Autoimmune markers in autoimmune diabetes

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, characterized by autoimmune mediated loss of insulin secreting Beta-cells. The disease is associated with certain HLA class 11 haplotypes. HLA DR3-DQ2 and DR4-DQ8 are positively while DQ6 (DQA1*0102-DQB1*0602) is negatively associated with the disease in Caucasians. Taken together, DQ8 and/or DQ2 account for 89% of Swedish T1DM patients. Other genetic loci might be associated with T1DM. The hope is that by assessing multiple risk loci, pattern of alleles that substantially increase the sensitivity of genetic typing can be identified. Besides HLA-DQ and DR, polymorphism in another gene, MHC class I chain related gene-A (MICA), located in HLA class I region has been reported to influence the susceptibility to T1DM.

Autoantibodies against beta-cell antigens GAD65, IA-2 and insulin (IAA) are markers for T1DM and are rarely found in healthy population. Certain group of patients clinically diagnosed as type 2 diabetes mellitus (T2DM) does not respond to oral hypoglycemic treatment and require insulin therapy. Many of these T2DM patients are positive for T1DM associated autoantibodies and become insulin deficient because of autoimmune beta-cell destruction. This form of diabetes is called as latent autoimmune diabetes in adults (LADA) or slow - onset T1DM. Viruses, in particular Coxsackie virus B (CBV), are one of the environmental factors proposed to be involved in disease pathogenesis.

Aims: To determine, in Swedish population, the association of MICA gene polymorphism with acute onset T1DM. with LADA, with antibodies against CBV among T1DM patients, with autoantibodies among T1DM patients and to determine the frequency of MICA alleles among newborn babies genetically at-risk to develop T1DM with respect to HLA-DQ.

Results and discussion: We found MICA5 to be positively associated among 0-35 year old T1DM. independent of high-risk HLA. MICA5 with DR3-DQ2 gave a higher risk compared to risk with DR3DQ2 alone. MICA6 was negatively associated with younger onset (0-20 years) T1DM. MICA5/5.1 was associated with T1DM and LADA. Association of DR3-DQ2/DR4-DQ8 and DR3DQ2/DR3DQ2 with LADA as reported earlier was confirmed. We found DR3-MICA5.1 to be more significantly associated with antibodies against CBV compared to DR3 alone or other high-risk HLA alone in the high incidence region of Linköping in southeast of Sweden. We still don't know how MICA polymorphism along with CBV infection might be important in T1DM pathogenesis. However, we cannot rule out that our observation could be a mere chance.

Among autoantibodies, IAA are believed to appear first and are more prevalent in disease onset at younger age. IA-2 antibodies are associated with acute onset of the disease and are also more important in younger age. MICA alleles and genotypes, especially MICA5/5, showed association with IAA and IA-2 autoantibodies. Thus, the presence of MICA5/5 in addition to IAA or IA-2 autoantibodies could be a valuable marker for prediction strategies. Finally, we report the frequency of MICA alleles in Swedish newborn babies at genetically high-risk with respect to HLA-DQ; frequency of MICA5 was 38% in DQ8+, 3 5% in DQ2DQ8+, 22.5% in DQ2+; frequency of MICA5.1 was 81% in DQ2+, 62% in DQ8+, 71% in DQ2DQ8+; frequency of MICA6 was between 20-22% among the three groups. MICA5/5.1 was present in 19% of DQ2-DQ8+ and 12-13% of DQ2+ and DQ8+.

Conclusion: MICA appears to be important in the etiology of T1DM. Inclusion of MICA typing in addition to HLA could be useful for screening of genetic markers associated with T1DM