Raif Geha's lab pursues the molecular basis of inherited immune deficiencies. The Geha lab has established a mouse model of Atopic Dermatitis and is studying the mechanisms of allergic sensitization through the skin and of recruitment of T cells & eosinophils to the skin. The researchers are pursuing several investigational avenues. One seeks to identify the molecular process by which a B cell switches from producing one class of antibody to another. A second explores inherited immune deficiency disorders, with special emphasis on Wiscott-Aldrich Syndrome. A third investigates the molecular basis of atopic dermatitis (AD) a common, an allergic inflammation of the skin that is common, but poorly understood. The lab has created an animal model of AD that may ultimately be used to develop potential drugs.
Isotype switching is the mechanism by which a B cell goes from producing one type of antibody to another while maintaining antigenic specificity. This phenomenon allows the immune system to produce various antibody types against the same antigen, but having different effector functions. Isotype switching is a highly orchestrated process with several cytokines and T and B cell surface molecules participating. The Geha laboratory has shown that B cell surface molecules CD40, BAFF and APRIL are important for the switching process, and that defects in these molecules, or in the signaling cascade emanating from them, could potentially lead to immunodeficiency. Geha and colleagues have also shown that C4BP, a complement regulatory protein, binds to CD40 and induces isotype switching. At present, they are studying the role of BAFF and APRIL in isotype switching and antibody affinity maturation.
Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency caused by mutation in the gene encoding for the WAS protein (WASP). The Geha group identified a novel cellular negative regulator of WASP they have named WIP. WASP and WIP together regulate most cell functions that require the remodeling of the actin-based cytoskeleton--the structural framework of the cell. The Geha lab is now studying the role of WASP and WIP in immune cell functions that require active cytoskeletal remodeling such as migrating in response to chemical signals and homing. They are also mapping the domains of WASP and WIP that are involved in discrete functions of these molecules.