Major histocompatibility complex class I shedding and programmed cell death stimulated through the proinflammatory P2X7 receptor: a candidate susceptibility gene for NOD diabetes.
It has been hypothesized that type 1 diabetes is initiated by neonatal physiological pancreatic beta-cell death, indicating that the early stages of this autoimmune response may reflect a dysregulated response to immune "danger" signals. One potential danger signal is ATP, high concentrations of which stimulate the purinergic receptor P2X7 on hematopoietic cells. We compared the sensitivity of lymphocytes from model type 1 diabetic (NOD) and control (C57BL/10) mice to activation of this pathway. Stimulation of the P2X7 receptor of NOD mice resulted in more pronounced shedding of the lymphocyte homing receptor CD62L and in increased programmed cell death. Levels of major histocompatibility complex class I molecules, which have previously been reported to be poorly expressed on NOD lymphocytes, were initially normal, but the molecules were shed preferentially from NOD cells after P2X7 receptor stimulation. Thus, although NOD lymphocytes have been considered resistant to programmed cell death, they are highly sensitive to that stimulated through the P2X7 receptor. Because NOD mice express a low activation threshold allele of the P2X7 receptor and the P2X7 gene maps to a locus associated with disease, P2X7 is a good candidate susceptibility gene for NOD diabetes.
Elliott
James I
JI
Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, UK. james.elliott@csc.mrc.ac.uk
Higgins
Christopher F
CF
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009336:Necrosis; D018048:Receptors, Purinergic P2 / Q000276:immunology*; D058486:Receptors, Purinergic P2X7
D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7