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Understanding the interplay between genetic risk factors and molecular pathways in rheumatoid arthritis (RA) is essential for developing effective treatments. This study aims to utilize genetic risk factors of RA and identify their key pathways and potential therapeutic targets through an integrated multi-omics approach. We developed a computational pipeline to construct a knowledge graph that combines genetic risk factor molecular networks with multi-omics enrichment analysis to estimate potential therapeutic target for RA. Genetic risk factors were extracted from the literature, curated, and annotated. Molecular interaction networks were constructed based on these genetic risk factors and their neighboring proteins. Enrichment analysis was performed to identify significantly impacted biological processes and pathways. Multi-omics knowledge graph was used to prioritize candidates potential therapeutic target for RA. Our analysis identified 35 significant genes associated with RA as potential therapeutic targets and biomarkers, categorized into three pathways: Cytokine Regulation and Production, Hematopoietic or Lymphoid Organ Development, and Myeloid Cell Differentiation. Among these, 25 genes were classified as risk genes, while 10 were neighboring genes. We identified nine novel risk proteins (RELA, ETS1, NFATC1, BATF, LCK, PIK3R1, PRKCB, RASGRP1,and FYN) as potential therapeutic targets for RA and they significantly contribute in the disease pathogenesis. This study provides a comprehensive integrative molecular network and knowledge graph analysis of genetic risk factors in RA, offering a solid framework for integrating multi-omics data in RA research. These findings may contribute to more accurate clinical decision-making and the development of targeted treatment regimens. Additionally, this study highlights the importance of inferring hidden relationships across networks based on disease associations and functional similarities, further enhancing our understanding of RA pathogenesis.

Reactive arthritis (ReA) is a form of sterile arthritis that occurs secondary to an extra-articular infection in genetically predisposed individuals. The extra-articular infection is typically an infection of the gastrointestinal tract or genitourinary tract. Infection-related arthritis is a sterile arthritis associated with streptococcal tonsillitis, extra-articular tuberculosis, or intravesical instillation of bacillus Calmette–Guérin (iBCG) therapy for bladder cancer. These infection-related arthritis diagnoses are often grouped with ReA based on the pathogenic mechanism. However, the unique characteristics of these entities may be masked by a group classification. Therefore, we reviewed the clinical characteristics of classic ReA, poststreptococcal ReA, Poncet’s disease, and iBCG-induced ReA. Considering the diversity in triggering microbes, infection sites, and frequency of HLA-B27, these are different disorders. However, the clinical symptoms and intracellular parasitism pathogenic mechanism among classic ReA and infection-related arthritis entities are similar. Therefore, poststreptococcal ReA, Poncet’s disease, and iBCG-induced ReA could be included in the expanding spectrum of ReA, especially based on the pathogenic mechanism.

Mixed connective tissue disease (MCTD) predominantly affects women in their reproductive age (30–40 years). This study is aimed to analyze a case series of MCTD-complicated pregnancies. The study design utilized a combined case-series and case–control approach. Pregnant women with MCTD were included and categorized into two groups: the live-birth and non-live birth (encompassing miscarriages at <12 weeks and stillbirths at ≥12 weeks) groups. Primary outcomes included delivery outcomes and factors associated with live births. A total of 57 pregnancies from 34 mothers (median age: 33.0 years) were included. Regarding delivery outcomes, the rates for live birth, miscarriage, and stillbirth were 64.9, 29.8, and 5.3%, respectively. Additionally, the respective rates of preterm delivery, fetal growth restriction (FGR), and small-for-gestational-age (SGA) were 18.9, 18.9, and 27.0%. Higher steroid usage (62.2 vs. 30.0%, p = 0.02) and lower prednisolone dosage in the live birth group (median dose: 7 vs. 10 mg, p = 0.03) were found to be significant factors contributing to live births. MCTD during pregnancy was associated with increased risks of miscarriage, stillbirth, preterm delivery, FGR, and SGA. Notably, low-dose steroid therapy was identified as a contributing factor to successful live births.

Background Interferon-α (IFN-α) is increased and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main producer of IFN-α, but their IFN-α producing capacity has been shown to be unchanged or reduced when stimulated with a Toll-like receptor 9 (TLR9) agonist in patients with SLE compared to in healthy individuals. In this study, we investigated the IFN-α-producing capacity of lupus pDCs under different stimulation. Methods pDCs from patients with SLE and healthy controls (HC) were stimulated with TLR9 or TLR7 agonist, and their IFN-α producing capacity was examined by intracellular cytokine staining and flow cytometry. The correlation of IFN-α-producing capacity with serum IFN-α levels and disease activity was assessed. The effect of in vitro IFN-α exposure on IFN-α production by pDCs was examined. Localization of TLR7 in cellular compartments in pDCs was investigated. Results The IFN-α producing capacity of pDCs was reduced after TLR9 stimulation, but increased when stimulated with a TLR7 agonist in SLE compared to in HC. IFN-α production by pDCs upon TLR9 stimulation was reduced and the percentage of IFN-α + pDC was inversely correlated with disease activity and serum IFN-α levels. However, the TLR7 agonist-induced IFN-α producing capacity of lupus pDCs was enhanced and correlated with disease activity and serum IFN-α. Exposure to IFN-α enhanced IFN-α production of TLR7-stimulated pDCs, but reduced that of pDCs activated with a TLR9 agonist. TLR7 localization was increased in late endosome/lysosome compartments in pDCs from SLE patients. Conclusions These findings indicate that enhanced TLR7 responses of lupus pDCs, owing to TLR7 retention in late endosome/lysosome and exposure to IFN-α, are associated with the pathogenesis of SLE.

IgG4-related disease (IgG4-RD) was recently described in Japan. It is characterised by extensive organ involvement with tissue fibrosis. We assessed the performance of the 2019 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification criteria and the 2020 revised comprehensive diagnostic (RCD) criteria as well as differences between patients with and without IgG4-RD. In this retrospective, single-centre study of 50 patients admitted with suspected IgG4-RD, we evaluated the sensitivity and specificity of both criteria. We also compared clinical characteristics and laboratory data of patients with IgG4-RD (n = 42) and patients without IgG4-RD (n = 8). The ACR/EULAR classification criteria had 88.1% sensitivity and 87.5% specificity for IgG4-RD diagnosis. The RCD criteria had 100% sensitivity and 50% specificity. Patients with IgG4-RD had significantly more affected organs (p = 0.002). Patients with a single affected organ and IgG4-RD had significantly higher serum IgG4/IgG ratios (p = 0.027), lower serum C-reactive protein levels (p = 0.020), and lower total haemolytic complement activity (p = 0.044) than those without IgG4-RD. The ACR/EULAR classification criteria have high specificity and the RCD criteria have high sensitivity for diagnosing IgG4-RD. The number of affected organs is important for diagnosing IgG4-RD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced adaptive responses have been well investigated. However, the effects of sex, age, and ethnic background on the immune responses elicited by the mRNA vaccine remain unclear. Here, we performed comprehensive analyses of adaptive immune responses elicited by the SARS-CoV-2 mRNA vaccine. Vaccine-induced antibody and T cell responses declined over time but persisted after 3 months, and switched memory B cells were even increased. Spike-specific CD4 + T and CD8 + T cell responses were decreased against the B.1.351 variant, but not against B.1.1.7. Interestingly, T cell reactivity against B.1.617.1 and B.1.617.2 variants was decreased in individuals carrying HLA-A24, suggesting adaptive immune responses against variants are influenced by different HLA haplotypes. T follicular helper cell responses declined with increasing age in both sexes, but age-related decreases in antibody levels were observed only in males, and this was associated with the decline of T peripheral helper cell responses. In contrast, vaccine-induced CD8 + T cell responses were enhanced in older males. Taken together, these findings highlight that significant differences in the reactogenicity of the adaptive immune system elicited by mRNA vaccine were related to factors including sex, age, and ethnic background.

Belimumab, a fully humanized B cell-activating factor (BAFF)-targeting monoclonal antibody, inhibits autoreactive B cell survival and improves systemic lupus erythematosus (SLE) clinical outcomes. However, its administration criteria remain unclear. To establish a basis for defining these criteria, we characterized the immune cell subpopulation alterations post-belimumab treatment and elucidated the underlying mechanisms. We hypothesized that belimumab modulates specific cell subsets and investigated the post-therapy changes. Flow cytometry and correlation analysis revealed that the frequency of B- and T-lymphocyte attenuator (BTLA)high memory B cells in peripheral blood and clinical improvement after belimumab treatment. Western blotting analysis of healthy control B cells revealed that BTLA engagement suppressed Bruton tyrosine kinase and phospholipase C-gamma 2 phosphorylation, which was enhanced by B cell and BAFF receptor co-stimulation. BTLA-expressing memory B cells, which positively correlate with disease improvement, possibly contributed to SLE improvement via BTLA-mediated signaling that attenuated B cell- and BAFF receptor-induced intracellular pathways. To validate these findings, we plan to further assess the effects of belimumab on BTLA expression and B cell signaling pathways in treatment-naive patients with SLE by western blotting. Collectively, our results provide a novel foundation for establish appropriate belimumab administration criteria.

Longitudinal studies have revealed large interindividual differences in antibody responses induced by SARS-CoV-2 mRNA vaccines. Thus, we performed a comprehensive analysis of adaptive immune responses induced by three doses of the BNT162b2 SARS-CoV-2 mRNA vaccines. The responses of spike-specific CD4 + T cells, CD8 + T cells and serum IgG, and the serum neutralization capacities induced by the two vaccines declined 6 months later. The 3 rd dose increased serum spike IgG and neutralizing capacities against the wild-type and Omicron spikes to higher levels than the 2 nd dose, and this was supported by memory B cell responses, which gradually increased after the 2 nd dose and were further enhanced by the 3 rd dose. The 3 rd dose moderately increased the frequencies of spike-specific CD4 + T cells, but the frequencies of spike-specific CD8 + T cells remained unchanged. T cells reactive against the Omicron spike were 1.3-fold fewer than those against the wild-type spike. The early responsiveness of spike-specific CD4 + T, circulating T follicular helper cells and circulating T peripheral helper cells correlated with memory B cell responses to the booster vaccination, and early spike-specific CD4 + T cell responses were also associated with spike-specific CD8 + T cell responses. These findings highlight the importance of evaluating cellular responses to optimize future vaccine strategies.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6C low patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.

To evaluate the radiological differences between diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) using whole spine computed tomography (CT), including the spine and sacroiliac joint (SIJ). The ossification and bridging of spinal ligament and fusion of the facet joint and SIJ were evaluated in 111 patients who were diagnosed with DISH and 27 patients with AS on the whole spine CT. The number of anterior bridging and shape of bridging (candle-wax-type/ smooth-type) were also evaluated. We further evaluated patients with DISH and AS by matching their age and sex. Complete SIJ fusion was more common in AS, whereas anterior and posterior bony bridging around SIJ was more common in DISH. However, 63% of patients with DISH had a partial or complete fusion. In spinal anterior bony bridging, the majority of patients with AS had the smooth-type, whereas those with DISH had the candle-wax-type. However, some of the patients with DISH (11%) had smooth-type. Intervertebral facet joint fusion is more common in AS. The number of anterior spinal bony bridging was greater in AS than in DISH, especially in the lumbar spine. These results are useful in differentiating DISH from AS and should therefore be considered when making a diagnosis.