Beyond conventional care : developing novel therapeutic approaches to combat arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder without a definitive cure. Although RA is driven by systemic autoimmunity, its most pronounced manifestation is organspecific inflammation, particularly synovitis in joints. Persistent synovitis results in progressive joint damage and deformity, ultimately compromising joint function. The etiology of RA is multifaceted, intricately intertwining genetic, environmental, and immunological elements. While autoreactive agents have traditionally been viewed as pathogenic contributors to the development of arthritis, our research, utilizing multiple experimental arthritis models, has pinpointed several pivotal autoreactive mediators, which are surprisingly regulatory.

In study I, we established a cartilage antibody induced arthritis (CAIA) model. The deficiency of Fc gamma receptor (FCGR) 2B enables swift onset of CAIA within a 12-hour time frame, and overrides the resistance arising from complement C5 deficiency. Notably, our results highlight that FCGR3 is essential and sufficient for CAIA development. The role of FCGR4 remains to be further elucidated.

In Study II, we engineered a range of recombinant antibodies targeting the F4 epitope on type-II collagen (COL2). One of these antibodies, denoted R69-4, not only prevented the onset of CAIA, but also effectively suppressed the established disease. Further screening revealed that R69-4 binds to numerous targets in the synovial fluid (SF), including the complement C1q. As a result, R69-4 markedly dampens FCGR3 signaling in SF neutrophils, thereby interrupting neutrophil self-orchestrated recruitment. Given this efficacy, R69-4 emerges as a promising therapeutic candidate for RA, particularly during its acute stage.

In study III, we introduced mutations to the immunodominant T cell epitope of COL2. A mutation resulting in higher affinity to major histocompatibility complex class II (MHC II) confers resistance to collagen-induced arthritis (CIA). However, the absence of either FCGR2B or neutrophil cytosolic factor 1 (NCF1) disrupts this tolerance. In particular, the deficiency of NCF1 leads to a reduction of regulatory T cells (Tregs), and a decrease of autoimmune regulator (AIRE) expression in medullary thymic epithelial cells (mTECs).

In Study IV, we identified a subset of autoreactive B cells that are ubiquitously present across species. These B cells target the C1 epitope on COL2. Transferring these C1 B cells effectively suppressed arthritis of recipient mice in an antigen-specific manner. We further discerned that the suppressive efficacy of C1 B cells stems from the activation of Tregs and the functional integrity of CD72. In RA patients, we noted a reduced frequency of C1 B cells, possibly attributed to their differentiation into plasma cells. Interventions that can reverse this transition may contribute to preventing the onset of RA.