Graves' Hyperthyroidism Is Antibody-Mediated But Is Predominantly a Th1-Type Cytokine Disease

We wish to comment on an assumption commonly made that Graves' disease and Hashimoto's thyroiditis are distinguished by immune responses involving T-cell helper type 1 and type 2 (Th1 and Th2), respectively. For example, the title of a paper recently published in the JCEM refers to this perceived Th1/Th2 dichotomy in thyroid autoimmune disorders (1). In the abstract, Marique et al (1) state that “Hashimoto's thyroiditis and Graves' disease are thyroid disorders driven by Th1 and Th2 responses, respectively,” and subsequently they state that Graves' disease “is driven by the humoral immune response and Th2 cytokines (IL-4 and IL-10)”. The authors are not alone in adopting this viewpoint which we, ourselves, did in earlier years. Subsequently, we (and possibly others) have been unsuccessful in convincing the thyroid community that these assumptions are incorrect. The purpose of this Commentary is to summarize key points of information in order to enhance insight into the pathogenesis of these complex, fascinating, and extremely common disorders.

The basis of the foregoing misperception is the simplified view that humoral immunity is driven by Th2 cytokines (such as IL-4) and cellular immunity is driven by Th1 cytokines (such as interferonγ and IL-12). Because Graves' hyperthyroidism is directly caused by thyroid-stimulating antibodies (TSAbs), it is logical to assume that the disease belongs to the Th2 category. Conversely, the dominance of cellular immunity and thyroid tissue damage in Hashimoto's thyroiditis implies a Th1 origin.

Addressing Graves' disease first, the IgG subclasses in humans (IgG1, -2, -3, or -4) provide the most specific insight into the cytokine bias, Th1 or Th2, involved in their generation. Th1 cytokines (eg, interferonγ) drive the generation of subclass IgG1, whereas Th2 cytokines (eg, IL-4) drive IgG4 (2). Furthermore, the early stage of a humoral immune response typically involves IgG1, whereas restriction of antibodies to subclass IgG4 is associated with prolonged immunization, as occurs in some parasitic diseases, as well as in the immune response to bee venom in beekeepers repeatedly subjected to bee stings (3). With this background, what information is available about the IgG subclasses of TSH receptor (TSHR) autoantibodies? In 11 Graves' patients, separation of IgG into the four human subclasses by affinity chromatography using mouse monoclonal antibodies showed that TSAb activity was confined to the IgG1 fraction (4). Moreover, two human monoclonal TSAbs derived from Graves' lymphocytes are also IgG1, for example (5). On the other hand, affinity enrichment of TSHR autoantibodies from Graves' sera using recombinant human TSHR protein provided a mixed picture: restriction to IgG1 in one patient, restriction to IgG4 in another, and the presence of both IgG1 and IgG4 in a third patient (6). Noteworthy in the latter study was the requirement for large volumes of sera, and IgG4 restriction was observed in serum obtained by plasmapheresis in an unusual patient with long-standing Graves' disease (6). Overall, therefore, the very strong bias toward IgG1 subclass TSHR autoantibodies favors Graves' disease as a Th1- (not Th2) associated disorder.

Part of the misunderstanding concerning the relationship between TSHR antibody generation and Th2 or Th1 cytokines arises from studies in mice. The IgG subclass categories in mice are different from those in humans, comprising IgG1, IgG2a, IgG2b, and IgG3. Confusingly, in mice, IgG1 is a Th2 subclass, whereas IgG2a is a Th1 subclass. Graves'-like disease can be induced in susceptible mouse strains by in vivo expression of the human TSHR or its A-subunit (reviewed in Ref. 7). Induced TSHR antibodies in these models are IgG2a and IgG1, reflecting Th1 and Th2 cytokines, respectively.

Hashimoto's thyroiditis is characterized by cell-mediated damage to thyrocytes as well as by autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg). Whether these autoantibodies also contribute to thyroid damage has long been debated. There is evidence that, although subservient to cytotoxic T cells, TPO and Tg autoantibodies may play a role in thyroid destruction by means of antibody-dependent cell-mediated cytotoxicity and activation of complement. Antibodies of subclass IgG1, but not IgG4, activate complement and can participate in antibody-dependent cell-mediated cytotoxicity. IgG subclasses are determined by their Fc component, and not by their antigen-binding region (“Fab”). In Graves' disease, the function of TSAb involves the Fab region and is unrelated to IgG subclass. In contrast, the ability of TPO and/or Tg autoantibodies to damage thyrocytes is dependent on the properties of the Fc region and therefore on their IgG subclass. As described above, in humans (not mice), IgG1 antibodies are associated with Th1 cytokines. If thyroid autoantibodies do, indeed, contribute to thyrocyte destruction in Hashimoto's disease, a Th1 cytokine bias would be required for their induction. Unlike the relative IgG1 restriction of TSHR autoantibodies, TPO and Tg autoantibodies are represented by all four human IgG subclasses (reviewed in Refs. 8 and 9). Consequently, if viewed from the perspective of thyroid-specific autoantibodies, Hashimoto's thyroiditis is both a Th1- and Th2-associated disease.

Complicating the situation further, Graves' disease and Hashimoto's thyroiditis have many common features. Most Graves' patients also have autoantibodies to TPO and, less commonly, to Tg. As already mentioned, TPO and Tg autoantibodies may comprise IgG4 as well as IgG1 subclasses, implying contributions from Th2 as well as Th1 cytokines. Therefore, in Graves' disease, as in Hashimoto thyroiditis, the autoimmune response comprises elements of both Th1 and Th2 types. The conclusion from these data is that it is incorrect to classify Graves' disease and Hashimoto's thyroiditis as being distinctly of Th1 or Th2 origin.

Finally, we wish to comment on a frequently overlooked implication that thyroid autoantibody subclass distribution carries regarding the pathogenesis of autoimmune thyroid disease. As mentioned above, IgG1 antibodies (such as Th1-related TSAb) arise early in the immune response, whereas IgG4 antibodies (to TPO and Tg, typically Th2-related) arise after long-standing immune stimulation, perhaps over many years in humans. These observations are entirely consistent with the clinical features of Graves' disease and Hashimoto's thyroiditis (10). When TSAbs arise, they can immediately activate the TSHR and cause hyperthyroidism. In contrast, thyroid failure in Hashimoto's thyroiditis occurs over a much longer period of time because a compensatory increase in TSH secretion maintains thyroid sufficient reserve until overwhelmed by massive thyroid follicle destruction and fibrosis (10). Indeed, in our view, recent reports of IgG4-associated thyroiditis and Graves' disease are likely to reflect the duration of the immune responses rather than separate forms of the disease.