Autoantibodies to pancreatic hsp60 precede the development of glucose intolerance in patients with cystic fibrosis

Persons expressing the genetic disease cystic fibrosis (CF) suffer from a h igh risk of developing impaired glucose tolerance and diabetes. The develop ment of diabetes in CF has been attributed, in the past, to the destruction of pancreatic islets and their resident P-cells secondary to the destructi on of the surrounding tissue by mechanical clogging of the pancreatic exocr ine ducts. However, the discovery that autoimmunity to the 60-kDa heat shoc k protein (hsp60) may cause type I diabetes in NOD mice raises the possibil ity that hsp60 autoimmunity may be involved in CF diabetes too; could the h yperimmunization to bacterial hsp60 characteristic of CF spread to self-hsp 60 and hence to autoimmune diabetes? We now report that rising levels of Ig G autoantibodies to hsp60 do indeed precede the appearance of glucose intol erance and diabetes in CF patients. We produced a recombinant human pancrea tic hsp60 protein and investigated the IgG antibody response to hsp60 in pr ediabetic and non-diabetic patients with CF. To detect hsp60 autoantibodies in the presence of high levels of antibodies to bacterial hsp60, we absorb ed test sera with the 60-kDa GroEL of Pseudomonas aeruginosa and used an im munostaining technique. Using this technique, 32 prediabetic CT patients we re evaluated over a five-year period, three years, on the average, before t he onset of glucose intolerance. We found that a significant increase in hs p60 autoantibody preceded impaired glucose tolerance (P=0.042, n=17), diabe tes (P=0.011, n=15) and glucose intolerance (P=0.005, n=32). As has been ob served in NOD mice and in type I diabetic patients, the hsp60 autoantibodie s decline at the outbreak of glucose intolerance in the CF patients. The as sociation of CF diabetes with the rise and fall of hsp60 autoimmunity sugge sts that the pathogenesis of the diabetes may not be merely mechanical, but arise in the wake of bacterial hyperimmunisation. (C) 2001 Academic Press.