Laboratory for Clinical Biochemistry Research
Huber Bio
Viral Research
Viruses are the ultimate obligate intracellular parasite. They have a diverse range of sizes, shapes and replicative cycles; and every living organism from bacteria to humans appears to be susceptible to one or more of these entities. Viruses have been associated with three types of cardiovascular disease in both humans and mice. These are myocarditis, dilated cardiomyopathy and atherosclerosis. Myocarditis is characterized by inflammation of the heart muscle and may follow infection of the heart with picornaviruses. Picornaviruses represent a family of small, non-enveloped viruses with an RNA genome which replicate in the cytoplasm of infected cells. Infection usually results in the death of the cell. Although virus is obviously involved in the disease process, most scientists agree cardiac injury results from immune responses triggered by the virus rather than from direct virus-induced myolysis. Thus, myocarditis represents one of a growing number of autoimmune diseases in which the body's defense mechanisms destroy vital organs by mistake.
The immune system is designed to recognize and eliminate anything in the body which is "non-self". Primarily, this includes all microorganisms as well as transformed (cancer) cells. However, under certain circumstances, this normally protective response is circumvented or redirected to become highly injurious to the individual. In my laboratory, we investigate the immunopathogenic mechanisms of virus-induced myocarditis using a murine model. Our investigations are designed to determine precisely how the virus triggers autoimmunity. Several possibilities exist. Proteins from the virus and heart may appear similar to the immune system, so that destructive agents generated to neutralize the virus also affect the cardiocytes. This process, called "antigenic mimicry" has been implicated in a number of autoimmune diseases including rheumatic heart disease and Chagus' disease. Alternatively, the stress on the cell due to the infection can induce the expression of "neoantigens" on the plasma membrane of the heart cells. These neoantigens represent a family of stress proteins which usually enable the cell to survive under unfavorable conditions. Because these stress proteins are absent in uninfected cells, they often appear "foreign" to the immune system and can trigger pathogenic responses. Immunity to stress proteins has also been implicated in a number of autoimmune diseases.
Other studies attempt to determine whether various immunologically active molecules called cytokines play an important role in either preventing or triggering autoimmunity. T lymphocytes are the major immunological mediator of tissue injury in myocarditis. Two subpopulations of T lymphocytes, called Th1 and Th2 cells, perform different functions in immune responsiveness. Th1 cells cause inflammatory cell infiltration of tissues while Th2 cells help in the production of antibody responses. Th1 and Th2 cells can only be distinguished by the cytokines they produce. Some cytokines secreted by the Th2 cell population, such as interleukin-10 (IL-10) and transforming growth factor beta (TGF), inhibit inflammation while other cytokines produced by Th1 cells, such as interleukin-2 (IL-2), enhance inflammation. During virus infections causing myocarditis, there may be an imbalance in these cytokines in favor of those enhancing inflammatory responses. During non-pathogenic infections, there may be preferential production of the anti-inflammatory cytokines. Identifying the complex interrelationships between the various cytokines could indicate how autoimmunity occurs during these infections. The murine model of myocarditis is ideally suited to investigations in myocarditis and should greatly advance knowledge regarding pathogenesis of autoimmune diseases and successful intervention therapies.
Dr. Huber's research group investigates the immunopathology of cardiovascular and infectious diseases. Research on myocarditis investigates how viruses, bacteria and drug hypersensitivity initiates pathogenic T lymphocyte immunity which causes myocyte apoptosis and necrosis. Emphasis is presently placed on upregulation of CD1 molecules and activation of T cells expressing specific types of T cell receptors, the gamma-delta T cell receptor (gamma delta TCR). These gamma delta+ cells belong to the "innate" immune response as the limited diversity of the TCR variable regions precludes highly heterogeneous antigen recognition as is seen with adaptive (antigen-specific alpha beta TCR+) T cells. Specifically, we have shown that gamma delta+ cells having a particular V gamma 4 TCR promote cellular immunity mediated by CD4+ Th1 cell responses whereas V gamma1+ cells in the gamma delta cell population promote CD4+ Th2 cell responses. We have shown that the V gamma 4+ cells are responsible for CD4+ Th1 cell responses and tissue injury in both virus-induced myocarditis and high cholesterol-induced murine atherosclerosis. Thus, the same population of gamma delta+ cells has the same biological function in diverse diseases irrespective of the type of initiating agent for the disease. We are presently collaborating with other investigators at UVM to investigate the interaction between oral microbiology and systemic disease (diabetes) and will be investigating whether specific gamma delta + cells in periodontal disease in response to bacterial infections correlate with diabetes. Since cytokines are considered major factors in insulin resistance, and innate immune factors such as gamma delta+ cells can be potent producers of cytokines, the type of innate immune response could have an important impact on promoting or suppressing susceptibility to various diseases.
