Keywords: Host Response to Infection, Autoimmunity, Innate Immune Lymphocytes, non-classical class I molecules.
My group has been focused on the study of a novel family of conserved class I histocompatibility proteins termed non-classical or class Ib molecules. Studies from our laboratory and others have shown that class Ib molecules can function to present peptide and non-peptide epitopes to T cells. Several class Ib molecules have been implicated in the immune response to intracellular bacterial pathogens and mouse/human counterparts have been identified. This information indicates that class Ib molecules have evolved to play key roles in the immune recognition. As part of our overall objective to understand the basic immunobiology of class Ib molecules, we have generated a new murine transgenic model for the analysis of mouse (and human) class Ib function. This model will allow the definition of the role for class Ib molecules in the selection and function of T cells and allow us to examine the range of pathogens for which class Ib molecules play a role in immune recognition. In addition, we study the structure of endogenous self-peptides bound to class Ib molecules. Our goal is to understand physical/chemical basis of peptide binding to class Ib molecules as a means to understand the physiological settings in which these molecules function.
A second area of interest is to understand the link between infection as a trigger for chronic inflammatory states such as autoimmunity. In a murine infection model, we have found that CD8+ CTLs evoked following Salmonella-infection recognize a GroEL derived peptide presented by the class Ib molecule Qa-1. These CTL cross recognize an analogous peptide derived from mammalian hsp60 as well as stressed macrophages. Thus some of the CTLs evoked following infection with Salmonella are autoreactive. It is know that several autoimmune diseases are etiologically linked to infection with Salmonella and we have proposed that these CTLs may play a role in the subsequent development of autoimmune disease. Our current studies are focusing on the disease potential of the hsp-reactive CD8+ CTLs and the role the intestinal mucosal immune compartment plays in controlling infection. We have also initiated a study of human Lyme disease triggered by infection with the spirochete Borrelia burgdorferi. This study involves immune cellular, genomic and proteomic profiling of patients over time with the goal to identify factors and/or pathways that are key to bacterial clearance and/or associated with persistent symptoms. Our goal is to use animal models of infection and human studies to determine how variation in the immune response to infection may trigger a chronic disease state.
Profile: Publications and Interests