A Reg family protein is overexpressed in islets from a patient with new-onset type 1 diabetes and acts as T-cell autoantigen in NOD mice.
Genes overexpressed in pancreatic islets of patients with new-onset type 1 diabetes are potential candidates for novel disease-related autoantigens. RT-PCR-based subtractive hybridization was used on islets from a patient who died at the onset of type 1 diabetes, and it identified a type 1 diabetes-related cDNA encoding hepatocarcinoma-intestine-pancreas/pancreatic-associated protein (HIP/PAP). This protein belongs to the family of Reg proteins implicated in islet regeneration; its gene contains a putative interleukin-6 (IL-6) response element. Islets from healthy cadaveric human donors released HIP/PAP protein into the culture medium, and this release was enhanced by the addition of IL-6. The expression pattern of mouse homologues of HIP/PAP was determined in pancreata of prediabetic and diabetic NOD mice. Both groups showed positive immunostaining for HIP/PAP in islets and ductal epithelium. To test whether HIP/PAP is a target of islet-directed autoimmunity, we measured splenic T-cell responses against HIP/PAP in NOD mice. Spontaneous proliferation was detected after 4 weeks. Lymphocytes from islet infiltrates and pancreatic lymph nodes from 7- to 10-week-old NOD mice were used to establish an HIP/PAP-specific I-A(g7)-restricted T-cell line, termed WY1, that also responded to mouse islets. WY1 cells homed to islets of NOD-SCID mice and adoptively transferred disease when coinjected with purified CD8(+) cells from diabetic NOD mice. Our conclusion was that differential cloning of Reg from islets of a type 1 diabetic patient and the response of Reg to the cytokine IL-6 suggests that HIP/PAP becomes overexpressed in human diabetic islets because of the local inflammatory response. HIP/PAP acts as a T-cell autoantigen in NOD mice. Therefore, autoimmunity to HIP/PAP might create a vicious cycle, accelerating the immune process leading to diabetes.
Gurr
Werner
W
Department of Internal Medicine, Yale University, New Haven, Connecticut 06520-8020, USA.
Yavari
Reza
R
Wen
Li
L
Shaw
Margaret
M
Mora
Conchi
C
Christa
Laurence
L
Sherwin
Robert S
RS
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm; D001324:Autoantigens / Q000276:immunology*; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000503:physiopathology*; D037102:Lectins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D051847:Lithostathine; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000276:immunology*; D018345:Mice, Knockout; D016513:Mice, SCID; D005810:Multigene Family; D009419:Nerve Tissue Proteins; D010179:Pancreas / Q000502:physiology; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation
D000951:Antigens, Neoplasm; D001324:Autoantigens; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D015850:Interleukin-6; D037102:Lectins; D037181:Lectins, C-Type; D051847:Lithostathine; D009419:Nerve Tissue Proteins; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C497617:REG1A protein, human; C000612141:REG3A protein, human; C497615:Reg1 protein, mouse; C490253:Reg3b protein, mouse