GAD65 Antibody Epitopes And Genetic Background In Latent Autoimmune Diabetes In Youth(LADY)

Objective: Autoimmune diabetes mellitus is a type of immune mediated diabetes that occurs under genetic background.Islet autoantibodies are the main markers of pancreatic autoimmunity.Glutamate decarboxylase antibody(GADA)is the islet autoantibody with the highest positive rate,and its epitope has significant heterogeneity.HLA molecules are the main genetic factor for autoimmune damage to pancreatic β cells in autoimmune diabetes.There is no research on epitope-specific GADA and HLA genetic background in latent autoimmune diabetes in youth(LADY).This article compares the frequencies of epitope-specific GAD65 antibody and HLA-DR-DQ gene among different subtypes of autoimmune diabetes.We try to explore and clarify the immune genetic characteristics of LADY and to provide evidence for the importance of early intervention and protection of pancreatic islet function in patients with LADY.This study included 17,536 patients from 46 research centers across the country.The islet autoantibodies(GADA,IA-2A and Zn T8A)were detected by radioligand assay(RLA)and patients were divided into GADA-positive patients and all islet autoantibody-negative type 2diabetes mellitus(T2DM)groups including GADA,IA-2A and Zn T8 A.Through screening and sampling,30 years old was used as the cut-off age.The frequencies of epitope-specific GAD65Ab(GAD65-NAb,GAD65-MAb and GAD65-NAb)were detected by radioligand assay in young T1DM(n =165),LADY(n=94),old T1DM(n=149)and LADA(n=78);HLA-DR-DQ genes were assayed in T1DM(n=168),LADY(n=62),LADA(n=59)and T2DM(n=234).Results:(1)The results of the frequencies of epitope-specific GAD65 Ab showed that the frequencies of GAD65-CAb were higher in young T1 DM LADY and old T1 DM groups than in LADA group(57.6% vs.33.3%,P<0.001;48.9% vs.33.3%,P<0.001;58.4% vs.33.3%,P<0.05);GAD65-NAb showed a higher frequency in LADA group than in the young T1 DM group(20.5% vs.7.3%,P<0.01);there was no significant difference in the frequencies of GAD65-NAb,GAD65-MAb and GAD65-CAb between LADY group and T1 DM group.(2)There was no significant difference in the frequency of GAD65 Ab binding to only one epitope of GAD65 among young T1 DM,LADY,and old T1 DM and LADA patients.Young T1 DM,LADY,and old T1 DM patients showed higher levels of reactivity against multiple epitopes of GAD65 than the levels of LADA patients(44.2% vs.26.9%,P<0.05;45.7% vs.26.9%,P<0.05;and 43.6% vs.26.9%,P<0.05,respectively).(3)The frequencies of DR3,total susceptible HLA haplotype and high-risk HLA genotypes were higher in T1 DM and LADY patients than that in LADA patients.In contrast,T1 DM and LADY patients had lower frequencies of low/no genetic risk genotypes(DRX/X)than LADA patients.There was no significant difference between LADA and T2 DM in DR3,total susceptible haplotype and high-risk susceptible genotype.(4)Logistic regression analysis suggested that DR3 and the susceptible HLA haplotype were risk factors for GAD65 Ab multiepitope positivity.There was no significant association between GAD65-CAb and susceptible HLA haplotypes and genotypes.(5)The levels of fasting C peptide in young T1 DM,LADY and old T1 DM subjects were lower than those in LADA subjects.Conclusions:Compared with LADA,GAD65 epitope-specific antibody profiles of LADY was closer to that of T1 DM.Compared with LADA,HLA genetic background profiles of LADY was closer to that of T1 DM.DR3 and HLA total susceptible haplotypes were risk factors for GAD65 Ab multiepitope positivity.Islet function was worse in LADY and T1 DM patients compared with LADA patients.The detection of GAD65epitope-specific antibody and the screening of susceptible HLA haplotype and genotypes are of great significance for predicting and protecting islet function in patients with autoimmune diabetes.