HLA MOLECULE AND IDDM1 GENE IDDM 1 (genes encoded within HLA region) remains the most powerful determinant of type 1 DM accounting for approximately 40% of familial inheritance of the disorder. HLA Molecules HLA are glycoproteins found on the surface of cells. They are comprised of class I and class II, both being encoded by different genes within the HLA region of chromosome 6. Class I molecules are found on surface of all nucleated cells and are involved in the ‘restriction’ of cytotoxic T lymphocyte activity. The antigen 325 peptides are recognised by CD8+ T lymphocytes only when they are presented along with HLA molecule. Class II molecules are normally confined to antigen presenting cells such as macrophages, B lymphocytes and activated T lymphocytes. Class II molecules are comprised of α and β chains which bind to foreign and self antigens in a cleft on the surface of molecule to be presented to CD4+ helper T lymphocytes. Owing to the crucial role played by HLA molecules in immune response, any alterations in their structure might influence the predisposition to autoimmune disorders. The genes for class I HLA are encoded in HLA, A, B and C loci while that for class II are located on HLA, DP, DQ and DR regions. The first evidence of allelic association between the HLA complex and type 1 DM was reported for the HLA-B15 allele and was based on serology. In subsequent studies, a positive association of type 1 DM with HLA-B8 and a negative association with HLA-B7 were established. Higher risks were shown to be associated with HLA class II specificities, namely DR3 and DR4, whereas DR2 (now renamed DR15) was shown to be protective. More than 90% of white Caucasian patients with type 1 DM have DR3 and/or DR4 as compared with 40% to 50% of controls. The greatest risk of type 1 DM is conferred by the simultaneous presence of DR3 and DR4, which are found together in 30% to 50% of patients but in only 1% to 6% of controls. Recent molecular studies indicated that the primary susceptibility genes are situated in the HLA-DQ rather than the DR region. In white Caucasians, the DQA1*0301, DQB1*0302 (DQ8) allele (associated with DR4) and DQA1*0501-DQB1*0201 (DQ2) allele (associated with DR3) have the strongest association with type 1 DM. In contrast, DR2 and DQ6 (DQA1*0102-DQB1*0602) provide protection against the development of type 1 DM. North Indian data suggests the strongest association is with DR3 unlike in south Indians where both DR3 and DR4 are associated with type 1 DM. Data from Orissa shows that DRB1*03 and DQ2 (DQA1*501, DQB1*0201), but not DR4 and DQ8, was significantly increased in patients with type 1 DM. IDDM2 IDDM2 has been mapped to 5’ end of insulin gene with variable number of tandem repeats (VNTR). IDDM2 contributes to 10% of familial inheritance. The class I allele of IDDM2 is associated with development of type 1 DM while class III is protective. prepare me flow chart with diagramatic representation of the pathogenesis