NOR) mice, were evaluated using immunofluorescence. IgG and IgA reactivity in serum and tears from these models were probed in three studies against a panel of 80-120 autoantigens using autoantibody microarrays relative to serum and tears from healthy male BALB/c mice. Sources of Ig in tears were investigated using scRNA-Seq of the LG (GSE132420). Data were analyzed by R package Limma and Seurat. Analysis of immunofluorescence in LG sections from both SjD models showed TLS. Only one autoantibody was significantly elevated in tears and serum in both SjD models across all studies. Three autoantibodies were significantly elevated in serum but not in tears in both SjD models across all studies. Conversely, six IgG and thirteen IgA autoantibodies (6 sharing the same autoantigen) were significantly elevated in tears but not serum in both SjD models. Igha and Ighg2b expressing cells were identified in the plasma cell cluster of NOD.H2b LG. NOD and NOR mice with SjD-associated AD have distinct autoantibody profiles in tears and serum. Tear IgA isotype autoantibodies showed a greater diversity than tear IgG autoantibodies. TLS observed in LG are a likely source of the tear autoantibodies.

T cell and autoantibody profiling for primary immune regulatory disorders.

Limited clinical tools exist for characterizing primary immune regulatory disorders (PIRD), which are often diagnoses of exclusion. Increased CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cell percentages have been identified as a marker of active disease in some, but not all, autoimmune disorders. To develop a diagnostic approach that combines measurements of cellular and serologic autoimmunity. We recruited 71 controls and 101 pediatric patients with PIRD with autoimmunity. Flow cytometry was used to measure CD4+CXCR5+ T cells expressing the chemokine receptors CXCR3 and/or CCR6. IgG and IgA autoantibodies were quantified in 56 patients and 20 controls using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the controls serves as the upper limit of normal for percentages of cTfh cells, CD4+CXCR5+ T cells expressing CXCR3 and/or CCR6, and autoantibody intensity and number. We found that 27.7% of patients had increased percentages of CD4+CXCR5+PD1+ cTfh cells and 42.5% had increased percentages of CD4+CXCR5+ cells expressing CXCR3 and/or CCR6. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 37.5% had increased numbers of high-titer autoantibodies. Integrating measurements of cTfh cells, CD4+CXCR5+ T cells with CXCR3 and/or CCR6, and numbers of high-titer autoantibodies had 71.4% sensitivity (95% CI: 0.5852 - 0.8158) and 85% specificity (95% CI: 0.6396 - 0.9476) for patients with PIRD compared to controls. By integrating CD4+ T cell phenotyping and total burden of autoantibodies, this approach provides additional tools for the diagnosis of PIRD lacking clinical diagnostic criteria.

Absence of Functional Autoantibodies Targeting Angiotensin II Receptor Type 1 and Endothelin-1 Type A Receptor in Circulation and Purified IgG From Patients With Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. Although previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II receptor type 1 (AT1) and endothelin-1 type A receptor (ETAR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of IgG derived from patients with SSc (SSc IgG) on AT1 and ETAR signaling, the downstream EC response, and the presence of AT1-binding autoantibodies in circulation. Quantitative polymerase chain reaction and cytokine enzyme-linked immunosorbent assay, alongside a real-time cell analyzer, were used to assess receptor-specific functional characteristics of purified SSc IgG (n = 18). Additionally, a novel protein capture assay using solubilized epitope-tagged AT1 was developed to detect AT1-binding autoantibodies in plasma samples from patients with SSc (n = 28) and healthy donors (n = 14). No evidence for EC activation in an AT1- or ETAR-dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation or alter G protein-coupled receptor signaling on agonist stimulation in a model with receptor overexpression. Lastly, no AT1-binding autoantibodies were detected in plasma samples from patients with SSc when using epitope-tagged solubilized AT1. Overall, our study did not provide evidence to support the presence of AT1- or ETAR-activating autoantibodies in purified SSc IgG or AT1-binding autoantibodies in the circulation of patients with SSc.

Novel Meningoencephalomyelitis Associated With Vimentin IgG Autoantibodies

ImportanceAutoantibodies targeting astrocytes, such as those against glial fibrillary acidic protein (GFAP) or aquaporin protein 4, are crucial diagnostic markers for autoimmune astrocytopathy among central nervous system (CNS) autoimmune disorders. However, diagnosis remains challenging for patients lacking specific autoantibodies.ObjectiveTo characterize a syndrome of unknown meningoencephalomyelitis associated with an astrocytic autoantibody.Design, Setting, and ParticipantsThis retrospective case series study included samples collected from April 2021 to May 2024 at a tertiary referral hospital among patients with uncharacterized CNS autoimmune disorders and similar clinical and radiological features. Single-cell RNA sequencing (scRNA-seq) was performed on cerebrospinal fluid (CSF) cells of 2 index patients to identify the putative target antigen of the clonally expanded B cells. A comprehensive screening for additional patients was conducted using blinded cell-based and tissue-based assay. Candidate patients were followed up for a median (range) duration of 23 (5-31) months.ExposuresscRNA-seq, autoantibody characterization, and testing.Main Outcomes and MeasuresDetection of the autoantibody and characterization of the associated autoimmune meningoencephalomyelitis.ResultsFourteen candidate patients (10 [71%] female; median [IQR] age, 33 [23-41] years) were identified. Initially, CSF from 2 female patients with unknown encephalomyelitis showed astrocytic reactivity on rat tissue but was negative for GFAP IgG. A total of 17 of 37 clonally expanded B cell clonotypes (46%) in their CSF expressed IgG autoantibodies targeting the astrocytic intermediate filament protein vimentin. Subsequent screening identified 12 additional patients. These 14 patients shared a unique clinical profile characterized by relapsing courses and symptoms prominently involving the cerebellum, brainstem, and corticospinal tract (CST). All patients also exhibited elevated CSF protein and cells, intrathecal immunoglobulin synthesis, and magnetic resonance imaging (MRI) showing bilateral lesions on CST. Notably, 8 of 12 patients (67%) who received first-line immunotherapy at their first episode responded well. At the last follow-up, 11 patients (79%) experienced significant disability (modified Rankin Scale ≥3).Conclusions and RelevanceIn this case series, autoantibodies targeting the astrocytic intermediate filament protein vimentin were identified in patients with previously undifferentiated meningoencephalomyelitis and common radiographic features.

Autoantibodies against phosphatidylserine and DNA during canine Dirofilaria immitis infection.

Autoantibodies against phosphatidylserine and DNA during canine Dirofilaria immitis infection.

Plasma anti-PRTN3 IgG and IgM autoantibodies: novel biomarkers for early detection of lung adenocarcinoma.

Proteinase 3 (PRTN3) has been recognized as a crucial target for anti-neutrophil cytoplasmic autoantibody. However, the relationship between anti-PRTN3 autoantibody and cancer remains largely unexplored. Immunohistochemistry was used to detect the level of PRTN3 in lung adenocarcinoma (LUAD) tissue array. Enzyme-linked immunosorbent assay was conducted to measure anti-PRTN3 IgG and IgM autoantibodies in plasma from patients with early- and advanced-stage LUAD, benign pulmonary nodules (BPN) and normal control (NC). Western blotting and immunofluorescence staining were performed to confirm the presence of plasma immune response to PRTN3. PRTN3 protein was highly expressed in LUAD tissues. Elevated plasma levels of anti-PRTN3 IgG and IgM autoantibodies were also detected in LUAD, especially in early LUAD. The AUC of anti-PRTN3 IgG autoantibodies in the diagnosis of early LUAD from NC was 0.782, and from BPN was 0.761. When CEA and anti-PRTN3 autoantibodies were combined, the AUC for the diagnosis of early LUAD was significantly higher than that of CEA alone. The presence of a plasma immune response to PRTN3 in LUAD was also confirmed. Anti-PRTN3 IgG and IgM autoantibodies maybe early biomarkers to differentiate LUAD from NC and BPN.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Neonatal Fc Receptor Inhibitor Rozanolixizumab: An Ethnic Sensitivity Study in Healthy Japanese, Chinese, and White Participants.

Rozanolixizumab is an anti-human neonatal Fc receptor humanized immunoglobulin (Ig) G4 monoclonal antibody that reduces IgG, including pathogenic IgG autoantibodies. Rozanolixizumab safety and tolerability have been assessed in previous clinical studies with predominantly White participants. We assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of rozanolixizumab in healthy Japanese and Chinese participants compared with White participants. This double-blind, single-center, UK-based, Phase 1 study randomized 65 participants to rozanolixizumab 4mg/kg (Japanese and White participants only), 7 mg/kg, or 10mg/kg. All treatment-emergent adverse events (TEAEs) were mild to moderate in severity; no severe TEAEs, serious TEAEs, or TEAEs leading to discontinuation occurred. Incidences of TEAEs in Japanese and Chinese participants were comparable to those in White participants. Japanese and Chinese participants had lower systemic rozanolixizumab exposure relative to Caucasian participants, attributable to lower actual doses administered due to lower body weight in Chinese and Japanese participants, indicating that body weight is not a relevant predictor of rozanolixizumab pharmacokinetics. All 3 ethnicities demonstrated dose-dependent IgG reductions, with IgG nadir achieved around Day 10 and gradual return to baseline levels by Day 56. These data support the applicability of safety data from previous clinical studies of rozanolixizumab to individuals of Japanese and Chinese ethnicity.

Investigation of circulating natural autoantibodies against ANXA1 and MYC as potential biomarkers in hepatocellular carcinoma.

Investigation of circulating natural autoantibodies against ANXA1 and MYC as potential biomarkers in hepatocellular carcinoma.

Evaluation of the effectiveness of combined therapy with intravenous immunoglobulin and plasmapheresis in patients with steroid-resistant form of pemphigus based on the cytokine and chemokine profiles assessment

BACKGROUND: Pemphigus is a serious life-threatening disease characterized by the formation of IgG autoantibodies against the cell membranes, leading to the formation of intraepidermal blisters. AIM: To evaluate the effectiveness of combined therapy with intravenous immunoglobulin and plasma exchange for steroid-resistant patients with pemphigus based on the cytokine, chemokine and granulysin profiles investigation. MATERIALS AND METHODS: The group of patients receiving systemic glucocorticoid monotherapy (Group 1; control group) consisted of 26 patients with pemphigus vulgaris. The group of steroid-resistant patients (Group 2; main group) who received combined therapy with systemic glucocorticoid, intravenous immunoglobulin (IVIg), and plasmapheresis included 15 people. The presence of steroid resistance was assessed by Murrell consensus (2008). All pemphigus patients received the initial dose of systemic glucocorticoids of 80–100 mg/day with subsequent slow tapering, according to guidelines. The treatment protocol for combined therapy included four sessions of discrete plasma exchange per week every other day. Immediately after completion of the plasma exchange cycle, IVIg was added to the ongoing treatment, with a total dose of 2 g/kg per cycle. The levels of IL-4, IL-10, IL-15, TNF-α, chemokines CXCL8, CCL11, and granulysin were assessed via ELISA method. RESULTS: We observed some discrepancies in cytokine profiles in both groups of patients. In patients who received combined therapy, there was a statistically significant decrease in the levels of IL-4, IL-15, TNF-α compared to those in patients on systemic glucocorticoid monotherapy ― IL-4, IL-15 TNF-α (p 0.01). Notably, that the level of CCL11 in serum of steroid-resistant patients before the IVIg therapy was significantly higher (Me=51 pg/ml) compared to systemic glucocorticoid monotherapy group (Me=10 pg/ml; p 0.01). The level of granulysin after the treatment with IVIg and plasma exchange in group 2 was also significantly lower (Me=0 ng/ml) compared to the group of control (Me=2700 ng/ml respectively; p 0.01). CONCLUSION: We found a trend towards higher serum levels of IL-4, IL-15, and CCL11 in steroid-resistant pemphigus patients who received combined therapy with IVIg and plasma exchange compared to the control group. Moreover, these cytokines can be considered as the potential biomarkers for refractory disease course, and might be used as therapeutic targets in the future. It should be also noted that the prolonged remission of patients receiving combined therapy with systemic glucocorticoid, IVIg, and plasma exchange, was on average two years.

Circulating Brain-Reactive Autoantibody Profiles in Military Breachers Exposed to Repetitive Occupational Blast

Military breachers are routinely exposed to repetitive low-level blast overpressure, placing them at elevated risk for long-term neurological sequelae. Mounting evidence suggests that circulating brain-reactive autoantibodies, generated following CNS injury, may serve as both biomarkers of cumulative damage and drivers of secondary neuroinflammation. In this study, we compared circulating autoantibody profiles in military breachers (n = 18) with extensive blast exposure against unexposed military controls (n = 19). Using high-sensitivity immunoassays, we quantified IgG and IgM autoantibodies targeting glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and pituitary (PIT) antigens. Breachers exhibited significantly elevated levels of anti-GFAP IgG (p &lt; 0.001) and anti-PIT IgG (p &lt; 0.001) compared to controls, while anti-MBP autoantibody levels remained unchanged. No significant differences were observed for any IgM autoantibody measurements. These patterns suggest that repetitive blast exposure induces a chronic, adaptive immune response rather than a short-lived acute phase. The elevated IgG autoantibodies highlight the vulnerability of astrocytes, myelin, and the hypothalamic–pituitary axis to ongoing immune-mediated injury following repeated blast insults, likely reflecting sustained blood–brain barrier disruption and neuroinflammatory processes. Our findings underscore the potential of CNS-targeted IgG autoantibodies as biomarkers of cumulative brain injury and immune dysregulation in blast-exposed populations. Further research is warranted to validate these markers in larger, more diverse cohorts, and to explore their utility in guiding interventions aimed at mitigating neuroinflammation, neuroendocrine dysfunction, and long-term neurodegenerative risks in military personnel and similarly exposed groups.

A case of glucocorticoid-refractory IgA vasculitis with diffuse alveolar hemorrhage: a therapeutic strategy for aberrant immunoglobulin depletion.

Diffuse alveolar hemorrhage (DAH) is a rare and severe complication of IgA vasculitis (IgAV). Although glucocorticoids and immunosuppressive agents are used for its treatment, there is no consensus on the optimal form of treatment. We herein report the case of a 53-year-old, female patient with IgAV. She was initially resistant to glucocorticoid therapy and experienced acute respiratory failure due to DAH but responded well to rituximab (RTX) and plasma exchange (PLEX). While some previous case reports have suggested that RTX or PLEX can be effective for severe IgAV, there are no reports of a combination of RTX and PLEX being used successfully to treat IgAV-associated DAH. In the model of IgAV pathogenesis proposed herein, aberrant IgA1 and IgA-specific IgG autoantibodies play a pivotal role. PLEX may facilitate the prompt removal of these circulating, aberrant immunoglobulins while RTX inhibits their further production. Consequently, a combination of RTX and PLEX may represent an effective treatment approach for severe glucocorticoid-refractory cases of IgAV.

Targeting the neonatal Fc receptor (FcRn) is not beneficial in an animal model of chronic neuritis

The inhibition of the neonatal Fc receptor (FcRn) is a promising therapeutic pathway in certain autoimmune disorders to reduce the amount of circulating pathogenic IgG autoantibodies by interfering with their recycling system. FcRn antibodies are currently being tested in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). This study aimed to investigate the therapeutic potential of an antibody targeting FcRn in the intracellular adhesion molecule 1 (ICAM1)-deficient NOD mouse—a model representative for many aspects of human CIDP. After the onset of clinical signs of neuropathy, ICAM1-deficient NOD mice were assigned to treatment twice per week with anti-FcRn antibody, isotype control antibody (negative control) or intraperitoneal (administered) immunoglobulin (positive control). Disease severity was monitored using disease-specific assessments for ataxia and paresis such as grip strength measurements. Serum immunoglobulin levels and peripheral nerve immune cell infiltration were quantified. Treatment with anti-FcRn antibody did not ameliorate disease progression, as determined by clinical scores and grip strength analysis. Disease progression was reduced in the positive control animals receiving immunoglobulin. Consistent with the clinical results, the composition of infiltrating immune cells was not altered in the peripheral nerve of anti-FcRn antibody-treated mice compared to controls. However, in anti-FcRn antibody-treated mice, significantly lower IgG levels were detectable compared to controls. These findings suggest that targeting the FcRn recycling system does not influence disease progression in the NOD-ICAM1-deficient mouse model of CIDP. Further studies will elucidate whether the reduction of IgG levels was insufficient to deplete pathogenic autoantibodies or whether the major inflammatory driver in the NOD-ICAM1-deficient mouse animal model is mediated by factors other than pathological immunoglobulins.

Extrarenal manifestations of atypical hemolytic uremic syndrome: a systematic review and meta-analysis.

Atypical Hemolytic Uremic Syndrome (aHUS) is categorized as a thrombotic microangiopathy (TMA), which arises due to abnormal or unregulated complement pathway activation. While the disease frequently affects renal blood vessels, it can also involve multiple other organ systems. This review examines the prevalence and clinical outcomes of aHUS patients with extrarenal involvement. A comprehensive literature search was performed using PubMed/Medline, Embase, the Web of Science Core Collection, and CINAHL. Search terms included 'aHUS', 'extrarenal', and specific organ systems such as neurological, gastrointestinal, and cardiovascular. Patient data was collected on clinical characteristics, including extrarenal symptoms, lab findings, genetic mutations, and adverse events. Meta-analysis was conducted using R software, version 3.1.0. A total of 47 studies were reviewed, comprising 890 aHUS patients, ranging in age from 3 months to 66 years. Common genetic abnormalities included factor H (CFH) mutations, seen in 12% (84/700 patients) across 19 studies, and anti-FH IgG autoantibodies, identified in 27.1% (102/376 patients) from 10 studies. The central nervous system was the most frequently involved extrarenal site [28% (240/858 patients) from 32 studies], with seizures as the predominant CNS symptom. Gastrointestinal symptoms were next most common [31% (230/741 patients) from 25 studies], followed by cardiovascular involvement [16% (97/607) from 23 studies]. Kidney failure was reported in 13.2% (61/463 patients) from 11 studies, with an overall mortality rate of 8.9% (56/632 patients) reported across 27 studies. Around 20-30% of aHUS patients experience extrarenal manifestations, with neurologic symptoms occurring most frequently. Due to the high costs and limited availability, genetic data is rarely reported, and studies are often small, underscoring the need for larger, multi-center cohort studies. 466915. Approximately 20-30% of patients with atypical Hemolytic Uremic Syndrome (aHUS) experienced extrarenal manifestations, with neurologic involvement being the most common. Current studies in aHUS patients are heterogeneous and inconsistent in reporting complement mutations with extrarenal manifestations. This systematic review highlights the significance of multi-system assessment in aHUS patients and the need for larger, multi-centered cohort studies.