Kenneth S. Tung
Primary AppointmentProfessor, Pathology
- MBBS, Medicine, Melbourne University, Melbourne, Australia
- Resident, Internal Medicine and Surgery, Melbourne University, Melbourne, Australia
- Resident, Pathology, Cleveland Clinic, Cleveland, Ohio
- Fellowship, Immunology, Scripps Clinic & Res. Fdn., La Jolla, CA
Mechanisms of Tolerance and Autoimmunity to Gonad-Specific Antigens
First, we investigate how Ag specific regulatory T cells bearing Foxp3 (Treg) control physiological self tolerance in normal mice. We discovered that regional lymph nodes of normal mice accumulate highly active Treg that suppress autoimmunity of the organ draining to it. We now want to know whether in this strategic location, Treg maintain self tolerance by preventing autoimmune disease triggered by endogenous "danger signal".
Second, we study sperm granuloma in unilaterally-vasectomized mice as endogenous "danger signal". Unexpectedly, vx mice develop tolerance to testis Ag, which is terminated by depletion of Treg, leading to severe testis autoimmune disease. We want to know how Treg normally control the choice between tolerance and autoimmune pathogenesis in autoimmune response. [The project is clinically relevant and of global significance, since the annual rate of vasectomy in the US alone is 0.5 million and rising.]
Third, we developed a model of spontaneous autoimmune disease in a mice expressing transgenic ovalbumin as male germ cell autoantigen and transgenic TCR specific for OVA peptide. [The model elucidates how human autoimmune diseases progress from preclinical to clinical stage, from remission to relapse, and design of appropriate therapy.] We discovered that transferred autoantibody rapidly forms immune complexes with OVA, which, contrary to current dogma, is not sequestered behind the blood-testis barrier. The immune complexes attract and activate Ag presenting cells and Ag specific T cells in a unique testis micro-environment, expanding pathogenic Th17 cells. We want to know the molecular mechanisms responsible for the events.
Fourth, we discover that maternal autoantibody, nonpathogenic in adults, induces pathogenic innate response, as well as de novo pathogenic T cell response in the progeny, leading to severe neonatal autoimmunity. Notably, antibody needs to reach the pups within but not beyond, the first 5 days of life. We found that the neonatal propensity for autoimmune disease is explicable by the functional supremacy of neonatal NK cell and FcgRIII+ cells over adult counterparts. [This is a model of congenital heart block: a serious human disease that occurs in the newborn of mothers suffering from Sjogren's disease, a type of lupus.]