Requirements of NK cells and proinflammatory cytokines in T cell-dependent neonatal autoimmune ovarian disease triggered by immune complex.
A model of neonatal autoimmune disease has been described recently in which an epitope-specific autoantibody to murine zona pellucida 3 induces severe ovarian disease in neonatal, but not adult, mice (neonatal AOD). The autoantibody forms immune complex with endogenous ovarian zona pellucida 3, and a pathogenic CD4(+) T cell response is triggered. The basis for the predominant neonatal susceptibility has not been clarified. In this study innate immunity, including neonatal NK cells, in neonatal AOD was investigated. Neonatal spleen contained readily detectable NK1.1(+)TCRVbeta(-), but not NK1.1(+)TCRVbeta(+), cells. Ab depletion of NK1.1(+)TCRVbeta(-) cells inhibited neonatal AOD development. Moreover, in adoptive transfer of neonatal AOD, recipient disease was ameliorated when either donor or recipient NK cells were depleted. Thus, NK cells operate in both induction and effector phases of the disease. IFN-gamma was produced by neonatal NK cells in vivo, and it may be important in neonatal AOD. Indeed, ovaries with neonatal AOD expressed high levels of IFN-gamma and TNF-alpha which correlated with disease severity, and the disease was inhibited by IFN-gamma or TNF-alpha Ab. Importantly, disease was enhanced by recombinant IFN-gamma, and treatment of T cell donors with IFN-gamma Ab also significantly reduced adoptive transfer of neonatal AOD. Finally, neonatal AOD was ameliorated in mice deficient in FcgammaRIII and was enhanced in FcgammaRIIB-deficient mice. We conclude that neonatal NK cells promote pathogenic T cell response at multiple stages during neonatal autoimmune disease pathogenesis. Also operative in neonatal AOD are other mediators of the innate system, including proinflammatory cytokines and FcgammaRIII signaling.
Setiady
Yulius Y
YY
Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA. js5bk@virginia.edu
Pramoonjago
Patcharin
P
Tung
Kenneth S K
KS
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D007105:Immune Complex Diseases / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D010049:Ovarian Diseases / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D007371:Interferon-gamma