Immunological Medicine最新文献

We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

Interleukin-1, a pro-inflammatory cytokine, plays a crucial role in inflammatory disease pathogenesis. Interleukin-1 receptor antagonist knockout (IL-1Ra KO) mice spontaneously develop aortitis, arthritis and dermatitis, and are employed as a model for human inflammatory diseases. Previous studies have shown that transferring total T cells from IL-1Ra KO mice into nude mice induces aortitis and arthritis; however, the roles of specific T cell subsets in these inflammatory responses remain unclear. In this study, we aimed to investigate the T cell subsets in IL-1Ra KO mice. We found that the proportion of PD-1+CD44+CD62L-CD4+ T cells in the spleen and lymph nodes of IL-1Ra KO mice was significantly higher than that of wild type mice. RNA sequencing revealed elevated expression of basic helix-loop-helix family member e40 and granulocyte macrophage colony stimulating factor (GM-CSF) in splenic CD44+CD62L-CD4+ T cells from IL-1Ra KO mice. In addition, GM-CSF production from splenic CD4+ T cells of IL-1Ra KO mice was significantly higher than that of wild type mice when stimulated with PMA and ionomycin in vitro. Notably, immunohistochemical staining showed infiltration of GM-CSF+CD4+ T cells at inflammatory sites in IL-1Ra KO mice. Our results suggest that a subset of GM-CSF+CD4 + T cells emerges under IL-1 signal-enhanced inflammatory conditions.

We sought to clarify the musculoskeletal ultrasound (MSUS) findings and serum concentrations of cytokines/growth factors in glucocorticoid-resistant polymyalgia rheumatica (GC-R PMR). Patients with PMR admitted to Nagasaki University Hospital (n = 41) were enrolled. MSUS of both shoulder joints was performed in 36 patients. Patients' sera were analyzed for cytokines/growth factors using multiplex assay kits. We examined the cases of 17 males and 24 females (median age 70 years). There were 27 GC-R patients and 14 non-GC-R patients. PD signals were detected in significantly more GC-R patients (65.2%) than non-GC-R patients (23.1%) (p = 0.035). The median serum level of vascular endothelial growth factor (VEGF) was significantly higher in the GC-R group at 871.4 pg/mL than the non-GC-R group (422.8 pg/mL) (p = 0.03) and significantly higher in the PD-positive versus PD-negative patients (p = 0.04). A multivariate analysis revealed that a high serum VEGF level was an independent variable contributing to GC resistance (p = 0.017, odds ratio: 10.34). These results suggest that a high serum VEGF level is a biomarker of GC resistance in PMR, which might be explained by PD-positive neovascularization in inflamed joints of PMR.

In recent years, various myositis-specific and myositis-associated autoantibodies have been identified in idiopathic inflammatory myopathies, including dermatomyositis (DM), anti-synthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). These autoantibodies exhibit unique characteristics in terms of organ involvement, severity, and treatment response, making their understanding crucial for accurate diagnosis and effective therapy. This review provides a comprehensive overview of the clinical features of recently discovered myositis-specific and associated autoantibodies, while exploring their potential roles in the pathogenesis and exacerbation of myositis. Key findings include the production of anti-TIF1γ antibodies in model mice, the upregulation of Mi2-related genes in anti-Mi2 antibody-positive dermatomyositis muscle tissue, and Jo-1 antigen-induced T cell activation, shedding light on whether disease mechanisms are driven by autoantibodies or autoantigens.

Anti-aminoacyl-tRNA synthetase (ARS) antibodies are myositis-specific antibodies associated with anti-synthetase syndrome (ASSD). Some patients are positive for anti-ARS antibodies on enzyme-linked immunosorbent assay (ELISA) but negative on RNA-immunoprecipitation (RNA-IP) (the gold standard method). Whether these patients should be considered truly positive for anti-ARS antibodies remains unclear. Therefore, we investigated the clinical characteristics of these patients and verified the authenticity of their anti-ARS positivity. Patients who were positive for anti-ARS antibodies on ELISA were divided into the non-discrepant (positive on RNA-IP, n = 52) and discrepant (negative on RNA-IP, n = 8) groups. Patient clinical characteristics were compared between the groups. For each positive individual, the authenticity of anti-ARS antibody positivity on ELISA was cross-examined using protein-IP and western blotting. All patients in the discrepant group had lung involvement, including five (63%) with interstitial lung disease. The overall survival time was significantly lower in the discrepant group than in the non-discrepant group (p < 0.05). Validation tests confirmed the presence of anti-ARS antibodies in the sera of the discrepant group but indicated different reactivity from typical anti-ARS antibodies. In conclusion, some anti-ARS antibodies are detected by ELISA but not RNA-IP. Such anti-ARS antibody discrepancies need further elucidation to attain validation of the diagnostic process in ASSD.

The detection of variants of unknown significance (VUS) in familial Mediterranean fever (FMF) is common; however, their diagnostic value remains elusive, and the interpretation of multiple VUS remains difficult. Therefore, we examined FMF diagnosis-associated factors 1-year post-genetic testing in patients with only VUS and assessed the impact of multiple VUS on diagnosis and clinical features. A 1-year follow-up was conducted on patients clinically suspected of having FMF without confirmatory diagnosis owing to the presence of only VUS. Clinical features were compared between patients with a single VUS and those with multiple VUS among patients diagnosed with FMF. Among 261 patients followed up, 202 were diagnosed with FMF based on clinical judgment. No specific clinical symptoms or variant patterns at genetic testing were associated with diagnosis at 1 year. Multiple VUS was significantly and independently associated with a lower response to colchicine than single VUS among patients diagnosed with FMF. However, clinical symptoms showed no correlation with the number of VUS. In conclusion, predicting FMF diagnosis 1-year post-genetic testing in patients with only VUS remains challenging. Moreover, the impact of multiple VUS on FMF may be limited owing to the lack of correlation with clinical features, except colchicine response.

'No evidence of disease activity (NEDA)', judged by clinical and radiological findings, is a therapeutic goal in patients with multiple sclerosis (MS). It is, however, unclear if distinct biological mechanisms contribute to the maintenance of NEDA. To clarify the immunological background of long-term disease stability defined by NEDA, circulating immune cell subsets in patients with relapsing-remitting MS (RRMS) were analyzed using flow cytometry. Patients showing long-term NEDA (n = 31) had significantly higher frequencies of non-classical monocytes (NCMs) (6.1% vs 1.4%) and activated regulatory T cells (Tregs; 2.1% vs 1.6%) than those with evidence of disease activity (n = 8). The NCM frequency and NCMs to classical monocytes ratio (NCM/CM) positively correlated with activated Treg frequency and duration of NEDA. Co-culture assays demonstrated that NCMs could increase the frequency of activated Tregs and the expression of PD-L1, contributing to development of Tregs, was particularly high in NCMs from patients with NEDA. Collectively, NCMs contribute to stable remission in patients with RRMS, possibly by increasing activated Treg frequency. In addition, the NCM frequency and NCM/CM ratio had high predictive values for disease stability (AUC = 0.97 and 0.94, respectively), suggesting these markers are potential predictors of a long-term NEDA status in RRMS.

B cells that produce anti-aquaporin-4 (AQP4) antibodies play a crucial role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis. We previously reported that naïve B (NB) cells from patients with NMOSD, unlike those from healthy controls, exhibit transcriptional changes suggesting the adoption of an antibody-secreting cell (ASCs) phenotype. CD25⁺ NB cells, whose numbers are increased in NMOSD patients, have a greater capacity to differentiate into ASCs than do CD25^- NB cells. Here, we attempted to establish novel B cell subset cell lines from patients with NMOSD to enable molecular analysis of their abnormalities. We generated Epstein-Barr virus-immortalized lymphoblastoid cell lines (LCLs) from CD25⁺ NB, CD25^- NB, and switched memory B (SMB) cells. All LCLs largely maintained the features of the original cell type in terms of cell surface marker expression and could differentiate into ASCs. Notably, CD25⁺ NB-LCLs derived from patients with NMOSD exhibited a greater capacity to differentiate into SMB-LCLs than did CD25^- NB-LCLs derived from patients with NMOSD, suggesting that the established LCLs maintained the characteristics of cells isolated from patients. The LCLs established in this study are likely to be useful for elucidating the mechanism by which cells that produce anti-AQP4 antibodies develop in NMOSD.

Recent single-cell RNA-sequencing analysis of rheumatoid arthritis (RA) synovial tissues revealed the heterogeneity of RA synovial fibroblasts (SFs) with distinct functions such as high IL-6 production. The molecular mechanisms responsible for high IL-6 production will become a promising drug target of RASFs to treat RA. In this study, we performed siRNA screening of 65 transcription factors (TFs) differentially expressed among RASF subsets to identify TFs involved in IL-6 production. The siRNA screening identified 7 TFs including ARID5B, a RA risk gene, that affected IL-6 production. Both long and short isoforms of ARID5B were expressed and negatively regulated by TNF-α in RASFs. The siRNA knockdown and lentiviral overexpression of long and short isoforms of ARID5B revealed that the long isoform suppressed IL-6 production stimulated with TNF-α. eQTL analysis using 58 SFs demonstrated that RA risk allele, rs10821944, in intron 4 of the ARID5B gene had a trend of eQTL effects to the expression of long isoform of ARID5B in SFs treated with TNF-α. ARID5B was found to be a negative modulator of IL-6 production in RASFs. The RA risk allele of ARID5B intron may cause high IL-6 production, suggesting that ARID5B will become a promising drug target to treat RA.

In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively.