Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and beyond

Abstract

The autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and autoimmune hypothyroidism (AIH) are the commonest of the autoimmune conditions affecting 2-5% of the western population. Twin studies have clearly demonstrated that AITDs are caused by a combination of both environmental and genetic factors. Association of the HLA class II region with AITD has been documented for over 20 years now, but the primary aetiological variant in this region remains unknown. More recently the CTLA-4 gene region has been identified as the second locus conferring susceptibility to AITD. In contrast to HLA, a polymorphism of the CTLA-4 gene, which encodes an important negative regulator of the immune system, has been identified as a candidate for a primary determinant for AITD. A large number of candidate gene and genome wide linkage studies have been involved in the search for the elusive 'third' locus. The thyroglobulin (Tg) gene in humans maps to chromosome 8q, which has been linked in family studies to AITD. A number of association studies in humans and the mouse model for AITD are beginning to implicate the Tg gene although convincing evidence for a primary causative role is still needed. The establishment of large DNA disease resources along with more detailed genetic maps and the development of faster, more effective, high throughput genotyping and sequencing methods, provides some sense of optimism that novel loci will be identified in the near future and the complex aetiology of AITD will be further unraveled.

Fig. 1

Simplified version of how Th1 and Th2 responses lead to the different clinical presentations of AITD.

Fig. 2

(a) HLA class I gene region. (b) HLA class II gene region with known haplotypes associated with GD and HT (transport associated with antigen processing genes (TAP1 and TAP2) and large multifunctional protein (LMP)). (c) HLA class II gene regions (Heat shock protein (HSP), tumour necrosis factor (TNF))

Fig. 3

The stimulatory pathway of CD28 and the antagonist effect of CTLA-4 on Th cell activation. T cell activation occurs via a two stage process. Stage 1 involves generation of a signal via the interaction of a presented antigen with the TCR-CD3 complex. Stage 2 of T cell activation involves a costimulatory signal from CD28 interaction with B7. Regulation of this second stage of T cell activation is provided by a down regulation of T cell activation by CTLA-4. Due to the negative control function of CTLA-4, functional mutations in this gene could increase susceptibility to autoimmune thyroid disease.

Fig. 4

Association of SNPs within the CD28-CTLA4-ICOS gene region with GD. When association with GD was plotted for all the SNPs, a region consisting of CTLA-4 and 5′ ICOS gene (CTLA4 LD BLOCK) was believed to contain the aetiological variant. This diagram highlights the CT60—JO30-JO31-J027–1 peak of linkage that is believed to contain the aetiological variant associated with GD and HT (reprinted by permission from Nature 2003; 423:506–511. Copyright 2003, Macmillan Publishers Ltd.)