Rheumatoid Arthritis: Pathogenic Roles of Diverse Immune Cells

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated with synovial tissue proliferation, pannus formation, cartilage destruction, and systemic complications. Currently, advanced understandings of the pathologic mechanisms of autoreactive CD4+ T cells, B cells, macrophages, inflammatory cytokines, chemokines, and autoantibodies that cause RA have been achieved, despite the fact that much remains to be elucidated. This review provides an updated pathogenesis of RA which will unveil novel therapeutic targets.

Associations between Sjögren Syndrome, Sociodemographic Factors, Comorbid Conditions, and Scleritis in a Taiwanese Population-Based Study

This nationwide, population-based, retrospective, matched case–control study included 111,960 newly diagnosed patients with scleritis who were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification code 379.0, selected from the Taiwan National Health Insurance Research Database. Demographic characteristics, Sjögren syndrome, and comorbid conditions within 1 year before the scleritis diagnosis were examined using univariate logistic regression analyses, and a paired t-test was used for continuous variables. Adjusted logistic regression was used to compare the prognosis odds ratio (OR) of the patients with scleritis with the controls. After adjustment for confounders, patients with Sjögren syndrome were remarkably more likely to have scleritis than the controls (OR = 33.53, 95% confidence interval (CI) = 27.43–40.97, p < 0.001). Other conditions found to have increased odds of scleritis included post ocular pterygium, glaucoma, and scleral surgery (OR = 4.01, 95% CI = 3.64–4.43; OR = 3.16, 95% CI = 2.24–4.47; OR = 6.83, 95% CI = 5.34–8.74, respectively); systemic infections, such as syphilis, tuberculosis, and a human herpes viral infection (OR = 4.01, 95% CI = 2.93–5.50; OR = 2.24, 95% CI = 1.94–2.58; OR = 8.54, 95% CI = 8.07–9.03, respectively); and systemic diseases, such as rheumatoid arthritis, granulomatous vasculitis, systemic lupus erythematosus, ankylosing spondylitis, and gout (OR = 2.93, 95% CI = 2.66–3.23; OR = 7.37, 95% CI = 3.91–13.88; OR = 3.18, 95% CI = 2.63–3.85; OR = 5.57, 95% CI = 4.99–6.22; OR = 2.84, 95% CI = 2.72–2.96, respectively). The results strongly support an association between Sjögren syndrome, post ocular surgery, systemic infection disease, systemic autoimmune disease, and scleritis.

Exposure to silicates and systemic autoimmune-related outcomes in rodents: a systematic review

Background Autoimmunity can result from the interplay between genetic background and effects of environmental and/or occupational exposure to hazardous materials. Several compounds, including silica dust, have been linked with systemic autoimmunity and systemic autoimmune diseases, based on epidemiological evidence. For asbestos, a strong link with systemic autoimmune diseases does not yet exist, however, several studies have documented features of autoimmunity following asbestos exposure. Even so, human studies are limited in their ability to identify and examine isolated exposures, making it difficult to demonstrate causation or to assess pathogenic mechanisms. Therefore, this systematic review examines the existing animal evidence regarding autoimmunity and exposure to silicates (silica and asbestos). Methods PubMed and EMBASE were systematically searched for peer-reviewed studies examining systemic autoimmune disease-related outcomes after silicate exposure in rodents. Literature databases were searched up to September 2021 for studies written in English and where the full text was available. Search strings were established based on a PECO (Population, Exposure, Comparator, Outcome) format. After title, abstract, and full-text screening, thirty-four studies were identified for further analysis. Quality assessment through ToxR tool and qualitative analysis of the results was performed. Results Although there was significant heterogeneity in the included studies in terms of exposure protocol and genetic background of the rodent models used, it was noted that both genetic background and exposure to silicates [(crystalline) silica and asbestos] are highly relevant to the development of (sub-) clinical systemic autoimmune disease. Conclusion Parallels were observed between the findings from the animal (this review) and human (epidemiological) studies, arguing that experimental animal models are valuable tools for examining exacerbation or development of autoimmune disease after silicate exposure. However, genetic background and synergism between exposures should be considered in future studies.

Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants

Objective Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000–200,000 worldwide and 1/6500–9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families. Methods We sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents. Results In total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison’s disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents. Conclusion Here, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.

miR-653-5p suppresses the viability and migration of fibroblast-like synoviocytes by targeting FGF2 and inactivation of the Wnt/beta-catenin pathway

Background Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Several studies reported that fibroblast-like synoviocytes (FLSs) and miRNAs are associated with RA pathogenesis. This study explored the function of miR-653-5p in the regulation of human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA) cells. Methods The mRNA and protein levels of genes were measured by RT-qPCR and western blot, respectively. MTT, wound healing, and invasion assays were used to evaluate the viability and metastasis of FLSs. Luciferase reporter and RNA pull-down assays were employed to determine the interaction between miR-653-5p and FGF2. Results RT-qPCR results demonstrated that miR-653-5p expression was decreased and FGF2 level was increased in synovial tissues and FLSs of RA. Moreover, the viability and metastasis of FLSs were accelerated by miR-653-5p addition, which was restrained by miR-653-5p suppression. Furthermore, we demonstrated that levels of Rac1, Cdc42, and RhoA were decreased after miR-653-5p addition. Besides, luciferase reporter and RNA pull-down assays implied that miR-653-5p targeted the 3′-UTR of FGF2. Functional assays showed that FGF2 overexpression neutralized the suppressive effects of miR-653-5p addition on HFLS-RA cell viability, metastasis, and the levels of Rho family proteins. Meanwhile, the levels of β-catenin, cyclin D1, and c-myc were declined by miR-653-5p supplementation, but enhanced by FGF2 addition. Conclusion In sum, we manifested that miR-653-5p restrained HFLS-RA cell viability and metastasis via targeting FGF2 and repressing the Wnt/beta-Catenin pathway.

B Lineage Cells in ANCA-Associated Vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that affects small sized blood vessels and can lead to serious complications in the lungs and kidneys. The prominent presence of ANCA autoantibodies in this disease implicates B cells in its pathogenesis, as these are the precursors of the ANCA-producing plasma cells (PCs). Further evidence supporting the potential role of B lineage cells in vasculitis are the increased B cell cytokine levels and the dysregulated B cell populations in patients. Confirmation of the contribution of B cells to pathology arose from the beneficial effect of anti-CD20 therapy (i.e., rituximab) in AAV patients. These anti-CD20 antibodies deplete circulating B cells, which results in amelioration of disease. However, not all patients respond completely, and this treatment does not target PCs, which can maintain ANCA production. Hence, it is important to develop more specific therapies for AAV patients. Intracellular signalling pathways may be potential therapeutic targets as they can show (disease-specific) alterations in certain B lineage cells, including pathogenic B cells, and contribute to differentiation and survival of PCs. Preliminary data on the inhibition of certain signalling molecules downstream of receptors specific for B lineage cells show promising therapeutic effects. In this narrative review, B cell specific receptors and their downstream signalling molecules that may contribute to pathology in AAV are discussed, including the potential to therapeutically target these pathways.

Rheumatoid Arthritis Diagnosis: Deep Learning vs. Humane

Rheumatoid arthritis (RA) is a systemic autoimmune disease that preferably affects small joints. As the well-timed diagnosis of the disease is essential for the treatment of the patient, several works have been conducted in the field of deep learning to develop fast and accurate automatic methods for RA diagnosis. These works mainly focus on medical images as they use X-ray and ultrasound images as input for their models. In this study, we review the conducted works and compare the methods that use deep learning with the procedure that is commonly followed by a medical doctor for the RA diagnosis. The results show that 93% of the works use only image modalities as input for the models as distinct from the medical procedure where more patient medical data are taken into account. Moreover, only 15% of the works use direct explainability methods, meaning that the efforts for solving the trustworthiness issue of deep learning models were limited. In this context, this work reveals the gap between the deep learning approaches and the medical doctors’ practices traditionally applied and brings to light the weaknesses of the current deep learning technology to be integrated into a trustworthy context inside the existed medical infrastructures.

Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.