PATHOGENESIS OF RHEUMATOID ARTHRITIS: The Role of T Cells and Other Beasts

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The pathogenesis of rheumatoid arthritis (RA) is a complex phenomenon, which is not yet fully understood. This review is based on the hypothesis that RA is a disease driven by T cells after an unknown initiating event. The persistent inflammation is maintained by autoantigens. In common with other autoimmune diseases, it is likely that early in the course of RA, the antigen drive may be dependent on a single or a few autoantigens. Later in the disease, however, it is likely that there is epitope and antigen spreading so that a potentially large number of autoantigens may be involved. This may be the explanation for the enlarging list of autoantigens as reviewed by Blass and colleagues.10 We have recently shown that BiP, the endoplasmic reticulum glucose-regulated (GRP78) chaperone, preferentially stimulated T cells from the synovial fluids of patients with RA.84 Blass and colleagues10 have also described this antigen as a protein of 68 kd. The fact that two groups have independently identified BiP as an RA autoantigen and its disease and tissue specificity suggest that BiP may be an important autoantigen in RA. The increasing number of putative autoantigens may be a blessing in disguise, as it may provide a number of candidate proteins, or peptides derived from them, that could be used in immunotherapy.

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CHRONIC INFLAMMATION IN THE RHEUMATOID ARTHRITIS SYNOVIUM: REGULATION OF T-CELL FUNCTION

RA synovitis is characterized by new blood vessel formation, thickening of the lining layer, and an inflammatory infiltrate constituted mainly of mononuclear cells consisting of strongly human leukocyte antigen (HLA)-DR–positive antigen-presenting cells (APCs) in close contact with T lymphocytes, most of which express the helper/memory phenotype (CD4+CD45R0+) and belong to the T helper (Th) 1 type.24, 59, 89, 90, 91 CD8+ cells are seen in much lower numbers, although B cells may be found in

CHRONIC INFLAMMATION IN THE RHEUMATOID ARTHRITIS SYNOVIUM: LYMPHOID ORGANOGENESIS

T cells police every tissue and organ in the body except the brain and other immunologically privileged sites, awaiting interaction with APCs carrying specific antigenic peptides to which they can respond. Subsequent to such interaction, there may be clonal expansion and initiation of the events that lead to protective immunity. In the RA synovium, these events proceed at an accelerated tempo and culminate in the development of ectopic lymphoid tissue with many of the features of lymph nodes.

Pro- and Anti-Inflammatory Cascades in Rheumatoid Arthritis

The role of cytokines in the pathogenesis of RA has long been recognized.5, 13 Their importance has been further emphasized by the success of new anti-TNFα therapies.26, 30, 52, 54, 78 It is, however, the balance of pro- and anti-inflammatory cytokines secreted that influences the final pathologic characteristics of the disease. These cytokine cascades have been extensively researched and reviewed over the last few years and are only briefly mentioned in this article, with reference to T cells.

SUMMARY

The evidence coming from the different experimental approaches reviewed in this article strongly supports the hypothesis that RA is T-cell driven at all stages of the disease. Although the effector phases responsible for the events that lead to joint destruction involve several different cell types, cytokines, and other mediators, T cells still direct operations behind the scenes. Direct experimental proof of this proposition in patients is still lacking, but the development of nondepleting

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    Address reprint requests to Gabriel S. Panayi, ScD, MD, FRCP, Department of Rheumatology, 5th Floor Thomas Guy House, Guy's Hospital, London SE1 9RT, United Kingdom

    *

    Department of Rheumatology, Guy's, King's and St Thomas' Medical School, London, United Kingdom

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