title: Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy.
abstract: Mycobacterium avium subspecies paratuberculosis (MAP) asymptomatic infection is speculated to play a role in type 1 diabetes (T1D) among Sardinian subjects. Data obtained analyzing a pediatric population from mainland Italy lends support to the hypothesis, which envisions MAP as an environmental factor at play in T1D pathogenesis. Aiming to investigate the likelihood of cross-recognition between linear determinants shared by self (proinsulin) and non-self (MAP) proteins, 59 children with new onset T1D and 60 healthy controls (HCs) from continental Italy were enrolled in the study. Serum samples were subjected to indirect enzyme-linked immunosorbent assay (ELISA) for the presence of antibodies (Abs) toward four homologues MAP/proinsulin epitopes. The rate of MAP infection (42.4% in T1D children and 5% in HCs; p < 0.0001) was estimated searching for Abs against MAP specific protein MptD. The homologous MAP2404c70-85 and proinsulin (PI)46-61 peptides were recognized by 42.4 and 39% of new-onset T1D children and only in 5% of HCs (AUC = 0.76, AUC = 0.7, p < 0.0001); whereas the prevalence of Abs against MAP 1,4-α-gbp157-173 and PI64-80 peptides was 45.7 and 49.1% in new-onset T1D children, respectively, compared with 3.3% of HCs (AUC = 0.74 and p < 0.0001 in both). Pre-incubation of MAP Ab-positive sera with proinsulin peptides was able to block the binding to the correspondent MAP epitopes, thus showing that Abs against these homologous peptides are cross-reactive. MAP/Proinsulin Ab mediated cross-recognition, most likely via molecular mimicry, maybe a factor in accelerating and/or initiating T1D in MAP-infected children. Indeed, it is known that anti-proinsulin and anti-Insulin autoantibodies are the earliest to appear.
authors.affiliation: Department of Biomedical Sciences, Section of Experimental and Clinical Microbiology, University of Sassari, Sassari, 07100, Italy.
authors.forename: Speranza
authors.initials: S
authors.lastname: Masala
authors.forename: Davide
authors.initials: D
authors.lastname: Cossu
authors.forename: Simona
authors.initials: S
authors.lastname: Piccinini
authors.forename: Novella
authors.initials: N
authors.lastname: Rapini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mameli
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Manca Bitti
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Sechi
mesh_terms: D000293:Adolescent; D000917:Antibody Formation; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology*; D011384:Proinsulin / Q000276:immunology*
chemical_list: D000939:Epitopes; D011384:Proinsulin
keywords: Mycobacterium avium subspecies paratuberculosis; new-onset type 1 diabetes; pediatrics; proinsulin