Dr. Rahul Pal, Emeritus Scientist

Summary of Research:

Humans are afflicted by several autoimmune diseases, the causes for many of which remain unknown. The pathological consequence of autoreactive immune responses are the subject of intense investigation. Systemic Lupus Erythematosus (SLE) is a prototypical non-organ specific autoimmune disease which generally manifests a life-long, relapsing-remitting phenotype. Multiple organs are targeted; chronic renal failure is a serious consequence, and patients can also exhibit arthritis, neurological involvement and hemolytic anemia. More than a hundred different autoantibody specificities have been described; drawing correlations between disease manifestations and autoimmune reactivity remains a high priority. Anti-phospholipid autoreactivity, a frequent occurrence in systemic autoimmune disease, has been associated with autoimmune hemolytic anemia, thrombotic events and early pregnancy loss. The immunological and physiological sequelae arising as a result of the release of sequestered hemoglobin in animals prone to autoimmunity form a focus of current investigations. Interestingly, in both SLE patients and in animals prone to systemic autoimmunity, aberrance in apoptotic processes has been observed. Excessive spontaneous apoptosis (or excessive susceptibility to apoptotic stimuli) as well as inefficient clearance of apoptotic debris have been documented in lupus patients, and animals genetically modified to impair the uptake of apoptotic cells exhibit lupus-like pathology. Autoimmune cascades initiated by early autoantibody responses specifically directed towards apoptotic cells are being investigated; since apoptotic debris appears to constitute the original antigenic insult, it is conceivable that such events could have a bearing on pathology. Human chorionic gonadotropin (hCG), a placental glycoprotein hormone, stimulates the release of progesterone from the corpus luteum, thereby sustaining pregnancy; successful pregnancy is believed to represent a Th2 skew. Given reports of pregnancy-associated lupus flares in humans and the ameliorating influence of hCG in murine models of organ-specific (Th1-mediated) autoimmune disease, the effects of administration of the hormone in animals genetically prone to systemic autoimmunity (a state which, like pregnancy, can also be notionally considered to constitute a Th2 skew, given associated hypergammaglobulinemia and antibody-mediated pathology) are being investigated. In recent years, hCG has been shown to be secreted by a variety of cancers as well, and its presence has been associated with chemo-resistance as well as with poor patient prognosis. Understanding the molecular pathways by which hCG potentially impacts on tumor progression, as well as the development of novel immunotherapeutic anti-hCG vaccination strategies, form another focus of the laboratory.