The mechanisms through which HLA molecules confer susceptibility to autoimmune diseases are now beginning to be understood. T cells recognize and respond to an antigen by interacting with a complex composed of an antigenic peptide, presented by an HLA molecule (reviewed in (30
)). It is thought that different HLA alleles have different affinities for peptides from autoantigens (e.g. thyroid antigens). Hence, a distinct HLA allele would be capable of binding a distinct peptidic repertoire. Once bound, peptides are then presented to and recognized by T cell receptors on cells that have escaped tolerance (5
). Ultimately, in terms of relevance to autoimmunity, specific HLA-DR alleles may permit an autoantigenic peptide to fit into their peptide binding pockets and to be recognized by the T-cell receptor, while other HLA-DR alleles would not be able to bind the same autoantigenic peptide (31
). Thus, we hypothesize that the molecular linchpin, of a burgeoning thyroid autoimmune response, is the presence of an HLA-DR allele with the appropriate amino acids, in its peptide binding cleft, that would enable the binding of an autoantigenic thyroidal peptide.
Studies on the structure of HLA polymorphisms associated with Type 1 DM provided strong evidence in support of this hypothesis. Sequencing of the HLA-DQ genes showed that an aspartic residue at position 57 of the DQ beta chain played a key role in the genetic susceptibility to Type 1 diabetes (32
). Individuals who did not have Asp57 on both of their DR alleles were at high risk for Type 1 diabetes (relative risk > 50) (33
). The lack of aspartic acid at position 57 permits immunogenic insulin peptides to fit into the antigen binding groove of the HLA molecule and to be recognized by the T-cell receptor (34
). In contrast, the presence of aspartic acid at position 57 of the DQ beta chain prevented insulin peptides from fitting, and hence prevented autoantigen presentation to the T-cell receptor (31
). Moreover, it has also been shown that an aspartic acid at position 57 on the DQ beta chain dictates the antigen binding properties of an HLA-DQ alpha-beta heterodimer (32
As discussed above, sequencing the DR beta chain has revealed a strong association between the presence of arginine at position 74 of the DR beta chain and GD in Caucasians. Position 74 of the DRb1 chain is strategically located in pocket 4 (P4) of the DR peptide binding cleft (). It is then possible that an arginine at position 74 alters the structure of the pocket in a way that would influence peptide binding and presentation to T-cells, much like the case in Type 1 DM and Asp57. Indeed, structural modeling analysis, performed by us, demonstrated that the change at position 74, from the common neutral amino acids (Ala or Gln) to a positively charged hydrophilic amino acid (Arg), significantly modified the three dimensional structure of the P4 peptide-binding pocket, and thus would be expected to modify the interaction of the DR peptide binding pocket with antigenic peptides during presentation to T-cells (28
).Very few studies, to date, have examined the binding and presentation of thyroidal autoantigens to T-cells by different HLA-DR subtypes. One study has shown a higher affinity of HLA-DR3 to TSHR immunodominant peptides than to TSHR non-immunodominant peptides, suggesting that certain DR sequences influence the binding and presentation of TSHR peptides (35
), and this may afford a mechanism through which DRb1-Arg74 can influence susceptibility to GD. Interestingly, we have found evidence for interaction, at the genetic level, between a thyroglobulin gene variant and DRb1-Arg74 in predisposing to GD resulting in an odds ratio of more than 16 (36
). This result may suggest that the thyroglobulin/DRb1-Arg74 genetic interaction is mirrored by a biochemical interaction, in which Arg74 influences the presentation of thyroglobulin peptides in the initiation phase of GD.
Figure 1 The HLA-DR3 molecule, shown in ribbon diagram format. The alpha chain (yellow) and the beta chain (turquoise) assemble to form a functional heterodimeric MHC II molecule. The peptide binding cleft is flanked by alpha helices, while anti-parallel beta (more ...)
For thyroid autoantigens to be presented by HLA molecules to T-cells, a mechanism of autoantigen presentation must exist within the thyroid gland or the draining lymph nodes of the gland. One potential intrathyroidal mechanism not utilizing professional antigen presenting cells (APC’s) may be through aberrant expression of HLA class II molecules on thyrocytes (37
). Unlike in thyroids from normal individuals, thyroid epithelial cells from patients with GD and HT have been shown to express HLA class II antigen molecules similar to those normally expressed on APC’s such as macrophages and dendritic cells (38
). The aberrant expression of HLA class II molecules on thyroid cells may initiate thyroid autoimmunity via direct thyroid autoantigen presentation (38
), where the thyroid cells serve as facultative APC’s. However, in order for thyrocytes to fully stimulate T-cells, a co-stimulatory signal from the thyrocyte to the T-cell is needed, in addition to the stimulus provided by the presented peptide, alone. Hence, thyrocytes need to express requisite co-stimulatory molecules that can stimulate the T-cells, during antigen presentation within the HLA-DR peptide binding pockets. In terms of candidate co-stimulatory molecules, recent data from our lab suggest that CD40 may be one of the co-stimulatory molecules, expressed on thyrocytes, which helps trigger Graves’ disease (39
). This paper is part of the Mosaic of Autoimmunity special issue and we note other papers on this theme as well as several related papers on the genetics of both thyroid and other autoimmune diseases (40–58).