Intrinsic autoimmune capacities of hematopoietic cells from female New Zealand hybrid mice.
Most systemic autoimmune diseases occur more frequently in females than in males. This is particularly evident in Sjögren's syndrome, systemic lupus erythromatosis (SLE) and thyroid autoimmunity, where the ratio of females to males ranges from 20:1 to 8:1. Our understanding of the etiology of SLE implies important roles for genetics, environmental factors and sex hormones, but the relative significance of each remains unknown. Using the New Zealand hybrid mouse model system of SLE, we present here a new fetal liver chimera-based system in which we can segregate effects of immune system genes from that of sex hormones in vivo. We show that female hematopoietic cells express an intrinsic capacity to drive lupus-like disease in both male and female recipient mice, suggesting that this capacity is hormone independent. Particularly, only chimeric mice with a female hematopoietic system showed significantly increased numbers of germinal center B cells, memory B cells and plasma cells followed by a spontaneous loss of tolerance to nuclear components and hence elevated serum antinuclear autoantibodies. A protective effect of testosterone was noted with regard to disease onset, but not disease incidence. Thus, genetic factors encoded within the female hematopoietic system can effectively drive lupus-like disease even in male recipients.
Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO, USA.
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David
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
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Trigunaite
Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO, USA.
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Macleod
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
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Johnson
Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO, USA.
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Marrack
1] Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO, USA [2] Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
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Jørgensen
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology; D015551:Autoimmunity; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D005260:Female; D005333:Fetus; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006412:Hematopoietic Stem Cells; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation; D006824:Hybridization, Genetic; D016898:Interferon-alpha / Q000097:blood; D007674:Kidney Diseases / Q000209:etiology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D011247:Pregnancy; D018183:Transplantation Chimera
D001323:Autoantibodies; D012739:Gonadal Steroid Hormones; D016898:Interferon-alpha