Laboratory of Clinical Microbiology and Immunology
John B. Zabriskie
Microbes. It is well known that microbes share antigenic determinants with a wide variety of mammalian tissues. In general this "molecular mimicry" between host and microbe are of no consequence to the host. However, in the context of a given genetic background, these microbial cross-reactive autoantigens may lead to autoimmune reactions in the host.
This general concept is currently being explored in three main areas of investigation. The first is concerned with rheumatic fever, a disease in which there is ample evidence for shared antigenic determinants between mammalian tissues and streptococcal antigens both at a humoral and cellular level. This abnormal response of the host appears to be genetically directed in that all rheumatic fever patients exhibit a B cell antigen unique to rheumatic fever patients. Present efforts are being directed to identification of the marker at a molecular level through cDNA libraries of lymphoblastoid lines obtained from rheumatic fever patients. The exact role this antigen plays in the pathologic manifestations of the disease is currently under investigation.
The second area of investigation is concerned with the question of whether microbial products play a role in rheumatoid arthritis. Present investigations have centered around an animal model of arthritis in which a single dose of streptococcal cell walls causes a relapsing remitting arthritis in rats with many features of the human disease. Using T cell lines derived from these animals, passive transfer of the disease with these lines has been achieved. These cell lines also cross-react with human proteoglycans as well as other microbial antigens such as mycobacterial walls but not tuberculosis heat-shock proteins. Similar synovial cell lines obtained from rheumatoid arthritis patients have been achieved and they also react to both microbial and proteoglycan antigens. Current efforts are being directed toward whether or not these T cell lines have restricted Vβ lineage and determining the exact molecular nature of these T cell-reactive microbial antigens.
The third area is concerned with the autoimmune mechanisms involved in multiple sclerosis. The current hypothesis is that genetically programmed individuals produce T cells autoreactive with the brain. Current efforts are being directed to the establishment of cerebrospinal fluid T cell lines to test their reactivity to brain and microbial antigens as well as a continuing search for environmental agents responsible for initiation of disease. The latter studies are being carried out by polymerase chain reaction amplification of viral probes in tissues obtained from multiple sclerosis patients.