Relationship of Type 1 Diabetes with Human Leukocyte Antigen (HLA) Class II Antigens Except for DR3 and DR4

Abstract

Type 1 diabetes (T1D) is the form of the disease that occurs primarily as a result of ┚-cell destruction. The American Diabetes Association (ADA) and the World Health Organization (WHO) have classified T1D into 2 categories, namely, immune-mediated (autoimmune) and idiopathic (Alberti & Zimmet, 1998; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997). In autoimmune T1D (type 1A diabetes), the rate of ┚-cell destruction is quite variable, being rapid in some individuals and slow in others (Zimmet et al., 1994). Markers of immune destruction, including islet cell autoantibodies (ICA), autoantibodies to insulin (IAA), autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to tyrosine phosphatases IA-2, are present in 85–90% of individuals with T1D when fasting diabetic hyperglycemia is initially detected (Verge et al., 1996). The rapidonset (“classic”) form of T1D is commonly observed in children, but also may occur in adults (Humphrey et al., 1998). The slow-onset form of T1D generally occurs in adults and is sometimes referred to as latent autoimmune diabetes in adults (LADA) (Zimmet et al., 1994). This term has been commonly used to refer to autoimmune forms of diabetes that do not initially require insulin. However, it is now clear that diabetes in these patients is not latent and is not limited to adults (Borg et al., 2003; Fourlanos et al., 2005; Landin-Olsson et al., 1992; Turner et al., 1997). On the other hand, idiopathic T1D (type 1B diabetes) lacks immunological evidence for ┚-cell autoimmunity (Alberti & Zimmet, 1998; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997). A new subtype known as “fulminant T1D” has been described in Japan. The clinical characteristics of this form of diabetes are remarkably abrupt onset of disease, very short (< 1 week) duration of diabetic symptoms, and virtually no C-peptide secretion (< 10 μg/day in urine) (Imagawa et al., 2000a). Although more than 250 patients with fulminant T1D have been reported in Japan, only few patients with fulminant T1D have been reported outside Japan (Imagawa & Hanafusa, 2005). Therefore, in the Japanese population, in contrast to other ethnic groups, there are 3 prevalent subtypes of T1D: rapid-onset (“classic”), slow-onset, and fulminant T1D. T1D is a multifactorial disease caused by a complex interaction of genetic and environmental factors. It is beyond doubt that the human leukocyte antigen (HLA) complex constitutes the most relevant susceptibility region. The HLA complex contributes 50% of the