HLA-haplotypes, anti- beta-cell antibodies: their role in prognostication of type 1 diabetes mellitus (results of 11-year observation)

The risk of type 1 diabetes mellitus (DM1) depends in the first place on the presence of predetermining HLA DR haplotypes, DQ genes, and specific autoantibodies.Aim.
Prospective observation of DM1 risk groups (healthy sibs of DM patients) for the elucidation of the role of genetic and autoimmune abnormalities in thedevelopment of DM1.
Materials and methods.
Predetermining and protective haplotypes (HLA-DRBI, DQ genes) in combination with immunological markers (autoantibodiesto cytoplasmic structures of betbeta-cells (ICA), anti-insulin autoantibodies (IAA), anti-glutamate decarboxylase autoantibodies (GAD)) were studied in healthysibs of mean age 11.9?5.8 years selected from 143 discordant families of patients with DM1. In addition, a random sample of 599 DM1 patients (mean age7.5?6.2 years) was enrolled for molecular genetic studies (HLA-DRBI-DG genes). The control group comprised 200 subjects.
Results.
DQAI*0501-DQB1+0201 (DQ2) and DQAI*0301-DQBI*0302 (DG8) haplotype heterozygosity creating the highest risk of DM1, the healthy sibswere divided into 3 risk groups. The high risk group 1 (DQ2/DQ8) included 23 (13.5%) subjects, moderate risk group 2 (DQ2/X, DQ8/X) 85 (59.7%), andlow risk group 3 (X/X; X - any haplotype besides DQ2, DQ8) 63 (36.8%). The frequency of autoantibodies (AB) of 2 or 3 species in group 1 was higher thanin groups 2 and 3 (26.1, 14.1, 11.1% respectively, p>0.05; 8.7, 2.4, 0%, p<0.05). A single AB species also occurred more frequently in group 1 than in groups2 and 3 (52.1, 27.6, 26.2%). GAD were more frequent in DQ2/DQ8 group compared with groups 2 and 3 (65, 37.9, 18% respectively, p<0.05). The same istrue of IAA (19, 12.9, 3,7%, p1.3<0.05).There was no significant difference in the ICA occurrence between the groups. Manifestation of DM1 during the 11-year observation period was documented in 11 (6.4%) subjects, in agreement with the DM1 risk estimates for healthy sibs obtained in early population studies.The disease was diagnosed in 8.7% of the sibs in group 1, 8.0% in group 2, and 3.3% in group 3. 82% of the new patients expressed high-risk haplotypes(DQ2/DQ8 genotype occurred in 18.2%, DQ2/X and DQ8X in 63.6% cases, and only18.2% patients had no predisposing haplotypes). 73% of the new patientswere AB-positive and 27% AB-negative. Sibs from group 1 were AB-negative 1-5 years before manifestation of DM1 when 85.7% and 100% of the sibs fromgroups 2 and 3 were AB-positive. ICA were detected in 16.7%, GAD in 66.6%, and CAD+ICA in 16.7% of the cases in group 2; ICA at significant titers occurred in 100% of the cases in group 3. The absence of AB in the newly diseased sibs from groups 1 and 2 can be accounted for by the wave-like character of the autoimmuneprocess or the destruction of most betbeta-cells (decrease in antigenic determinants responsible for immune reactions on their surface).
Conclusion.
The study confirmed that the presence of DQ2,DQ8 haplotypes in healthy sibs increases the risk of DM1 while their absence do not reliablyguarantee protection from the disease

diabetes mellitus, HLA-haplotypes, autoantibodies, prognostication

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