Professor Dan Mueller

Autoimmunity develops as the consequence of a loss of tolerance to self-antigens. Investigations carried out by this researcher are leading to a better understanding of the biological and biochemical nature of immune self-tolerance. Of particular interest are those factors that determine whether prolonged and continuous antigen stimulation of a T-cell will lead to an increase in the clone size and the development of protective (or pathological) effector function, or lead to its functional inactivation (clonal anergy) and T-cell tolerance. Chronic antigen recognition in the absence of costimulatory ligands normally leads to clonal anergy induction, rather than aggressive immunity. This does not appear to be true, however, for individuals who are deficient in Foxp3+ T regulatory cells, where antigen recognition invariably leads to an expansion of the clone, continued functional responsiveness, and in some case immunopathology. Loss of T cell tolerance also leads to the expansion and differentiation of autoreactive B cells, and the development of B-dependent autoimmune disease. Currently, these biological principles are being investigated in models of CD4+ T cell-mediated immunopathology using both monoclonal TCR-transgenic mice, as well as self antigen-specific polyclonal responder T cells from normal mice. Finally, translational experiments are underway that investigate the repertoire of human autoreactive B cells in normals as well as in patients with rheumatoid arthritis and systemic lupus erythematosus.