The Geha laboratory investigates the mechanisms of primary immunodeficiency diseases, IgE regulation and atopic dermatitis. It cloned a WASP interacting protein in the yeast two-hybrid system and named it WIP. WIP inhibits WASP function in vitro and binds both G and F actin. WIP KO were made and were shown to have a severea T cell activation defect. WIP was shown to shuttle WASP to the immune synapse. Recently, we disvovered a novel function of WIP as a chaperone for WAP. WASP protein, but not mRNA, levels were severely diminished in T cells from WIP-/- mice, and were restored by introduction of WIP. Calpain and proteasome inhibitors restored WASP levels in T cells from WIP-/- mice and from WAS patients with missense mutations that disrupt WIP binding, and corrected the defect in actin polymerization. This suggests novel therapies for WAS patients.
The Geha lab has recently conducted a series of studies on the TNF family molecules BAFF and APRIL and showed that they induce isotype switching, particularly to IgA, mostly via TACI, but also via BAFF-R receptors engaged by both APRIL and BAFF. APRIL KO were also generated and were found IgA deficient. Very recently mutation in TACI were found in patients with common variable immunodeficiency (CVID) and IgA deficiency. The Geha lab pursues in parallel mouse models of PID to dissect the role of discrete genes in the pathogenesis of these diseases. The lab has focused on SLP-76 and more recently 3BP2 KO and CBP KO have been generated. A knockout for LRRC8 implicated in agammaglobulinemia is in progress. Mouse models of point mutations in TACI associated with CVD are being constructed.
The Geha lab has had a sustained interest in IgE isotype switching. Following our discovery of the role of CD40 in isotype switching we generated CD40 KO mice. To examine the role of TRAF proteins in CD40 isotype switching,we introduced wild type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40DTRAF6), TRAF2 and TRAF3 (CD40DTRAF2/3) or both (CD40DTRAFs) into B cells of CD40-/- mice. The results showed that binding to TRAF2 and/or TRAF3, but not TRAF6, is essential for CD40 isotype switching and activation in B cells. We have recently introduced into CD40 KO mice CD40 transgenes that selectively lack the ability to bind TRAF2 or TRAF 3 to defdine the respective roleds of these two molecules in CD40 driven switching. A similar reconstitution approach is being taken to nalyze the role of TACI interacting proteins in activation B cells including isotype switching. These studies are driven by our discovery of mutations in the intracytoplasmic domain of TACI in patients with CVID.
The Geha lab developed, 7 years ago, a mouse model of atopic dermatitis (AD) elicited by epicutaneous (EC) sensitization with ovalbumin (OVA). We have used and continue to use this model to understand the local factors elicited by mechanical skin injury caused by scratching that modulate the strong Th2 response observed following EC sensitization. We demonstrated that IL-10 released by injury promotes the Th2 response while C3a and prostaglandins inhibit it. We are currently focusing on understanding the mechanisms of collagen deposition and skin thickening in AD, the trafficking of T cells and eosinophils to the lesion and the role of Toll receptor ligands in eliciting and in exacerbating the disease.
Dr Geha heads the Animal Consortium of NIH Atopic Dermatitis Vaccinia Network (ADVN), a multicenter study aimed at understanding the basis of the susceptibility of patients with AD to eczema vaccinatum (EV) and vaccinia dissemination. He has 2 projects: one aims to establish an EV model in mice, the other to understand the role of cells cytokines and skin mediators in the EV model.
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Papers & Publications:
Gallego, M.D., dela Fuente, M.A., Anton. I.M., Snapper, S., Fuhlbrigge, R. and R. S. Geha. WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1a. Int. Immunol. 18:221-32, 2006.
Yalcindag, A., Rui, H., Laouini, D., Alenius. H., Oettgen, H., and R. S. Geha. The complement component C3 is important for both the Th1 and Th2 response to antigen. J. All. Clin. Immunol. 117:1455-61, 2006.
De la Fuente, M.A., Lu, B.P., Kumar, L., and R. S. Geha. 3BP2 deficiency impairs the response of B cells, but not T cells, to antigen receptor ligation. Mol. Cell. Biol. In Press.
Bryce, P., Harrison, K. Clinton, M. Watanabe, T., R.S. Geha and H., Oettgen The H1 histamine receptor regulates allergic lung responses . J. Clin. Invest. 116:1624-32, 2006.
De la Fuente, M.A., Sasahara, Y., Calamito, M., Gallego, L., Antón Suresh, K., Siminovitch, K., Ochs, H., Rosen, F., R. S. Geha and Ramesh, N. WIP is chaperone for WASP. Proc. Nat. Acad Sci |
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