MHC class II-dependent abnormal reactivity toward bacterial superantigens in immune cells of NOD mice.
Superantigens have been implicated in the pathogenesis of type I diabetes and other immune-mediated diseases. We therefore tested the hypothesis of an abnormal reactivity of the immune system toward bacterial superantigens during the prediabetic phase. For this purpose, splenocytes from NOD (H-2g7) mice were exposed to two well-characterized superantigens: Staphylococcal aureus enterotoxin-B (SEB) and toxic shock syndrome toxin-1 (TSST-1). Cells from BALB/c (H-2d) and C57BL/6 (H-2b) mice as well as those from NON (H-2non) and NOR (H-2g7) mice were used as controls. After 72 h of co-culture with the superantigens or the mitogen concanavalin A (Con A), proliferative response and mitochondrial activity were determined. In the culture supernatants, the cytokines gamma-interferon (IFN-gamma) and interleukin 10 (IL-10) were measured. Striking similarities between NOD cells and major histocompatiblity complex (MHC)-identical NOR cells could be observed with regard to a low proliferative and mitochondrial response to SEB, accompanied by a normal response to TSST-1 and Con A, respectively. In addition, only NOD and NOR spleen cells were low producers of the T-helper 1 (Th1) cytokine IFN-gamma in response to SEB. Conversely, abnormally high IFN-gamma levels were induced by TSST-1 in NOD and NOR spleen cells. The cytokine response to Con A was also biased toward IFN-gamma in both NOD and NOR. Since IFN-gamma and IL-10 are crucial disease-promoting or -protecting mediators in prediabetic NOD mice, superantigens may affect pathogenesis by acting on the Th1/Th2 cytokine balance. The low responder status toward SEB in NOD spleen cells may be of pathogenetic relevance in view of recent findings that the insulin B-chain also interacts with the SEB binding site on MHC class II molecules. In conclusion, we show here that immune cells from mice with a diabetes-associated MHC type respond differently to common environmental superantigens than do immune cells from control strains.
Radons
J
J
Diabetes Research Institute at the University of Dusseldorf, Germany.
Burkart
V
V
Kolb
H
H
D000818:Animals; D001427:Bacterial Toxins; D003208:Concanavalin A / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D004768:Enterotoxins / Q000494:pharmacology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013211:Staphylococcus aureus; D018089:Superantigens / Q000494:pharmacology*
D001427:Bacterial Toxins; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; D003208:Concanavalin A; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma