As already discussed, B cells specific for certain thyroid antigens are not deleted during development in transgenic animal models. Such ignorant but potentially autoaggressive populations of B cells may become activated non- specifically in response to the right combination of cytokines, leading to autoantibody production. It is unknown in humans which thyroid autoantigens, if any, can actually induce B- cell tolerance, either through deletion or anergy mechanisms. Judging by the frequent appearance of low levels of low- affinity IgM class thyroglobulin antibodies in healthy individuals, B cells specific for thyroglobulin are frequently not tolerized, but whether such natural autoantibodies have a pathogenic role is uncertain. Maturation of the B- cell response, leading to the pro duction of high levels of high- affinity, IgG class thyroglobulin anti bodies, requires CD4+ T- cell help, and it is these antibodies that characterize autoimmune thyroid disease.

TSH receptor and thyroid peroxidase are much more localized to the thyroid than thyroglobulin and therefore might be expected to impose even less tolerance on B cells than thyroglobulin, which circulates at relatively high levels. However, little is known about the frequency of B cells with these specificities in normal individuals. A priori, it would seem that TSH- receptor- specific B cells are un common, particularly those capable of producing thyroid- stimulating antibodies, and there is even the possibility that such antibodies are the product of only a very small number of B- cell clones.

Circulating B- cell numbers are largely normal in autoimmune thyroid disease, although increases in the CD5+ B- cell subset, re sponsible for synthesis of polyreactive natural autoantibodies, can occur. Such increases in CD5+ B cells occur in other autoimmune diseases and have no known pathogenic role in thyroiditis. B cells and plasma cells are found in varying numbers in the thyroid, and may be organized in germinal follicles, especially in Hashimoto’s thyroiditis. Rarely, these follicles can show light- chain restriction, from which a single dominant clone may emerge to produce non- Hodgkin’s lymphoma, a recognized complication of Hashimoto’s thyroiditis.

Although both blood- borne and thyroid lymphocytes can produce thyroid antibodies in vitro after mitogen stimulation, only the thyroid lymphocytes produce antibody spontaneously, so that the thyroid seems likely to be a major source of antibodies in vivo. In addition, however, the bone marrow and lymph nodes draining the thyroid are sites of thyroid antibody production. The decline in thy roid antibody production which occurs after thyroid ablation is explicable as the result of either removal of thyroidal B cells or removal of thyroid antigen and thyroid- specific helper T cells. In simple terms of B- cell population size, it would seem that the thyroid is not the major site of antibody synthesis, but the real importance of this compartment may lie in the ability of B cells to take up specific autoantigen. B cells are uniquely able to amplify the T- cell response to any given autoantigen and may even break T- cell tolerance by presentation of cryptic self- epitopes generated by processing within the B cell. Thus, within the thyroid, the autoimmune response will be sustained and increased by B- cell- mediated presentation of locally derived thyroglobulin, thyroid peroxidase, and TSH receptor, and supported by the intrathyroidal production of cytokines which cause B- cell proliferation and differentiation (Figure 1). This information has been behind attempts to treat Graves’ disease and ophthalmopathy with rituximab, a monoclonal antibody that depletes B cells but not plasma cells, although results so far remain rather equivocal.

Fig1. Cognate interaction of B cells, capturing specific thyroid antigens by surface autoantibody, and T cells.

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مواضيع ذات صلة

T- cell Function in Autoimmune Thyroid Disease

Autoimmune Thyroid Disease: Autoantigens

Factors Determining Susceptibility of Autoimmune Thyroid Disease

Pathological Features of Autoimmune Thyroid Disease

The Spectrum of Thyroid Autoimmunity

Autoimmune lymphoproliferative syndrome

Severe Congenital Neutropenia

Autoimmune type 1 diabetes and immune checkpoint inhibitors

Autoimmune diabetes in adults

Genetic aetiology to initiate islet autoimmunity

Islet autoantibodies as biomarkers

Natural history and staging type 1 diabetes