Research | Publications
Keith A. Krolick, Ph.D.
Distinguished Teaching Professor
Room 4.023D Tel: (210) 567-3968Fax: (210) 567-6612Email:
We have entered a new phase in our understanding of cellular and molecular mechanisms that result in immune responsiveness. The players have, for the most part, been identified..... the network of cells, and the soluble factors that mediate their growth and differentiation, thus allowing necessary collaborative intercellular interactions. However, the job is not done and one challenge with which we are still faced is to sort through the regulatory pathways that provide a system of carefully placed biological 'filters' designed to eliminate self-reactive lymphocytes. The distinction between 'self' and 'non-self' must be made in order to guarantee beneficial rather than detrimental immunity. Thus, autoimmunity (immunity against one's self), the focal point of a variety of health problems, has been the central theme my interests. For nearly thirty years, my laboratory used numerous strategies for studying one particular autoimmune disease, myasthenia gravis (MG). I have since closed my lab and instead have chosen to emphasize my contributions to the educational missions of the university.
In MG, one of 40 or so muscle diseases classified as muscular dystrophy, antibodies produced by one�s own immune system against muscle acetylcholine receptors (AChR) leads to muscle damage and impaired nerve-muscle communication. The symptoms of MG include weakness and rapid-onset fatigue. Contrary to what was once believed, we learned that the relationship between AChR antibody production and disease induction is not simple. That is, from individual-to-individual, the severity of disease symptoms and the aggressiveness of disease progression are not strictly correlated with the amount of AChR antibody that an individual produces. Two major observations were the driving force behind much of our work:
Observation 1: The exact fine specificity of an AChR antibody determines the level of resulting interference with neuromuscular transmission. Unless an antibody binds to the receptor at exactly the right spot, no effect on contractile function will be observed. Different individuals produce mixtures of AChR antibodies that demonstrate different T lymphocyte-determined proportions of the disease-causing subset, and therefore differences in disease symptom severity.
Observation 2: Soluble and cell-membrane factors, originating from muscle, have the ability to either amplify or inhibit immune responses. It was very exciting to consider that the various pathological outcomes in MG individuals may be based on the fact that the target tissue (i.e., muscle) is not just sitting there getting 'beat up' and that disease severity is not determined simply by the intensity of the antibody response itself. Clearly, muscle has the capacity to produce factors that promote resistance to, and repair of, the damage done by the immune system and plays an active, not passive, role in determining disease outcome. Curiously, most of these muscle-derived factors are cytokines/chemokines and adhesion molecules that are also produced by cells of the immune system, making communication with the immune system highly efficient. Moreover, the stimuli that trigger the production of these muscle-derived factors often come from the stimulated immune system itself. Therefore, a circular communication path back to the immune system exists that determines the composite set and intensities of cells of the immune system that participate in subsequent rounds of immune responsiveness and muscle pathology and the severity of symptoms demonstrated by an individual.