My laboratory studies structure/function relationships in adhesion receptors of the immune system. These molecules are critical for the specialized movement of leukocytes from blood into lymphoid organs and into inflamed tissues. They may also have a role in the traffic of malignant cells into sites of metastasis. We use molecular biology in conjunction with in vitro and in vivo mouse models to characterize these receptors and the effects resulting from their manipulation. Our interests are focused on lymphocyte adhesion molecules and their counter-ligands on vascular endothelial cells.
Effector and/or memory T cells are known to express increased surface levels of the receptor CD44. We have shown that the interaction of activated CD44 with its major ligand on vascular endothelium (hyaluronan) can mediate primary lymphocyte adhesion, resulting in extravasation at inflammatory sites. We have also shown that the activation of CD44 and induction of primary adhesion occurs directly through T cell receptor initiated signaling. These studies have been extended to in vivo murine models of inflammation, including superantigen induced inflammation, psoriasis, arthritis, SLE, and diabetes. Concurrent studies on endothelial cells have demonstrated that hyaluronan expression is regulated in response to proinflammatory cytokines. The signaling pathways for induction of both CD44 (lymphocyte) and hyaluronan (endothelial cell) expression are actively under investigation.
We are also analyzing CD44-mediated primary adhesion in patients with autoimmune disease and have demonstrated a correlation between disease exacerbation and expression of activated CD44 on peripheral blood lymphocytes. Recent studies indicate a strong association of expression of the activated, ligand-binding form of CD44 (CD44act) with highly efficacious CD4+CD25+ regulatory T cells.
RESEARCH INTERESTS
Molecular Immunology
Lymphocyte adhesion
Inflammation
Autoimmunity
RECENT PUBLICATIONS
Firan, M., Dhillon, S., Estess, P., and Siegelman, M. H., "Suppressor potency among regulatory T cells is discriminated by functionally active CD44" Blood, 107:619-627, January 2006
Siegelman, M.H., Stanescu, D., and Estess, P., "The CD44 initiated pathway of T cell extravasation utilizes VLA-4 but not LFA-1 for firm adhesion." J. Clinical Investigation, 105:683-691, 2000
Nandi, A., Estess, P., and Siegelman, M.H., "Hyaluronan anchoring and regulation on the surface of vascular endothelial cells is mediated through the functionally active form of CD44" J. of Biological Chemistry, 275:14939-14948, 2000
Estess, P., Nandi, A., Mohamadzadeh, M., and Siegelman, M.H., "IL-15 induces endothelial hyaluronan expression in vitro and promotes activated T cell extravasation through a CD44 dependent pathway in vivo" J. Experimental Medicine, 190:9-19, 1999
Animesh Nandi, Pila Estess, and Mark Siegelman, "Bimolecular Complex between Rolling and Firm Adhesion Receptors Required for Cell Arrest: CD44 Association with VLA-4 in T Cell Extravasation" Immunity, 20:455-465, 2004
SIGNIFICANT PUBLICATIONS
Firan, M., Dhillon, S., Estess, P., and Siegelman, M. H., "Suppressor potency among regulatory T cells is discriminated by functionally active CD44" Blood, 107:619-627, January 2006
Estess, P., DeGrendele, H.C., Pascual, V., and Siegelman, M.H., "Functional Activation of Lymphocyte CD44 in Peripheral Blood is a Marker of Autoimmune Disease Activity" J. Clinical Investigation, 102:1173-1182, 1998
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