Stephen Malawista MD
Professor of Medicine (Rheumatology)
Motile functions of leukocytes that bear on aspects of the inflammatory response; Lyme disease and of gouty inflammation
My work has been devoted primarily to two general areas of investigation: motile functions of leukocytes that bear on aspects of the inflammatory response, and the continued elucidation of Lyme disease, which we discovered in 1975. The former began a half-century ago with studies of the interaction of leukocytes with urate crystals, whose ingestion by leukocytes drives the inflammation of acute gouty arthritis. This work allowed some of the earliest insights into the acute inflammatory response, in a sterile system. We went on to examine interactions of leukocytes with other particles and stimuli, including the causative agent of Lyme disease, Borrelia burgdorferi.
The elucidation of Lyme disease has been irresistible by virtue of its linkage of inflammatory rheumatology to infectious disease. We have addressed its natural history, antiquity, immunopathogenesis, etiology, molecular biology, diagnosis, treatment, and prevention. Current work is especially aimed at how the causative spirochete, B. burgdorferi, is cleared by phagocytic cells.
Extensive Research Description
The leukocyte work is particularly aimed at the relationships among specific but overlapping areas of leukocyte activity: adherence, locomotion, target recognition, chemotaxis, penetration of endothelial monolayers, ingestion, the increased metabolic activity that ordinarily accompanies phagocytosis or other cell-triggering reactions, degranulation of lysosomal structures, and intracellular killing. The ways in which these activities can be separated from one another may distinguish obligate interactions from mere concomitance, and may reveal the specific pathways by which cell function is altered. The experimental approach is through various agents and situations in which one or more of these activities appear to be altered, including 1) leukocytes treated in a variety of ways to produce granule-poor anucleate fragments (cytoplasts) that retain motile and/or respiratory functions of the parent cell, 2) cytoplasts or leukocytes treated with agents that affect their killing capacity for microorganisms, 3) cytoplasts or leukocytes treated with molecules and particles that initiate or inhibit calcium fluxes, activation of protein kinase C or of adenylate cyclase, protein phosphorylation, polymerization of microtubules and microfilaments, and rearrangements or altered expression of specific cell-surface receptors, 4) leukocytes treated with controlled brief heat to alter their respiratory burst oxidase activity, 5) leukocytes from patients with chronic granulomatous disease, leukocyte adhesion deficiency, or other disorders of leukocyte structure and function, and 6) cytoplasts, leukocytes, or cell lines treated with substances that produce ultrastructural alterations in fibrillar elements, such as the metaphase-arresting agents, colchicine, vinblastine and griseofulvin (affecting microtubules), and cytochalasins (affecting microfilaments). Current work involves the mechanics of the innate immune response.