Development of Autoantibodies Against TSHR

The central dogma in immunology is defined by the ability of immune cells to discriminate between self and non-self. The discrimination against self is governed by mechanisms that mediate tolerance to normal antigens in the body. When tolerance is broken, self is recognized as non-self or foreign, and therefore the immune system begins to attack the organ in question. Evidence from transgenic models that use foreign antigen hen egg lysozyme (HEL) expressed on the thyroid cells and HEL antigen-specific B and T cells suggests that a breakdown in T-cell tolerance to a thyroid antigen is required before B cells can produce anti-thyroid antibodies [11, 12]. Specifically, B cells that express trans-genic receptors that recognize the HEL expressed on the thyroid as a transgene are not eliminated or inactivated. This means that the pre-immune B-cell repertoire against the thyroid antigen (i.e., HEL) is intact and that the tolerance would have to depend on mechanisms other than B-cell deletion to avoid auto-antibody production. Since TSHR (as well as HEL) is a protein antigen, it likely requires T-cell help for both initiation and maintenance of anti-TSHR antibody response. This is clearly illustrated by experiments showing that T cells that carry the transgenic T-cell receptor against thyroid-expressed HEL are hyporespon-sive to the HEL antigen. This T-cell tolerance could not only help keep T cells in check but also could prevent T cell-dependent activation of autoreactive B

cells. However, in the same study the authors were able to stimulate HEL-specif-ic T cells with a stronger stimulus, suggesting a putative mechanism by which a break in T-cell tolerance to thyroid antigens may occur. Once T-cell tolerance is overcome, the thyroid antigen-specific B cells can be readily activated, leading to antibody production. In Graves' patients, a majority of the stimulatory activity in the serum resides in the IgG fraction of the antibodies [13, 14]. This is consistent with the concept that a breakdown in T-cell tolerance is required for the production of pathogenic autoantibodies because B cells require T-cell help for isotype switching from IgM to IgG and affinity maturation.

Given the right circumstances, a breakdown in tolerance precipitated by thyroid injury (e.g., environmental stress factors) could lead to thyroid autoimmunity. At the site of injury and inflammation, thyroid antigens could be processed by professional antigen-presenting cells (APCs). The APCs will carry the antigen to the draining lymph nodes and present the thyroid antigen in the context of the right MHC class II to an appropriate CD4+ T helper cell, leading to its activation. In the same context, an autoreactive B cell could also acquire the thyroid antigen by binding to it with its IgM receptor and present it to the appropriate T cells. This interaction between T cells and B cells with a common antigen specificity (linked recognition), and in the presence of sufficient amounts of the thyroid antigen, could result in the formation of germinal centers where B-cell differentiation could take place with T-cell help. A continued antigenic stimulation would lead to B-cell isotype switching and somatic hypermutation of the B-cell receptors, resulting in high-affinity antibody production. Interestingly, there is evidence to suggest that anti-thyroid antibody-producing B cells accumulate in the thyroid where they are continuously exposed to the antigen [1]. Once sufficient amounts of anti-TSHR antibodies of high affinity accumulate in the serum, they can continually stimulate the TSHR, resulting in Graves' disease. What predisposes certain individuals to GD and what triggers the initial autoimmune response are not completely understood. However, it is generally accepted that genetic and environmental factors could act in concert to initiate an anti-thyroid autoimmune response.

0 0

Post a comment