Thyrotropin (TSH) receptor (R)-reactive B cells are typically observed in GD and eventually present this autoantigen to T-cells, which, in turn, secrete several pro-inflammatory cytokines and chemokines.
It usually presents as a component of the syndrome known as Graves' disease where loss of immune tolerance to the thyrotropin receptor (TSHR) results in the generation of activating antibodies against that protein and hyperthyroidism.
Recombinant human IFNalpha stimulated primary cultured thyrocytes resulted in not only high level expression of IFIGs, but also, more importantly, expression of MHC-II antigens (HLA-DR3 and HLA-DR5) and TSHR in GD subjects.
Further, because 6 of 6 individuals who possessed both DR3 and the thyrotropin receptor polymorphism had Graves' disease, while no individual in the normal control group possessed both alleles, study of a larger population to assess the potential synergism between these 2 alleles is warranted.
Twenty-eight SNPs from CTLA-4, PTPN22, PTPN12, FCRL3, TSHR and Tg genes were genotyped and their associations with the risk and severity of GD were analysed.
The data do not support the notion that TSAb production is Th2-dependent in murine GD but they also suggest that codelivery of TSHR and Th1-promoting IL-12 genes may not be sufficient to enhance disease incidence and/or severity in this model.
The prevalence of nonautoimmune hyperthyroidism with TSH receptor mutations is lower than that of latent Graves' disease in TRAb-negative patients with hyperthyroidism.
Fourth, despite many unsuccessful attempts at implicating the TSHR gene as a susceptibility locus for GD, a recent approach of 'tagging' all the common variation within the gene has led to its identification as the first GD specific locus.
PTPN12 interacts with the same T cell activation accessory molecules, Grb2 and Csk kinase, as the Graves' disease (GD) associated PTPN22 encoded lymphoid tyrosine phosphatase (LYP) molecule and also plays a key role in T cell receptor signalling, leading to the hypothesis that it too may be involved in GD susceptibility.
Comparison of hNIS-Ab, thyroid peroxidase, and TSH receptor antibodies in individual sera revealed that the additional detection of hNIS-Ab did not increase the diagnostic power for GD or HT.
Genetic polymorphisms related to GD were identified, levels of thyroid stimulating hormone receptor antibodies (TRAb) were measured, and genetic interactions were assessed by logistic regression analysis.
We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms.
Based on our earlier finding and on the large body of evidence here reviewed, we propose that DDT-induced formation of extracellular vesicles containing the TSH receptor could be directly involved in the development of autoimmune responses against the TSH receptor and that, therefore, their release could lead to the development of the Graves' disease.
To this purpose, we will firstly focus our attention on the role of genetic factors (the HLA complex, the genes encoding for thyroglobulin, the TSH receptor, CD40, CTLA-4 and PTPN22), and of environmental factors (iodine, infections, psychological stress, gender, smoking, thyroid damage, vitamin D, selenium, immune modulating agents) as possible causes of BD.
The TSH receptor-specific T cells from different Graves' disease patients recognize variable distinct sites within the extracellular region of the TSH receptor, and the immunodominant epitope apparently shifts toward the N-terminus of the receptor protein during the course of treated Graves' disease.
The presence of such TSHR antibodies suggests that they may play an active role in the immune repertoire marshaled against the TSHR and may influence the Graves' disease phenotype.
Application of these techniques is likely to lead to an understanding of how TSH receptor antibodies interact with the receptor to cause Graves' disease and also to the identification of novel orbital autoantigens in thyroid-associated ophthalmopathy.