Immunohistochemical analyses have also shown that within the lymphocytic infiltrates in the synovial tissue, plasma cells may be organized in concentric rings around large cellular clusters of T cells and CD20+ B cells, or as perivascular clusters [43]. the pathogenesis of rheumatoid arthritis (RA) were molded by experimental models of immune complex disease. IgG aggregates are abundant in RA synovial fluids, and can trigger complement activation. Hence, it seemed logical that tissue damage in RA was attributable to the local deposition of immune complexes. Rheumatoid factors (RFs), which are autoantibodies specific for the constant regions of IgG, are detectable in more than 80% of RA patients, and may also be present in a ‘hidden’ or complexed form in the synovial fluids of some seronegative patients. RFs efficiently fix and activate complement em in vitro /em by the classic pathway [1]. em In vivo /em turnover studies of radiotagged complement proteins in seropositive RA patients demonstrated that, compared with control individuals, complement consumption was greatly accelerated, especially at the extravascular sites of inflammation [2]. Consistent with the notion that immune complex Naproxen etemesil formation was maximal at the synovial sites of inflammation, complement activation was shown to be much greater in RA synovial Naproxen etemesil fluid than in blood [2-4]. Levels of C4 fragments at these sites also correlated with titers of IgM RFs. Infiltrating leukocytes are known to be recruited by the downstream products of complement activation, especially the soluble anaphylatoxin C5a, with subsequent enlistment of other components of the membrane attack complex [5,6]. Flares of clinical activity in RA correlate with increased levels of RF secreting cells, which are especially prevalent in the bone marrow and synovial fluid of RA patients [7]. IgM RFs have been reported to account for more than 10% of local plasma cells in RA synovia [8,9]. However, infusions of RF into healthy individuals causes neither sustained nor transient synovitis [10], Naproxen etemesil indicating that RF autoantibodies by themselves are not pathogenic. Nevertheless, IgM-RF-containing immune complexes may also include IgG antibodies and unidentified peptides, which could derive from self or exogenous antigens. In addition, the recently resolved crystallographic structure of a human IgM RFCFc co-complex revealed that contacts with IgG antigen involved only the periphery of the antigen-binding cleft of the autoantibody [11]. These findings may indicate that RA RF is capable of binding IgG as well as another self or foreign antigen. Thus, although RF alone is not proinflammatory, RF associated with immune complexes can enhance local inflammatory processes, and there is compelling clinical evidence that RFs contribute to extra-articular disease. Antigen-presenting function of B cells In addition to being the precursors of antibody-secreting plasma cells, the B cells in RA can play a critical role in the afferent arm of the immune response (Table ?(Table1).1). Thus, B cells can act as highly efficient antigen-presenting cells (APCs), supporting the activation of autoreactive T cells. In fact, by virtue of the high affinity of a specific membrane-associated immunoglobulin for antigen, an antigen-specific B cell can take up, process, and present peptides from nominal antigen with 1000-fold or greater efficiency than a ‘professional’ APC. In addition, activated B cells can synthesize cytokines and membrane-associated molecules that provide nonspecific help to adjacent T cells. Table 1 Major physiologic functions of B lymphocytes Precursors of antibody producing plasma cellsProvide noncognate help for T cell activationEfficient antigen-presenting cells, especially for recall antigensProduce cytokines (i.e. IL-4 and IL-10) that support the survival other mononuclear cellsGenerate and respond to chemotactic factors responsible for leukocyte migration and development of granulation tissueSustain immunologic memory Open in a separate window Strong experimental support for a central role of B cells in RA pathogenesis, independent of antibody formation, came from studies of human synovium/SCID mouse chimeras [12]. Those studies confirmed that the T cell activation is B cell dependent, in that targeted deletion of B cells impaired local T cell responsiveness, and APCs other than B cells could not substitute for the maintenance of T cell activation. Role of B cells in murine models of rheumatoid arthritis Following the development of methods for introduction of transgenes and for targeted gene disruption, em in vivo /em murine models have been developed that have enabled a re-evaluation of the role of B cells in arthritis. The KRN/NOD murine model has been particularly revealing, because in these mice there is complete penetrance of a genetically determined disease process that results in severe distal joint Rabbit Polyclonal to BCL2L12 inflammation, which emulates key features of RA [13]. Moreover, development of the disease involves the coordinated functions of both B.