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Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: James R. Baker, Jr., Department of Internal Medicine, Medical School, University of Michigan, 1150 West Medical Center Drive, 1520/MSRBI, Ann Arbor, Michigan 48109. E-mail: jbakerjr{at}umich.edu.
Graves’ disease is recognized as an organ-specific autoimmune disorder. Autoimmunity by definition is caused by autoantibodies against certain self-antigens in one or more organs or tissues in the host. The hyperthyroidism of Graves’ disease results from the TSH receptor’s (TSHR)-stimulating autoantibodies (TSAb), which leads to overproduction of thyroid hormones. Although the mechanism leading to the occurrence of TSAb in Graves’ disease is complicated and not yet fully clear, TSAb have been a useful marker in monitoring the efficiency of various treatments against Graves’ disease, such as radioiodine and antithyroid drug, and these treatments decrease the level of TSAb in some patients with Graves’ disease (1, 2). However, the treatments, in terms of autoantibody inhibition, are inefficacious and unpredictable, which is probably because none of these approaches are capable of targeting B cells or autoantibodies directly. In the past few years, some researchers have tried to block TSAb with monoclonal antibodies (mAbs) (3). However, despite the strong thyroid-blocking antibody (TBAb) activity of the mAbs in vitro, their effect on TSAb-induced TSHR activation of sera from patients with Graves’ disease is weaker. This is probably due to the fact that a broader spectrum of TBAb is present in the sera of patients with Graves’ disease, and the mAbs can only interact with a very limited number of TSAb epitopes. This assumption is supported by the experiment showing that sera from hypothyroid patients that contain bona fide TBAb are much more effective than mAbs in inhibition of TSAb activity (3). Collectively, current treatments aiming to block autoantibodies do not provide an effective therapy for patients with Graves’ disease, and a new approach is needed.
Emerging data from clinical trials and case reports with the B cell-deleting agent rituximab, which is initially introduced for the treatment of malignant lymphomas (4), have shown promising results in ameliorating disease symptoms in a variety of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren syndrome (5). These exciting outcomes have prompted a hypothesis that B cell depletion may be an efficient therapy to reduce or abolish the production of the autoantibodies that are responsible for Graves’ disease and autoimmune thyroiditis (6). In the article by Gilbert et al. (7) in this issue of Endocrinology, Dr. Banga’s laboratory reports that the intervention to eliminate autoreactive B cells with B cell activating factor (BAFF) receptor (BAFFR) and B cell maturation antigen (BCMA) fusion proteins is efficacious in reducing the activity of TSAb and the level of T4 in mice with established hyperthyroidism.
BAFF is a member of the TNF ligand superfamily. It binds three TNF family receptors: BAFFR, BCMA, and transmembrane activator and cyclophilin ligand interactor (TACI). A second, highly related homologous aproliferation-inducing ligand (APRIL) also binds TACI and BCMA but not BAFFR. Despite similar structure and shared receptor specificity, BAFF and APRIL have distinct functions. APRIL appears to play a role in T cell-independent type II antigen responses and T cell survival. BAFF induces functions of B cells, including their activation, proliferation, and differentiation. In addition, BAFF may also function as a regulator of T cell-independent responses and as a survival factor of the activated T cells.
The results presented by Gilbert et al. (7) suggest that both BAFF and APRIL may contribute to the development and survival of pathogenic B cells in Graves’ disease and therefore promote the autoantibody production and hyperthyroidism, the major features of this disorder. The study was performed in a well-recognized hyperthyroid Graves’ disease model in female BCLB/c mice induced by an adenovirus containing TSHR A-subunit. They found that BAFF blockage with BAFFR-Fc or blockage of both BAFF and APRIL with BCMA-Fc resulted in a significant decrease in T4 and TSAb levels, indicating a marked improvement in the hyperthyroidism. Accompanying the reduction of T4 and TSAb, the overall peripheral blood B cell numbers and the number and size of B cell follicles in the spleen were also significantly decreased by the treatments, raising the possibility that the resultant decline in peripheral B cell numbers may contribute to the decrease in T4 and TSAb levels seen in the disease model treated by BAFFR-Fc or BCMA-Fc. These data are in agreement with the results of knock-in and -out animal study of BAFF. Mice overexpressing BAFF exhibit an increased number of B cells in the spleen and lymph nodes and a phenotype reminiscent of autoimmunity, including spontaneous autoantibody production, Ig deposits in the kidneys, and glomerulonephritis (8, 9). In contrast, mice deficient in BAFF have reduced B cell numbers and antigenic responses (10, 11). The feasibility of the application of BAFF and APRIL blockers for the treatment of Graves’ disease may be even stronger because the requirement for BAFF-mediated survival of B-cells is greater in self-reactive B cells than in non autoreactive ones (5), suggesting that the self-reactive B cells may be more sensitive to BAFF inhibition. Therefore, the inhibition of BAFF may preferentially promote the death of pathogenic B cells while sparing normal ones.
It appears that study of BAFF and APRIL in Graves’ disease is, unfortunately, very limited compared with other autoimmune diseases such as SLE and RA, although the function of B cells in the pathogenesis of Graves’ disease is no less important than in other autoimmune disorders. This pioneer study by Gilbert et al. in this area should be followed by more laboratory and clinical studies into the role of BAFF and APRIL in Graves’ disease and their clinical and therapeutic significance. The level of BAFF has been found to be increased in several autoimmune diseases such as SLE, RA, and Sjögren syndrome (12, 13, 14), but data are lacking on Graves’ disease in both human and animal models. Similarly, it is also important to look into how BAFF and APRIL function locally in the thyroid microenvironment. Thyroid-infiltrating B-lymphocyte subsets in Graves’ disease are related to marginal zone and memory B cell compartments (15). A decrease in the marginal zone B cells is thought to play an important role in the development of human autoimmune disease (16, 17).
Although the importance of BAFF and APRIL in the pathogenesis of autoimmune diseases including Graves’ disease has been emphasized in the studies of Gilbert et al. and others, it should be noted that a direct correlation between B cell depletion and the reduction of autoantibodies may not always be necessary in autoimmune disease (18), particularly in disorders with heterogeneity, such as in the case of Graves’ disease. Furthermore, a significantly higher level of BAFF may also occur in some healthy subjects (5).
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Received June 22, 2006.
Accepted for publication June 23, 2006.
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