Early Requirement for B Cells for Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

Abstract

B cells are known to play an important role in the pathogenesis of several autoimmune diseases. NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and anti-mouse thyroglobulin (MTg) autoantibodies, the levels of which correlate closely with the severity of thyroid lesions. NOD.H-2h4 mice genetically deficient in B cells (NOD.Kμnull) or rendered B cell-deficient by treatment from birth with anti-IgM develop minimal SAT. B cells were required some time in the first 4–6 wk after birth, because NOD.Kμnull or NOD.H-2h4 mice did not develop SAT when they were reconstituted with B cells as adults. The requirement for B cells was apparently not solely to produce anti-MTg autoantibodies, because passive transfer of anti-MTg Ab did not enable B cell-deficient mice to develop SAT, and mice given B cells as adults produced autoantibodies but did not develop SAT. B cell-deficient mice developed SAT if their T cells developed from bone marrow precursors in the presence of B cells. Because B cells are required early in life and their function cannot be replaced by anti-MTg autoantibodies, B cells may be required for the activation or selection of autoreactive T cells. These autoreactive T cells are apparently unable to respond to Ag if B cells are absent in the first 4–6 wk after birth.

B Cell Depletion Inhibits Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice

“…CD4 ϩ T cells are the primary pathogenic effector cells for SAT and are required for both initiation and maintenance of SAT (1)(2)(3). B cells are required for development of SAT, because B cell-deficient NOD.H-2h4 mice do not develop SAT (7). Our previous studies suggested that B cells were required for activation of pathogenic CD4 ϩ T cells, possibly functioning as important APCs (7).…”

“…B cells are required for development of SAT, because B cell-deficient NOD.H-2h4 mice do not develop SAT (7). Our previous studies suggested that B cells were required for activation of pathogenic CD4 ϩ T cells, possibly functioning as important APCs (7).…”

“…B cells are important for development of most spontaneous autoimmune diseases including SAT, diabetes in NOD mice, systemic lupus erythematosus (SLE) in MRL/Mp-lpr/lpr mice, scleroderma in tight-skin mice, and arthritis in K/BxN mice (7)(8)(9)(10)(11)(12). B cells produce autoantibodies that contribute to the pathogenesis of autoimmune diseases by multiple mechanisms (13).…”

The rationale for B lymphocyte depletion in Graves’ disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option

“…In murine autoimmune thyroiditis, Braley-Mullen et al (11) demonstrated the importance of B cells in the initiation of thyroiditis, in an autoantibody-independent manner. In a GD model, Pichurin et al (12) showed that B cell-deficient mice were unable to elicit the normal T cell response to immunization with TSH-R. Conversely, the production of autoantibodies seems dependent on the help of CD4 þ T cells (53).…”

“…In addition to being precursors for antibody-secreting plasma cells, B cells are also efficient antigen-presenting cells (APC) in autoimmune disease, as shown in animal models of diabetes (5), rheumatoid arthritis (RA) (6) and systemic lupus erythematosus (SLE) (7,8). In murine models of autoimmune thyroid disease (AITD), B cells are shown to act as APCs (9,10) and are a prerequisite for the initiation of the disease process (11). Recently, Pichurin et al (12) have demonstrated the importance of B cells on T cell activation in GD.…”