B lymphocyte cytokines and rheumatic autoimmune disease

Abstract

There is some debate as to which type of lym-phocyte prevails in the pathogenesis of autoimmunity.This controversy is borne out by the fact that T cellshave, for years, been viewed as competent in their ownright to initiate rheumatoid arthritis (RA), primarySjo¨gren’s syndrome (SS), and systemic lupus erythema-tosus (SLE), while B cells were confined to a subservientrole as producers of antibodies to self antigens. Doubtshave, however, been cast when T cell–directed treat-ments proved to be disappointing.B cells have attracted significant interest follow-ing new information on the key roles they play in RA,SS, and SLE. Encouraged by the promising results ofsmall-scale clinical trials of the anti-CD20 antibodyrituximab in patients with RA (1), several groups haveembarked on similar treatment of patients with RA, SS,or SLE (2). The clinical benefits were found to becorrelated with a decline in B cell numbers, but not witha reduction in the levels of most autoantibodies, exceptfor rheumatoid factor and anti–cyclic citrullinated pep-tide (3). This finding implies that B cell depletion mayameliorate these disorders through mechanisms otherthan suppressing autoantibody production. Given the Bcell dependence of T cell activation in the rheumatoidjoint, it makes sense that heavy infiltration of B cells intothe synovium accompanies a modest response to ritux-imab, that patients in whom depletion of circulating Bcells is incomplete have worse outcomes than those inwhom it is complete (4), and that removal of B cellssignificantly reduces the severity of experimental arthri-tis in mice (5).Furthermore, consistent with this view are theresults of experiments in SLE-prone mice geneticallyengineered to be deficient in B cells. While mice with noB lymphocytes do not suffer from end-organ damage,those with B cells incapable of antibody secretion retainmany features of the syndrome (6). Such observationsindicate that B cells promote autoimmunity by interact-ing with any one of several pathways that impact theregulation of immunity to the self. Although a role of Blymphocytes in SLE, RA, and SS has been suspected formany years, recent discoveries have unveiled new in-sights into B cell–derived cytokines, includinginterferon- (IFN ) and interleukin-4 (IL-4), that mod-ulate the response. They are likely to serve as effectorsof some biologic functions of B cells.Early studies of the functions of B lymphocytesfocused on splitting the B cell population into subpopu-lations. For example, B lymphocytes are classified basedon the expression of CD5 as B-1 cells, which express thisT cell marker, and B-2 cells, which do not. The ensuingmodel of the maturation of B lymphocytes asserts thatB-2 cells leave the bone marrow as immature B cells,populate secondary lymphoid organs as transitional type1 (T1) cells, and evolve into type 2 (T2) cells, whichdifferentiate either into marginal zone or follicular Bcells. Upon antigen encounter, these latter B cellsinitiate the development of a germinal center (GC).