Insulin-dependent diabetes mellitus (IDDM) is a disease resulting from the autoimmune destruction of the insulin-producing .beta.-cells of the pancreas. Studies directed at identifying the autoantigen(s) responsible for .beta.-cell destruction have generated several candidates, including poorly characterized islet cell antigens (ICA) (Bottazzo et al., Lancet 2: 1279-83, 1974), insulin (Palmer et al., Science 222: 1337-39, 1983), glutamic acid decarboxylase (GAD) (Baekkeskov et al., Nature 298: 167-69, 1982; Baekkeskov et al., Nature 347: 151-56, 1990), and a 64 kD islet cell antigen that is distinct from GAD and that which yields 37 kD and 40 kD fragments upon trypsin-digestion (Christie et al., Diabetes 41: 782-87, 1992).
Detection of specific autoantigens in prediabetic individuals has been used as a predictive marker to identify, before clinical onset and significant .beta.-cell loss has occurred, those at greater risk of developing IDDM (Gorsuch et al., Lancet 2: 1363-65, 1981; Baekkeskov et al., J. Clin. Invest. 79: 926-34, 1987; Johnstone et al., Diabetologia 32: 382-86, 1989; Ziegler et al., Diabetes 38: 1320-25, 1989; Baekkeskov et al., Nature (Lond) 347: 151-56, 1990; Bonifacio et al., Lancet 335: 147-49, 1990; and Bingley et al. Diabetes 43: 1304-10, 1994).
Antibodies to the 40 kD, and more particularly the 37 kD, ICA fragments are detected when clinical onset of IDDM is imminent and are found to be closely associated with IDDM development (Christie et al., Diabetes 41: 782-87, 1992). Diabetic sera containing antibodies specific to the 40 kD fragment were recently found to bind to the intracellular domain of the protein tyrosine phosphatase, IA-2/ICA512 (Lu et al., Biochem. Biophys. Res. Comm. 204: 930-36, 1994; Lan et al., DNA Cell Biol. 13: 505-14, 1994; Rabin et al., J. Immunol. 152: 3183-88, 1994; Payton et al., J. Clinc. Invest. 96: 1506-11, 1995; and Passini et al., Proc. Natl. Acad. Sci. USA 92: 9412-16, 1995). Antibodies specific to the 37 kD fragment are thought to bind either to a posttranslational in vivo modification of IA-2/ICA512 or a different, but probably related, protein precursor (Passini et al., ibid.).
ICA 512 was initially isolated as an autoantigen from an islet cell cDNA library, and was subsequently shown to be related to the receptor-linked protein tyrosine phosphatase family (Rabin et al., ibid.). ICA 512 was later found to be identical to a mouse and human protein tyrosine phosphatase, IA-2, isolated from brain and insulinoma cDNA libraries (Lu et al., ibid.; and Lan et al., ibid.).
Detection of diabetes-associated autoantigens, especially combinations of autoantigens, genotypes, such as HLA DR and HLA DQ, and loci, such as the polymorphic region in the 5' flanking region of the insulin gene; in prediabetic individuals have been shown to be useful predictive markers of IDDM, see for example, Bell et al., (Diabetes 33:176-83, 1984); Sheehy et al., (J. Clin. Invest. 83:830-35, 1989); and Bingley et al., (Diabetes 43: 1304-10, 1994). There is therefore a need in the art for autoantigens that would serve to improve detection and diagnosis of IDDM. The present invention fulfills this need by providing novel autoantigens as well as related compositions and methods. The autoantigens of the present invention represent a new .beta.-cell antigen. The present invention also provides other, related advantages.