Current state and future directions of basic research in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Despite advances in biologic therapies targeting inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, Janus kinase (JAK), and B cells, many patients do not respond adequately, emphasizing the need for deeper insights into RA pathogenesis. Research highlights the intricate interplay of genetic and epigenetic factors driving immune dysregulation. The breakdown of immune tolerance, often initiated in mucosal sites such as the gut, lung, and oral cavity, promotes the citrullination of antigens, leading to anti-citrullinated protein antibody production and subsequent immune activation. Single-cell and multi-omics approaches have shed light on underexplored immune cell types, such as T peripheral helper cells, CD4+/CD8+ cytotoxic T cells, and autoreactive B cells, broadening the understanding beyond traditionally studied Th17, Th1 cells, macrophages, and fibroblast-like synoviocytes. Future basic research in RA should prioritize elucidating the mechanisms behind peripheral tolerance breakdown, the pathogenesis of seronegative RA, and the molecular pathways driving refractory and recurrent disease. Moreover, leveraging multi-omics approaches to dissect disease heterogeneity will be pivotal for advancing personalized treatment strategies and improving long-term outcomes in RA patients.

Keywords: Anti-citrullinated protein antibody; Disease heterogeneity; Immune dysregulation; Rheumatoid arthritis; Synovial inflammation.

Figure 1

Loss of tolerance to citrullinated antigens at mucosal sites initiates the activation of adaptive immunity. NETs in the gut, lungs, and gingiva lead to increased protein citrullination in the presence of PAD enzymes and calcium. Dendritic cells that phagocytose these citrullinated antigens present them to T cells via HLA-DRB1 molecules containing the shared epitope. The weak binding between the citrullinated antigens and HLA-DRB1 enables T cells to escape the thymic selection, ultimately becoming autoreactive. These autoreactive T cells proliferate and migrate into synovial tissues, where they contribute to the development of synovitis. COPD: chronic obstructive pulmonary disease, NETs: neutrophil extracellular traps, PAD: peptidylarginine deiminase, DCs: dendritic cells, ACPA: anti-citrullinated protein antibodies, CD8⁺ CTL: CD8⁺ cytotoxic T lymphocyte.

Figure 2

Crosstalk among immune cells driving synovial inflammation in the pathogenesis of RA, as illustrated by the research findings discussed in this review. DCs phagocytose citrullinated antigens from the gut, lungs, and gingiva, and transport them to lymph nodes, where they present MHC-associated citrullinated antigens to naive T cells. This interaction activates T cells, prompting their proliferation and differentiation into effector and memory CD4⁺ T cells that migrate to the synovium. CD4⁺ effector T cells, particularly Th1 and Th17 subsets, recognize citrullinated antigens and produce IFN-γ and IL-17, respectively, which activate macrophages and FLSs to release inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Cytotoxic GZMB⁺CD8⁺ T cells exhibit strong cytotoxic activity, while GZMK⁺CD8⁺ T cells have effector T cell transcriptional profiles. ITGA5⁺ FLSs enhance the differentiation of T_PH through TGF-β1 signaling, promoting B cell activation and ACPA production. Neutrophils are recruited to the synovium by IL-8 from activated B cells and IL-17 from Th17 cells, where ACPAs, in combination with inflammatory cytokines, trigger NETosis, further amplifying the inflammatory response. The activation of the NLRC4 inflammasome in CD1c⁺ DCs by dsDNA enhances the production of IL-1β, IL-8, and CCL3, effectively activating Th1 and Th17 cells. This cascade drives synovitis and exacerbates tissue damage, highlighting the complex interplay of immune cells and cytokines in RA pathogenesis. The number following the # within the square brackets represents the reference number. RA: rheumatoid arthritis, DC: dendritic cell, MHC: major histocompatiblity complex, IFN: interferon IL: interleukin, FLSs: fibroblast-like synoviocytes, TNF: tumor necrosis factor, GZMB: granzyme B, T_PH: T peripheral helper cell, ACPA: anti-citrullinated protein antibody, NLRC4: NOD-like receptor family caspase activation and recruitment domain containing 4, dsDNA: double strand deoxyribonucleic acid, CD8⁺ CTL: CD8⁺ cytotoxic T lymphocyte, PFN: perforin, GZMK: granzyme K, MMP: matrix metalloproteinase, PB: plasmablast, NETs: neutrophil extracellular traps.