Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.

Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes

Systemic lupus erythematosus: Diagnosis and clinical management.

Neutrophils in the Tumor Microenvironment

Efforts to understand autoimmunity have been pursued relentlessly for several decades. It has become apparent that the immune system evolved multiple mechanisms for controlling self-reactivity, and defects in one or more of these mechanisms can lead to a breakdown of tolerance. Among the multitude of lesions associated with disease, the most common seem to affect peripheral tolerance rather than central tolerance. The initial trigger for both systemic autoimmune disorders and organ-specific autoimmune disorders probably involves the recognition of self or foreign molecules, especially nucleic acids, by innate sensors. Such recognition, in turn, triggers inflammatory responses and the engagement of previously quiescent autoreactive T cells and B cells. Here we summarize the most prominent autoimmune pathways and identify key issues that require resolution for full understanding of pathogenic autoimmunity.

/pdf/the-multiple-pathways-to-autoimmunity-31v0esv0ow.pdf

The multiple pathways to autoimmunity

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKposTREM2high and MerTKposLYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA

/pdf/distinct-synovial-tissue-macrophage-subsets-regulate-50gh4yz6si.pdf

Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.

Kelley and Firestein's textbook of rheumatology / , Kelley and Firestein's textbook of rheumatology / , کتابخانه دیجیتال دانشگاه علوم پزشکی گلستان

Kelley and Firestein's textbook of rheumatology /

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Kelley and Firestein's textbook of rheumatology /