Islet autoantibodies in cord blood from children who developed Type I (insulin-dependent) diabetes mellitus before 15 years of age

Abstract

Type I (insulin-dependent) diabetes mellitus is a multifactorial disease that develops after exposure to unknown environmental factors in children with specific HLA susceptibility genes. At the time of clinical diagnosis, the majority of the insulin-producing cells in the pancreatic islets have been eradicated in association with autoimmune phenomena including insulitis [1 ,2, 3], lymphocyte proliferation abnormalities [4,5,6] and autoantibodies to islet cell antigens [7±9]. Studies in first-degree relatives [7,8], twins [9], pregnant mothers [10,11] and school children [12,13,14] have found that islet autoantibodies can be present years before clinical diagnosis. Some [15±17], but not Diabetologia (1999) Summary Islet autoantibodies are early markers for Type I (insulin-dependent) diabetes mellitus. The aim of this study was to establish whether islet autoantibodies were present at birth in children who developed Type I diabetes before 15 years of age. Cord blood sera from 81 children who developed Type I diabetes between 10 months and 14.9 years of age were tested for glutamic acid decarboxylase autoantibodies (GAD65Ab), islet cell antigen 512 autoantibodies (ICA512Ab), insulin autoantibodies (IAA) all by quantitative radioligand binding assays and islet cell autoantibodies (ICA) by indirect immunofluorescence. Cord blood sera from 320 randomly selected matched children were controls. The children who developed Type I diabetes had an increased frequency of cord blood islet autoantibodies compared with control subjects: Glutamic acid decarboxylase autoantibodies were detected in 6 % (5/81) patients and 2 % (5/320) control subjects (p = 0.03); islet cell antigen 512 autoantibodies in 5 % (4/73) patients and 1 % (4/288) control subjects (p = 0.06); insulin autoantibodies (IAA) in 0 % (0/79) patients and 0.3 % (1/320) control subjects (p = 0.36); and islet cell autoantibodies in 10 % (8/81) patients compared with 0.6 % (2/320) control subjects (p = 0.0001). Taken together, 17 % (14/81) patients had one or more islet autoantibody compared with 4 % (12/320) control subjects (p = 0.0001). Whereas none of the control children had more than one antibody, 4 % (3/81) children who later developed Type I diabetes were double positive (p = 0.002). Although glutamic acid decarboxylase autoantibodies' concentrations in cordblood correlated to those in the mothers' blood at the time of delivery, no corresponding correlation was found for the other two types of autoantibodies. The increased frequency of cord blood islet autoantibodies suggests that the Type I diabetes process could already be initiated in utero. [Diabetologia (1999)

Evidence for a locus (IDDM16) in the immunoglobulin heavy chain region on chromosome 14q32.3 producing susceptibility to type 1 diabetes

“…66 Recent studies have shown increased frequencies of autoantibodies in blood taken from infants and young children who subsequently develop diabetes, suggesting that the autoimmune process may begin very early. [31][32][33] Among relatives of type 1 diabetics, those with anti-GAD antibodies who progressed to develop diabetes ('progressors') were more likely to have anti-GAD of subclass IgG1 and/or IgG3. On the other hand, relatives with anti-GAD antibodies who did not progress to develop diabetes ('non-progressors') were more likely to have IgG2 and/or IgG4 antibodies.…”

“…Presence of autoantibodies (especially multiple antibodies at high titres) is strongly associated with risk of progressing to clinical diabetes, both in relatives of type I diabetics [30][31][32][33] and in the general population. 34 It is not clear whether these autoantibodies directly participate in ␤-cell destruction by binding with ␤-cell antigens, or whether they arise as a consequence of ␤-cell destruction following release of self-antigens from destroyed ␤-cells 35 or both.…”

Genetic linkage and association studies of Type I diabetes: challenges and rewards

“…Either way, the presence of antibodies to islet cell components (especially multiple autoantibodies at high titres) is strongly associated with risk of progressing to clinical diabetes, both in relatives of Type I diabetic patients [7] and in the general population [28]. Recent studies have shown that autoantibodies occur even in infants and young children who later develop diabetes, suggesting that the autoimmune process could begin very early in life, perhaps prenatally [8,29,30]. Because autoantibodies are biological markers for preclinical diabetes, it is important to know whether these autoantibodies show evidence for genetic determination, or whether they merely reflect the presence of non-genetic diabetes-predisposing factors (such as viruses that damage beta cells).…”

Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring

“…Vitamin D has several effects on the immune system that could be of relevance in the pathogenesis of type 1 diabetes [8,9]. The process leading to the destruction of the beta cells might be initiated even before birth [10], therefore the effect of early environmental determinants in utero may be of crucial importance. Because maternal vitamin D intake and status during pregnancy affect neonatal vitamin D status [11][12][13], the former is an important area to study when searching for factors potentially involved in the development of type 1 diabetes.…”