Significant progress has been made in unraveling the complex genetic mechanisms that modulate T1D susceptibility and in dissecting the relative molecular pathways. The main component of IDDM1, the HLA/DQ/DR loci, is involved in antigen presentation and controls immune responsiveness to one or more islet cell antigens, either in the thymus or in the periphery, or in both. For IDDM2, VNTR alleles seem to influence INS expression in the thymus, and thus may affect the development of tolerance to insulin. Thus, IDDM1 and IDDM2 may influence basic immunologic functions, such as antigen presentation and thymic selection, and seem to control the specificity of the immune response rather than mediate a generic predisposition to autoimmunity. Other loci, such as IDDM12 (CTLA4), may control more generic aspects of the immune response and be shared with other autoimmune diseases. CTLA4 is a strong candidate gene for autoimmune diseases because its protein product functions as a key negative regulator of T-cell activation. The susceptibility loci identified thus far harbor alleles that are commonly observed in the general population, and all seem to have normal sequence. This finding suggests that susceptibility may simply derive from polymorphisms affecting the function and expression of certain proteins. It is plausible that several loci may map to regulatory sequences (eg, VNTRs) and act as quantitative traits. Complex parental effects and other genetic mechanisms, such as alternative splicing, may modify the transmission and expression of inherited genes, or interact with inherited polymorphisms, increasing the complexity of the genetic mechanisms involved in T1D susceptibility. All of the three loci discussed in detail harbor predisposing and protective alleles, and protection is usually dominant over susceptibility. A full understanding of the molecular mechanisms controlled by these loci could unveil natural protective mechanisms that might be exploited for the prevention and cure of T1D.
|Original language||English (US)|
|Number of pages||16|
|Journal||Endocrinology and Metabolism Clinics of North America|
|State||Published - Mar 2004|
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism