Molecules encoded within the class II region of the major histocompatibility (MHC) locus are known to play a critical role in many of the intercellular interactions that comprise the normally functioning immune system. Regulation of the expression of class II MHC glycoproteins on macrophages plays a role in the generation and control of immune responsiveness. Expression of these molecules is subject to both positive and negative regulation by various stimuli. The susceptibility to certain human diseases in influenced by an individual's class II MHC genotype. Many of the disease states for which class II associations exist are autoimmune in nature, and in many instances, cells within tissues that are targets of autoimmune pathology express high levels of class II molecules. Because of these findings, one attractive proposal is that the aberrant regulation of class II is an important factor in the development of autoimmune disease. A second form of disease that highlights the importance of proper class II MHC expression for normal immune function is known as the bare lymphocyte syndrome, or BLS. BLS patients with defects in class II expression typically present with recurrent bacterial infections within the first few years of life. Class II MHC molecules also are important elements in a variety of infectious diseases. Human immunodeficiency virus, for instance, is known to possess tropism for a variety of immunological cell types, including CD4+ T cells and macrophages. It has recently been shown that the expression of class II MHC molecules can be affected by HIV infection. Recent studies also have supported a role for class II MHC molecules in the defense against Gram negative bacterial infection. While a variety of microbial products are known to influence class II MHC expression, it has been shown that LPS is the primary determinant of class II induction by Gram negative bacteria. Given the importance of class II molecules in a variety of immune defense mechanisms, this result suggests that the class II NGC response to LPS is an important factor in the resolution of infection with Gram negative bacteria. The presence of a particular bacterial product or the hosts ability to respond to a microbial agent may dictate the genesis of specific T cell responses. As such, regulation of macrophage MHC expression may play a pivotal role in bridging the interface between innate and acquired defense reactions. The proposed research will be conducted to investigate the mechanism(s) by which LPS and other bacterial toxins modulate the biosynthesis and expression of Ia molecules on murine macrophages. The applicant will continue to test and define a working hypothesis involving the LPS-mediated production of gamma interferon by NK cells and/or T cells and the subsequent inductive effects of gamma interferon on macrophage Ia expression. The identification of Ia-inducing molecules produced by other microbial pathogens, the regulatory mechanism(s) operative, and the impact of such reactions on the infectious disease process are challenges for future study. An ongoing study of the function and regulation of class II MHC gene products is likely to provide critical insights into the prevention and treatment of human disease.
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