The influence of immunogenetic parameters on the course of RA has been explored by a number of prospective studies [22
]. In several Caucasian study populations, patients positive for RA-associated DRB1 alleles, and in particular those expressing the so-called shared epitope on a DRB1*04 allele, were found to suffer from a more rapid and severe course of joint destruction. With regards to RF production, one copy of the shared epitope seems sufficient to transmit a significantly increased risk for the development of RF IgM-positive RA [31
A predominant role for B-cell activation and autoreactive humoral responses has been invoked not only for human RA, but also for many animal arthritis models. Immunoglobulins are crucial for the classical collagen-induced arthritis [13
], while the recently published K/BxN mouse system absolutely requires autoreactive B cells for the erosive arthritis to develop [32
]. B-cell activation by newly described stimulatory interactions between the B-cell surface receptor B lymphocyte stimulator (BlyS) and the transmembrane activator and CAML interactor (TACI) [33
] has also recently been reported to be required for the induction of collagen-induced arthritis in rodents [34
Our chief finding of a significant influence of the RA-associated shared epitope on the numbers of circulating B cells in RA patients has not been reported previously. Several different explanations for this phenomenon are feasible, none of which can be ruled out at present.
Since SE-positive RA is generally regarded as a more severe disease, it can be hypothesized that high numbers of involved lymphocytes, including B cells, are consumed in the long-standing autoimmune response in SE-positive RA patients. This is contradicted, however, by the lack of association of diminished B-cell numbers with prolonged disease duration or with increased DMARD therapy, or a more rapid joint destruction found in both study cohorts.
In view of animal experiments demonstrating clonal deletion of RF-producing B cells on encounter of their antigen [35
], decreased absolute B-cell numbers could reflect a substantial loss of B cells in SE-positive RA. It can be hypothesized that this loss is accompanied by repertoire contraction and oligoclonality in the B-cell compartment of RA patients, which parallels T-cell repertoire changes found in RA [36
In a recent study, widespread clonal expansion could be shown in B cells from peripheral blood and synovial membranes from patients with RA [37
]. The immunoglobulin VH
gene fingerprinting assay used in that study allowed the discrimination of numerically expanded B-cell specificities from merely activated clones. The detected numerical clonal expansions could therefore be indications for a restricted repertoire of B lymphocytes in RA, which parallels the B lymphocytopenia described in the present study and is likely to be the consequence of the disturbed B-cell homeostasis in RA. The primary mechanism driving those B-cell repertoire aberrations is likely to act in the synovial membranes of synovitic joints, since clonality is more pronounced there [37
] and the frequencies of B cells specific for relevant autoantigens that have already undergone the isotype class switch to IgG/IgA are higher among synovial B cells [38
]. Taken together, these repertoire studies indicate that clonal growth and depletion, possibly in the context of MHC-restricted T-cell help [39
], might be a regulatory factor in B-cell homeostasis in RA.
Alternatively, since only a small fraction of the total B-cell pool is found in the peripheral circulation, diminished numbers of circulating CD19+ B cells might be the result of increased accumulation of autoreactive B cells in the synovial membrane of affected joints. Irrespective of the underlying mechanisms, the association of diminished numbers of circulating CD19+ B cells with increased disease activity in the prospective study population indicates that an absolute B-cell count might be used as an additional, readily available clinical parameter. Whether this parameter is of clinical relevance and possibly might be used as a prognostic or response indicator needs to be explored in further prospective studies.