GAD65 Antibody Epitopes and Genetic Background in Latent Autoimmune Diabetes in Youth (LADY)

Abstract

Epitope-specific GAD65Abs and HLA-DR-DQ gene assays help improve the value of risk stratification in autoimmune diabetes mellitus and protect islet function. Identification and early intervention are important for latent autoimmune diabetes in youth (LADY). The aims of this study were to investigate 1) the frequencies of the epitope-specific GAD65Abs and HLA-DR-DQ genes in LADY and 2) the association between HLA-DR-DQ genes and epitope-specific GAD65Abs. Higher frequencies of GAD65-CAb and multiepitope GAD65Abs were observed in young type 1 diabetes, LADY, and old type 1 diabetes subjects than those in latent autoimmune diabetes in adult (LADA) patients. The frequencies of the specific susceptible HLA haplotype DR3, total susceptible HLA haplotypes, and high-risk genotypes were higher in type 1 diabetes and LADY patients than those in LADA patients. In contrast, type 1 diabetes and LADY patients had lower frequencies of low/no genetic risk genotypes (DRX/X) than those of LADA patients. Logistic regression analysis suggested that the susceptible HLA haplotypes were risk factors for glutamic acid decarboxylase antibody (GADA) multiepitope positivity in autoimmune diabetes mellitus. LADY may be more severe than LADA, and LADY seemed to be a transitional type of type 1 diabetes and LADA. GADA epitope and HLA-DR-DQ gene assays are important for risk stratification in autoimmune diabetes mellitus and protection of islet function.

Distribution of autoantibodies to insulinoma‐associated antigen‐2 and zinc transporter 8 in type 1 diabetes and latent autoimmune diabetes: A nationwide, multicentre, cross‐sectional study

“…These results demonstrated that autoimmune beta cell destruction may be slower and weaker in patients with T2D. In addition, the HLA analysis found that there was no significant difference between patients with ADM with the exception of DR4 , which is in agreement with previous studies showing that most T1D‐associated HLA haplotypes confer LAD susceptibility as well, 8 , 9 , 10 , 24 suggesting that patients with ADM share a similar pathogenesis and that the autoimmune response of patients with ADM is derived from similar HLA genetic backgrounds. In addition, it is noteworthy that patients with T2D may have a higher risk of cardiovascular disease owing to more obesity and higher blood pressure levels than those in patients with ADM.…”

“…The detailed methods of HLA‐DR‐DQ genetic analysis have been described previously. 8 The susceptible HLA haplotypes included DR3 ( DRB1*0301‐DQA1*0501‐DQB1*0201 ), DR4 ( DRB1*0405‐DQA1*0303‐DQB1*0401 ), DRB1*0405‐DQA1*0301‐DQB1*0302, and DR9 (DRB1*0901‐DQA1*0303‐DQB1*0302). 7 , 11 , 12 DR3/3 , DR3/9 , and DR9/9 are considered high‐risk HLA genotypes.…”

“…The detailed methods of HLA-DR-DQ genetic analysis have been described previously. 8 The susceptible HLA haplotypes included 2A) and LAD (Figure 2B) with IA-2A positivity. Based on the bimodal distribution, we chose a nadir value (600 units/ml) between the two peaks as the threshold for classifying T1D and LAD into two subpopulations; high IA-2A titres (IA-2A titre ≥600 units/ml, range 623.6-1420.2 units/ml) were observed in 36.5% of patients with T1D (69 of 189), low IA-2A F I G U R E 2 Distribution of IA-2A and ZnT8A in patients with T1D and LAD.…”

“…HLA class II genes are well recognized as a major genetic factor. Several lines of evidence support that both DQ and DR confer a high risk of T1D, 7 LADY, 8,9 and LADA. 10,11 However, it is noteworthy that HLA genes conferring the risk of ADM vary depending on ethnic origin.…”

HLA‐DR3 mediated CD4 T cell response against GAD65 in type 1 diabetes patients

“…19,20,[26][27][28] A recent study that investigated the association between epitope-specific GADA and the HLA-DR-DQ haplotypes revealed that T1D-susceptible HLA haplotypes, particularly DR3 positive haplotypes, associate strongly with GAD65Ab multiepitope positivity, suggesting that an important pathological mechanism in T1D might involve the presentation of GAD65 peptides by both HLA-DR and HLA-DQ molecules. 29 The present study was carried out to characterize the GAD65 epitopes possibly presented by HLA-DR3/DQ2 molecules to CD4 T cells and compare them between T1D patients and HC. We used four pools of GAD65 peptides (the top 30 overlapping peptides, predicted to bind in silico to HLA-DR3 molecule, HLA-DQ2 molecule, or both) to stimulate the CD4 T cells for the expression of proinflammatory cytokines IFN-γ, IL-17, and TNF-α and anti-inflammatory cytokine IL-10.…”