Other Target Antigens

Antibodies to insulin, GAD65 and IA-2 are well established as distinct and important markers for diabetes diagnosis and prediction and the latter two antigens contribute to ICA reactivity on frozen sections of pancreas [103]. However it is clear that diabetic patients have increased immune reactivity to several other components of pancreatic islets, including proteins and glycolipids (Table 15.1). There is evidence that the sialo-ganglioside GM2-1 may represent a major component of ICA [104] and that antibodies to the glycolipid are associated with progression to diabetes in relatives with ICA. Sulfatides have also been shown to be reactive with antibodies in a high proportion of diabetic patients at disease onset [105]. Other protein antigens, such as ICA69 [106] and Glima 38 [107], have shown some promise as predictive markers for diabetes, but difficulties in establishing reproducible assays for these antibodies have prevented their widespread use in large-scale screening studies. Some antibodies, such as those to Glima 38, may be strongly associated with other established antibody markers, such as IA-2A [108]. It seems likely that, as a consequence of islet damage and antigen release in an inflamed islet, there is increased immune reactivity to a wide range of pancreatic islet components. Some of these immune responses are detected at low frequency in the diabetic population, their target antigens may be widely expressed in tissues, and antibodies may be detected in autoimmune diseases other than diabetes [109, 110]. There is currently little evidence that detection of autoantibodies to antigens other than insulin, GAD, and IA-2 adds significantly to diabetes prediction.

Antibodies that are reactive to heat shock proteins have also been detected in type 1 diabetes [111]. Since heat shock proteins are ubiquitous, it may seem surprising that immune reactivity to heat shock protein should be found in an organ-specific autoimmune disease such as diabetes. Increased T-cell reactivity is also a feature of the NOD mouse [112, 113], and immune responses to heat shock proteins have also been associated with other autoimmune disorders, in-

Table 15.1 Targets for islet-cell autoantibodies in type 1 diabetes.

Antigen

Ref.

Antigen

Ref.

Insulin

46

Glima-38

107

GAD65

49

Ganglioside GM2-1

104

GAD67

68

Sulfatide

105

IA-2 (ICA512)

50

ICA69

106

Phogrin (IA-2b)

51

Heat shock protein

111

eluding rheumatoid arthritis and systemic lupus erythematosus [114]. In some experimental diseases, T cells to heat shock proteins may be pathogenic, but there is considerable evidence that immunity to hsp60 is part of normal immunoregulation [114]. Heat shock proteins are upregulated in inflamed tissues, and the immune system may exploit this as a "danger signal" for the recruitment and regulation of inflammatory cells [115]. Immune regulation may be mediated by the secretion of cytokines that downregulate pathogenic responses; in the case of type 1 diabetes, such bystander suppression could be mediated by Th2 cytokines, IL-4, IL-10, or TGF-/5. Detection of antibody or T-cell reactivity to heat shock protein may therefore provide a general indication of an ongoing inflammatory response [116] and may explain the association of immune responses to these antigens in a number of chronic autoimmune disorders. If these responses do turn out to participate in immune regulation, then there may be the potential to exploit this as a general therapy for autoimmune disease, and trials of heat shock protein peptide therapy have already been initiated in diabetes [117].

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