ABSTRACT
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease characterised by symmetric polyarthritis o f the small joints o f the hands and feet and the larger appendicular joints. The etiology o f RA is still unknown. Although several features o f autoimmunity are prominent in these patients, the nature o f the antigen(s) driving joint inflammation remains unclear. While the initiation phase o f RA might result from an (auto)antigen-specificT cell response, the perpetuation o f inflammation leading to joint destruction in the late chronic phases o f the disease is a consequence o f complex pathogenetic mechanisms involving aberrant interactions between T cells, macrophages, and synovial fibroblasts. T cells are the most frequently observed inflammatory cell in the rheumatoid joint (1-3). Not all authorities agree that RA is a purely T cell-mediated dis ease; however, an important pathogenetic role o f the T cells has been clearly established. Besides their frequency, the fact that the majority possess both a memory and an activated T cell phenotype, as well as the association o f RA with specific molecules o f the major histocompatibility complex (M H C) class II underscore the central role o f T cells in the pathogenesis o f RA.3,4
Two signals are necessary for a productive T cell stimulation which is required for all T cell-dependent immune processes. The first signal confers specificity and is transduced via th eT cell-surface antigen receptor (TCR) when antigen is properly presented to theT cell by an antigen presenting cell (APC) in the context o f M H C molecules. The very same APC has to provide a second or co-stimulatory signal in order to sustain and enhance T cell activity; otherwise a state o f long-term specific unresponsiveness or anergy is reached. While costimulation can be given by the interaction o f several pairs o f surface molecules between the T cell and the APC, the most important costimulatory signal is produced by the ligation o f the C D 28 molecule present on the surface o f T cells to the B7 family o f molecules [B7-1 (CD80) and/or B7-2 (CD86)] found on the surface o f the professional APC.5’6
The C D 28 molecule and the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or C D 152) have important similarities and perhaps more important differences. They are homologous proteins (31% sequence homology) belonging to the immunoglobulin su perfamily. CTLA-4 shares the same counter-receptors with C D 28 but has up to 100 times higher affinity to C D 80 and C D 86 compared to C D 28.6 While C D 28 is expressed on the surface o f virtually all the resting C D 4+ T cells and on the surface o f 50% o f the resting C D 8+ population, CTLA-4 can be found on the surface o f activated T cells only. Al though some reports have suggested that CTLA-4 has a function similar to that o f C D 28
CTLA-4 in Autoimmune Disease, edited by Flemming Pociot. © 2004 Eurekah.com.
