The cardinal property of the normal immune system is the ability to distinguish antigens of self from non-self. A number of mechanisms have been proposed to account for this unresponsiveness to self, but a great deal remains to be learned. One of the most productive approaches to the study of self/nonself discrimination has been to examine in detail the instances where self-recognition is lost and autoimmunity arises. Often, autoimmunity is harmless, but sometimes it gives rise to autoimmune disease. The goal of our research, then, is twofold: first, to uncover the mechanisms by which animals usually avoid producing autoimmune responses, and, a second, to discover the avenues by which autoimmunity leads to pathological changes.

We are studying two well-defined models of autoimmune disease, thyroiditis and myocarditis. In both diseases, the induction depends upon a combination of genetic and environmental factors. The principal trait determining susceptibility to autoimmune disease is the major histocompatibility complex (MHC), but additional non-MHC genes are also involved. As environmental factors, dietary iodine is a trigger for thyroiditis and Coxsackievirus infection instigates myocarditis. To determine the pathological consequences of autoimmune responses, we are concentrating on particular cytokines and cytokine products. These experiments depend upon examining the local production of cytokines in autoimmune infiltrates, producing cytokines locally by constructing transgenic mice, and blocking cytokine action by administration of monoclonal antibodies or receptor antagonists. In parallel to experiments in mice, we are carrying out correlative investigations in patient populations.

Frisancho-Kiss S, Nyland JF, Davis SE, Barrett MA, Gatewood SJ, Njoku DB, Cihakova D, Silbergeld EK, Rose NR, Fairweather D. (2006) Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J. Immunol. 161:6128-6132 [PubMed]

Fairweather D, Frisancho-Kiss S, Njoku DB, Nyland JF, Kaya Z, Yusung SA, Davis SE, Frisancho JA, Barrett MA, Rose NR. (2006) Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. J. Immunol. 6:215-218 [PubMed]

Njoku DB, Mellerson JL, Talor MV, Kerr DR, Faraday NR, Outschoorn I, Rose NR. (2006) Role of CYP2E1 immunoglobulin G4 subclass antibodies and complement in pathogenesis of idiosyncratic drug-induced hepatitis. Clin. Vaccine Immunol. 14-15:1249-1259 [PubMed]

Rose NR. (2006) The significance of autoimmunity in myocarditis. Ernst Schering Res. Found. Workshop 72:2843-2849 [PubMed]

Goser S, Ottl R, Brodner A, Dengler TJ, Torzewski J, Egashira K, Rose NR, Katus HA, Kaya Z. (2005) Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy. Circulation 170:5027-5033 [PubMed]