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

Yiman Peng,Xiaohan Tang,Xia Li,Houde Zhou,Jing Liu,Qiuhe Ji,Xiaohong Niu,Gan Huang,Zhiguang Zhou,Yufei Xiang,Linong Ji,Jin Cheng,Xiang Yan

doi:10.3389/fimmu.2022.836952

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.

Highlights

Autoimmune diabetes mellitus (ADM) is a group of highly heterogeneous autoimmune diseases characterized by autoimmune mediation and destruction of islet beta cells
65-kDa isoform of GAD (GAD65) epitope analysis was performed on 165 young type 1 diabetes (T1D) patients, 94 latent autoimmune diabetes in youth (LADY) patients, 149 old T1D patients, and 78 Latent autoimmune diabetes in adults (LADA) patients
No reactivity to any of the epitopes of GAD65 was detected in 24.8%, 26.6%, 23.5%, and 41.0% of samples from young T1D patients, LADY patients, old T1D patients, and LADA patients, respectively

Summary

Introduction

Autoimmune diabetes mellitus (ADM) is a group of highly heterogeneous autoimmune diseases characterized by autoimmune mediation and destruction of islet beta cells. Type 1 diabetes (T1D) is characterized by islet autoantibody positivity, juvenile onset, and the requirement for insulin therapy. Subjects with phenotypic type 2 diabetes and islet antibody positivity, which has been described as “type 1.5 diabetes” (T1.5DM) or “latent autoimmune diabetes in adults (LADA)”, are non-insulin dependent for at least 6 months after onset [1]. Studies have reported that 10%–75% of Caucasians and 11.7% of Chinese juvenile-onset phenotypes may have “latent autoimmune diabetes in youth (LADY)” [2, 3]. Patients with LADY have a younger age of onset than those with LADA, and clinically, islet function and Cpeptide levels decline more rapidly in LADY than in LADA. There has been limited research on LADY, and it has not yet received attention from the international community

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