Increased seroreactivity to proinsulin and homologous mycobacterial peptides in latent autoimmune diabetes in adults.

Magdalena Niegowska,Alessandro Delitala,Giovanni Mario Pes,Leonardo A Sechi,Giuseppe Delitala,Seyed Ehtesham Hasnain

doi:10.1371/journal.pone.0176584

Abstract

Latent Autoimmune Diabetes in Adults (LADA) is a slowly progressing form of immune-mediated diabetes that combines phenotypical features of type 2 diabetes (T2D) with the presence of islet cell antigens detected in type 1 diabetes (T1D). Heterogeneous clinical picture have led to the classification of patients based on the levels of antibodies against glutamic acid decarboxylase 65 (GADA) that correlate with clinical phenotypes closer to T1D or T2D when GADA titers are high or low, respectively. To date, LADA etiology remains elusive despite numerous studies investigating on genetic predisposition and environmental risk factors. To our knowledge, this is the first study aimed at evaluation of a putative role played by Mycobacterium avium subsp. paratuberculosis (MAP) as an infective agent in LADA pathogenesis. MAP is known to cause chronic enteritis in ruminants and has been associated with autoimmune disorders in humans. We analyzed seroreactivity of 223 Sardinian LADA subjects and 182 healthy volunteers against MAP-derived peptides and their human homologs of proinsulin and zinc transporter 8 protein. A significantly elevated positivity for MAP/proinsulin was detected among patients, with the highest prevalence in the 32-41-year-old T1D-like LADA subgroup, supporting our hypothesis of a possible MAP contribution in the development of autoimmunity.

Highlights

Latent Autoimmune Diabetes in Adults (LADA) is a slowly developing subtype of immunemediated diabetes characterized by a combination of clinical features typical to type 2 diabetes (T2D) and reactivity to islet cell antigens commonly detected in type 1 diabetes (T1D)
We here demonstrated the increased prevalence of Abs targeting a portion belonging to a Mycobacterium avuim subsp. paratuberculosis (MAP)-derived putative regulator for proline utilization (MAP2404c) and its human PI homolog with high sequence identity corresponding to contiguous fragments of B chain and C-peptide in Sardinian LADA patients
The study cohort was recruited from the local population known for an elevated incidence of autoimmune diseases [25] that has previously shown a significant reactivity against glucan branching protein of MAP (MAP1,4-αgbp) and the homologous peptide derived from B chain of human PI in subjects suffering from Hashimoto’s thyroiditis [26]

Summary

Introduction

Latent Autoimmune Diabetes in Adults (LADA) is a slowly developing subtype of immunemediated diabetes characterized by a combination of clinical features typical to type 2 diabetes (T2D) and reactivity to islet cell antigens commonly detected in type 1 diabetes (T1D). Even though some studies reported increased frequency of predisposing genotypes such as the T2D-associated variant in TCF7L2 transcription factor [5] or HLA T1D-susceptibility haplotypes [6, 7], major occurrence of less protective genotypes [8] and familial clustering linked to LADA pathogenesis [9], hereditary factors alone cannot explain progression towards β-cell failure in subjects at low genetic risk. Paratuberculosis (MAP) as an environmental agent at play in LADA pathogenesis. We have previously demonstrated a high prevalence of Abs targeting MAP-derived epitopes and their human homologs of proinsulin (PI) and zinc transporter 8 protein (ZnT8) in T1D at-risk subjects reaching 43% for MAP/PI homologous pair in Sardinian infants [19] and exceeding 62% for MAP/ZnT8 pair in youth from mainland Italy [20]. No significant anti-MAP seroreactivity was associated to T2D [21]

Methods

Results

Conclusion