Molecular Mechanisms of Rheumatoid Arthritis Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes

Abstract

The immune system is a highly organized defense system, which recognizes invading microorganisms and aims to exclude them. In order to do this effectively and safely, the immune system must distinguish between selfand non-self-antigens, and be tolerant of self-antigens. Autoimmune diseases develop through the breakdown of self-tolerance, as a result of immune deregulation. This is caused by the combined influence of genetic and environmental factors, including infectious microorganisms. Rheumatoid arthritis (RA) is a systemic autoimmune disease, characterized by synovial hyperplasia leading to the destruction of bones and joints. This severely impairs the life of patients. RA is a relatively common autoimmune disease, occurring in approximately 1% of the population. However, its etiology and pathophysiology are not completely understood. The incidence of RA is correlated with certain human leukocyte antigen (HLA)-DR haplotypes, and the production of autoantibodies such as rheumatoid factor and anticitrullinated protein autoantibody. Thus, the involvement of the deregulated immune system is strongly implicated. Various molecules, including type II collagen, gp39, citrullinated peptides, and glucose-6phosphoisomerase, have been reported as potential pathogenic autoantigens. However, their involvement explains only a proportion of RA cases. Autoantigens are abundant in the body and, theoretically, the immune response to them continues indefinitely. Thus, systemic autoimmune diseases exhibit the characteristics of chronic inflammation. In the pathological condition of RA, the joints are infiltrated with T cells, B cells, macrophages, and plasma cells, all of which are characteristic chronic inflammation cells driven by the immune system. Recently, Th17, a novel helper T-cell subset producing interleukin (IL)-17, has been recognized as a pivotal player in the local inflammation driven by acquired immunity. In addition to immune-competent cells, there is accumulating evidence for abnormalities in non-hematopoietic cells, especially fibroblast-like synoviocytes (FLSs) (Bartok & Firestein, 2010; Firestein, 2009; Mor et al., 2005; Pap & Gay, 2009). The cartilage and bone are destroyed by the invasion of pannus, which is formed from proliferating FLSs and multi-nucleated osteoclasts. Osteoclasts are specialized to resolve bone, and play a major role in bone destruction in RA. However, there is strong evidence that FLSs themselves are aggressive enough to destroy bone. When cultured FLSs derived from RA or osteoarthritis (OA) were co-implanted with human cartilage under the renal