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Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria.

ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by chronic erosive polyarthritis. A complex interaction between a favorable genetic background, and the presence of a specific immune response against a broad-spectrum of environmental factors seems to play a role in determining susceptibility to RA. Among different pathogens, mycobacteria (including Mycobacterium avium subspecies paratuberculosis, MAP), and Epstein-Barr virus (EBV), have extensively been proposed to promote specific cellular and humoral response in susceptible individuals, by activating pathways linked to RA development. In this review, we discuss the available experimental and clinical evidence on the interplay between mycobacterial and EBV infections, and the development of the immune dysregulation in RA.

SUBMITTER: Bo M

PROVIDER: S-EPMC7598258 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria.

Bo Marco M Jasemi Seyedesomaye S Uras Giuseppe G Erre Gian Luca GL Passiu Giuseppe G Sechi Leonardo A LA

Microorganisms 20200923 10

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by chronic erosive polyarthritis. A complex interaction between a favorable genetic background, and the presence of a specific immune response against a broad-spectrum of environmental factors seems to play a role in determining susceptibility to RA. Among different pathogens, mycobacteria (including Mycobacterium avium subspecies paratuberculosis, MAP), and Epstein-Barr virus (EBV), ...[more]

PMID: 32977590

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Role of Adiponectin in the Pathogenesis of Rheumatoid Arthritis.

Project description:Rheumatoid arthritis (RA) is a systemic chronic inflammatory autoimmune joint disease, characterized by progressive articular damage and joint dysfunction. One of the symptoms of this disease is persistent inflammatory infiltration of the synovial membrane, the principle site of inflammation in RA. In the affected conditions, the cells of the synovial membrane, fibroblast-like synoviocytes and macrophage-like synovial cells, produce enzymes degrading cartilage and underlining bone tissue, as well as cytokines increasing the infiltration of immune cells. In patients with RA, higher levels of adiponectin are measured in the serum and synovial fluid. Adiponectin, a secretory product that is mainly white adipose tissue, is a multifunctional protein with dual anti-inflammatory and pro-inflammatory properties. Several studies underline the fact that adiponectin can play an important pro-inflammatory role in the pathophysiology of RA via stimulating the secretion of inflammatory mediators. This narrative review is devoted to the presentation of recent knowledge on the role played by one of the adipokines produced by adipose tissue-adiponectin-in the pathogenesis of rheumatoid arthritis.

| S-EPMC7662687 | biostudies-literature

The Role of Posttranslational Protein Modifications in Rheumatological Diseases: Focus on Rheumatoid Arthritis.

Project description:The definition of posttranslational modification (PTM) encompasses a wide group of chemical reactions that allow modification and modulation of protein functions. The regulation of PTMs is crucial for the activity and survival of the cells. Dysregulation of PTMs has been observed in several pathological conditions, including rheumatoid arthritis (RA). RA is a systemic autoimmune disease primarily targeting the joints. The three PTMs mainly involved in this disease are glycosylation, citrullination, and carbamylation. Glycosylation is essential for antigen processing and presentation and can modulate immunoglobulin activity. Citrullination of self-antigens is strongly associated with RA, as demonstrated by the presence of antibodies directed to anti-citrullinated proteins in patients' sera. Carbamylation and its dysregulation have been recently associated with RA. Aim of this review is to illustrate the most significant alterations of these PTMs in RA and to evaluate their possible involvement in the pathogenesis of the disease.

| S-EPMC4451265 | biostudies-other

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis.

Project description:Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA.

| S-EPMC7226773 | biostudies-literature

Emerging therapies in rheumatoid arthritis: focus on monoclonal antibodies.

Project description:Advances in the treatment of rheumatoid arthritis (RA) are attributed to several aspects such as new classification criteria enabling early diagnosis and intensive treatment with the application of treat-to-target principles as well as better understanding of the pathogenesis of RA contributing to the development of targeted therapies. However, reaching remission is still not achieved in most patients with RA, which is one of the driving forces behind the continuous development of novel therapies and the optimization of therapeutic strategies. This review will outline several new therapeutic antibodies modulating anti-inflammatory cytokines interleukin (IL)-2 and IL-10 and pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor, fractalkine, and IL-6 that are in various stages of clinical development as well as the progress in manufacturing biotechnologies contributing to the next generation of antibodies and their potential to expand the therapeutic armamentarium for RA. In addition, the fate of unsuccessful therapies including agents targeting IL-15, the IL-20 family, IL-21, chemokine CXCL10, B-cell activating factor (BAFF), and regulatory T (Treg) cells or a novel concept targeting synovial fibroblasts via cadherin-11 will be discussed.

| S-EPMC6719675 | biostudies-literature

Epigenetic Changes in the Pathogenesis of Rheumatoid Arthritis.

Project description:Rheumatoid arthritis (RA) is a systemic autoimmune disease that affects about 1% of the world's population. The etiology of RA remains unknown. It is considered to occur in the presence of genetic and environmental factors. An increasing body of evidence pinpoints that epigenetic modifications play an important role in the regulation of RA pathogenesis. Epigenetics causes heritable phenotype changes that are not determined by changes in the DNA sequence. The major epigenetic mechanisms include DNA methylation, histone proteins modifications and changes in gene expression caused by microRNAs and other non-coding RNAs. These modifications are reversible and could be modulated by diet, drugs, and other environmental factors. Specific changes in DNA methylation, histone modifications and abnormal expression of non-coding RNAs associated with RA have already been identified. This review focuses on the role of these multiple epigenetic factors in the pathogenesis and progression of the disease, not only in synovial fibroblasts, immune cells, but also in the peripheral blood of patients with RA, which clearly shows their high diagnostic potential and promising targets for therapy in the future.

| S-EPMC6587113 | biostudies-literature

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis.

Project description:Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27+ cells and PD-1+ cells per GC in FTH-RA group were significantly higher than those in FTH-MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α-SMA, tenascin-C, and l-caldesmon expression, was significantly increased in the FTH-RA group compared with the FTH-MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH-RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

| S-EPMC9304286 | biostudies-literature

The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis.

Project description:Helper T (Th) cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). It has been revealed that Th17 cells can shift to Th1 cells (i.e., "nonclassic Th1 cells"), which are reported to be more pathogenic than Th17 cells per se. Thus, the association of Th cells in the pathogenesis of autoimmune disease has become more complicated. We recently reported using peripheral blood from untreated and early-onset RA patients that the ratio of CD161+Th1 cells (i.e., Th17-derived Th1 cells to CD161+Th17 cells) is elevated and that levels of interferon-γ (IFNγ)+Th17 cells are inversely correlated with levels of anti-CCP antibodies. Here, we review the plasticity of Th17 cells in the pathogenesis of RA, suggesting possible implications for novel therapies.

| S-EPMC5532575 | biostudies-other

The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: a preliminary study.

Project description:ObjectiveTo examine whether human endogenous retrovirus K10 is associated with autoimmune rheumatic disease.DesignA novel multiplex reverse transcription polymerase chain reaction (RT-PCR) system was developed to investigate HERV-K10 mRNA expression in patients with rheumatoid arthritis.Methods40 patients with rheumatoid arthritis, 17 with osteoarthritis, and 27 healthy individuals were recruited and total RNA was extracted from peripheral blood mononuclear cells (PBMCs) and analysed using multiplex RT-PCR for the level of HERV-K10 gag mRNA expression. Southern blot and DNA sequencing confirmed the authenticity of the PCR products.ResultsUsing the histidyl tRNA synthetase (HtRNAS) gene as a housekeeping gene in the optimised multiplex RT-PCR, a significantly higher level of HERV-K10 gag mRNA expression was found in rheumatoid arthritis than in osteoarthritis (p = 0.01) or in the healthy controls (p = 0.02).ConclusionThere is enhanced mRNA expression of the HERV-K10 gag region in rheumatoid arthritis compared with osteoarthritis or healthy controls. This could contribute to the pathogenesis of rheumatoid arthritis.

| S-EPMC1798125 | biostudies-literature

MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis.

Project description:MicroRNAs (miRNAs) play crucial roles in regulating the transcriptome and development of rheumatoid arthritis (RA). Currently, a comprehensive map illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interactions with terminal cells such as fibroblast-like synoviocytes (FLS), immune-cells, osteoblasts, and osteoclasts are still laking. In this review, we summarize the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA and regulate target genes and pathways, including NF-κB, Fas-FasL, JAK-STAT, and mTOR pathways. We outline how functional genetic variants of miR-499 and miR-146a partly explain susceptibility to RA. By regulating gene expression, miRNAs affect T cell differentiation into diverse cell types, including Th17 and Treg cells, thus constituting promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the opportunity to combine these miRNAs with antibodies to cyclic citrullinated peptide (ACCP) to allow accurate diagnosis and prognosis, particularly for seronegative patients. Furthermore, we review the evidence implicating miRNAs as promising biomarkers of efficiency and response of, and resistance to, disease-modifying anti-rheumatic drugs and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.

| S-EPMC8987113 | biostudies-literature

Differential effects of periodontal microbiome on the rheumatoid factor induction during rheumatoid arthritis pathogenesis.

Project description:Association between exposure to periodontal bacteria and development of autoantibodies related to rheumatoid arthritis (RA) has been widely accepted; however, direct causal relationship between periodontal bacteria and rheumatoid factor (RF) is currently not fully understood. We investigated whether periodontal bacteria could affect RF status. Patients with preclinical, new-onset, or chronic RA underwent periodontal examination, and investigation of subgingival microbiome via 16S rRNA sequencing. Degree of arthritis and RF induction was examined in collagen-induced arthritis (CIA) mice that were orally inoculated with different periodontal bacteria species. Subsequently, single-cell RNA sequencing analysis of the mouse spleen cells was performed. Patients with preclinical RA showed an increased abundance of the Porphyromonadacae family in the subgingival microbiome compared to those with new-onset or chronic RA, despite comparable periodontitis severity among them. Notably, a distinct subgingival microbial community was found between patients with high-positive RF and those with negative or low-positive RF (p=0.022). Oral infections with the periodontal pathogens P. gingivalis and Treponema denticola in CIA mice similarly enhanced arthritis score, but resulted in different levels of RF induction. Genes related to B cell receptor signaling, B cell proliferation, activation, and differentiation, and CD4+ T cell costimulation and cytokine production were involved in the differential induction of RF in mice exposed to different bacteria. In summary, periodontal microbiome might shape RF status by affecting the humoral immune response during RA pathogenesis.

| S-EPMC9668994 | biostudies-literature

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