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Early induction of type 1 diabetes

Type 1 diabetes is the second most common chronic childhood illness, after asthma, in Europe and North America. The disease is due to destruction of the insulin secreting (cells of the pancreatic islets of Langerhans [1]. At the clinical onset of type 1 diabetes about 80% of islets contain no (cells and the islets may be infiltrated with mononuclear cells [2]. Mononuclear cell infiltration is not a consistent feature, but includes macrophages and T lymphocytes with lymphocytes predominating and CD8 positive cells being most prevalent [1]. It is thought that the destructive process is mediated directly or indirectly by these immune effector cells. In the years before the clinical onset of type 1 diabetes, immune and metabolic changes can be detected in peripheral blood [3]. Since the nature, intensity, extent and persistence of these immune changes distinguishes individuals who develop diabetes from those who do not, these changes can predict type 1 diabetes [4]. The long prediabetic period and the potential for prediction have led to attempts to prevent clinical disease. But for how long is this prediabetic period and when are the immune changes which lead to diabetes induced? In this issue of Clinical and Experimental Immunology, Mikhail Knip and his colleagues seek evidence that the process may be induced in utero [5]. 
 
Antibodies have been identified against a number of antigens in patients with newly diagnosed type 1 diabetes and antibodies against two of these, glutamic acid decarboxylase (GAD) and a protein tyrosine phosphatase (IA-2), are detected in about 90% of such patients, while insulin autoantibodies (IAA) are prevalent in young newly diagnosed diabetic children [3]. These antibodies are probably induced by the interaction of genetic and environmental factors. Type 1 diabetes represents a heterogeneous and polygenic disorder in which genes within the major histocompatibility complex (MHC) HLA class II region on chromosome 6p21 account for about 45% of disease susceptibility [6] while a non HLA loci on chromosome 11p5.5 [7] contributes about 10% toward disease susceptibility [6]. 
 
The most powerful evidence that nongenetic factors play a major role in causing type 1 diabetes comes from the study of monozygotic (MZ) and dizygotic (DZ) twins [8]. Differences or discordance between MZ twins must be due to nongenetically determined factors; while greater disease concordance in MZ than DZ twins indicates a genetic effect. Table 1 summarizes the results of concordance rates in population based cross-sectional twin studies for three immune-mediated diseases and is consistent with a major nongenetic effect causing these diseases, in association with limited genetic susceptibility. Although concordance is greater in MZ than DZ twins with autoimmune disease, the majority of MZ twins do not display concordance [8–11]. Recently a large prospective study of MZ diabetic twins found a diabetes concordance rate after up to 40 years review of about 50%, though the concordance rate was only 5% in adult onset cases, confirming that a major nongenetic effect causes type 1 diabetes [12]. 
 
 
 
Table 1 
 
Concordance rates (%) in population-based studies of immune-mediated diseases [9–11]