Studies on autoimmune diabetes in Latvians and other populations

Abstract

IDDM is an autoimmune disease, characterized by autoimmune mediated loss of insulin secreting B- cells. GAD65 and IA-2 are major B-cell specific autoantibodies and are not found in healthy population. IDDM is associated with certain HLA class II alleles. IDDM is positively associated with HLA DR3 and DR4 in Caucasians. From HLA-DQ molecules, DQ8 (DQA1*0301- DQB1*0302) is the most prevalent IDDM haplotype in Caucasians, followed by DQ2 (DQA1*0201-DQB1*0501). Taken together, DQ8, DQ2 or both account for as many as 89% of Caucasian IDDM patients. DQ6 (DQA1*0102 DQB1*0602) is associated with the protection against IDDM in most populations.

A certain group of NIDDM patients doesn't respond to oral hypoglycemic treatment and insulin therapy is required. Majority becomes insulin - deficient because of autoimmune B- cell destruction. It is described as latent autoimmune diabetes in adults (LADA) or slow - onset Type 1 (autoimmune) diabetes.

MRDM as a separate form if diabetes mellitus, described in tropical regions and associated with undenutrition. The question remains if autoimmunity and genetic markers are associated with the development of MRDM.

The aim of this thesis was to investigate prevalence of different HLA class 11 molecules in different types of diabetes and different populations to answer the question if autoimmune diabetes is similar in most populations and if different genetic background in general population is responsible for different incidence of IDDM.

Another question was if GAD65 and IA-2 are main autoantigens in IDDM and autoantibodies against them are associated with IDDM, irrespective of ethnic background. And final question was if slow-onset autoimmunity is present among patients diagnosed as NIDDM in different populations.

The study on HLA markers showed that DR3-DQ2 and DR4-DQ8 were positively associated with the disease in Latvian diabetics. The negatively associated DQ taken together were present in more than 75% of healthy controls. The excess frequency of the negative associated DQ molecules in the general population could explain the lower incidence of IDDM in Latvia.

Indian diabetics showed positive association of IDDM with DR3 and DQ2 but not DR4 and DQ8. DQ6 (A*0102-B*0601) showed to be negatively associated with IDDM in South Indians. In the MRDM group - PDDM patients showed positive association with DR3 and DQ2, while FCPD patients had association with DR7 and DQ9.

GAD65ab were present in 57% of South Indian IDDM patients while 97% of Latvian IDDM patients carried either GAD65 or IA-2 autoantibodies. 55% of NIDDM patients carried one of the autoantibodies suggesting high prevalence of slow onset autoimmunity. Antibodies against minor autoantigens (TTG and 21-OH) add 1% of positivity in IDDM group. Still 10% of IDDM patients are negative for any of analyzed autoantibodies, suggesting involvement of other possible autoantigens. Antibodies against new beta cell antigen ICA12 (SOX13) alone, are present in only 3% of IDDM patients and 1% of NIDDM patients and adding ICA12ab to GAD65 and IA-2ab, gives only 1% increase in antibody positivity in both IDDM and NIDDM groups both in Latvian and Swedish diabetics.