Developments in the scientific understanding of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is recognized to be an autoimmune disease that causes preclinical systemic abnormalities and eventually leads to synovial inflammation and destruction of the joint architecture. Recently identified genetic risk factors and novel insights from animal models of spontaneous arthritis have lent support to the concept that thymic selection of an autoreactive T-cell repertoire is an important risk factor for this disease. With advancing age, defects in the homeostatic control of the T-cell pool and in the setting of signaling thresholds lead to the accumulation of pro-inflammatory T-effector cell populations and loss of tolerance to neo-antigens, such as citrullinated peptides. As the breakdown of tolerance to modified self-antigens can precede synovitis by decades, repair of homeostatic defects may open a unique window of opportunity for preventive interventions in RA. The end result of RA, destruction of cartilage and bone, appears to be driven by cytokine- and cell contact-induced activation of synoviocytes and monocytic cells, some of which differentiate into tissue-destructive osteoclasts. Targeting mediators involved in this process has greatly improved the management of this chronic inflammatory syndrome.

Figure 1

Shown is a T cell-APC interaction to illustrate biologic pathways involving rheumatoid arthritis-associated genes (indicated in italics). APC, antigen-presenting cell; IKK, IκB kinase; MHC, major histocompatibility complex; NF-κB, nuclear factor-κB; TCR, T-cell receptor; Th, T-helper; TLR, Toll-like receptor; TNFR2, type 2 TNF receptor.

Figure 2

Central and peripheral T-cell selection and differentiation as risk factors for synovial inflammation. HPC, hematopoietic progenitor cells; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 3

Major tissue destructive pathways in the rheumatoid joint. (a) Osteoclast differentiation and (b) fibroblast-like synoviocyte (FLS) proliferation. CX₃CR1, chemokine [C-X₃-C motif] receptor 1; FLS, fibroblast-like synoviocyte; HPC, hematopoietic progenitor cells; ICAM, intercellular adhesion molecule; LFA, lymphocyte function-associated antigen; LT, lymphotoxin; M, macrophage; MHC, major histocompatibility complex; RANKL, receptor activator of nuclear factor-κB ligand; SCF, stem cell factor; TCR, T-cell receptor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.