Recent genome-wide association studies in autoimmunity have identified the association of a coding region polymorphism (R77H) of ITGAM, a gene that encodes for the 1 chain of the CD11b integrin molecule, with SLE. The ITGAM polymorphism is associated with SLE across ethnic groups and also confers increased disease severity with an increased incidence of SLE nephritis. Recent studies from our laboratory have shown that increased expression of CD11b on resident renal macrophages is associated with nephritis onset in three different SLE models and that this phenotype reverses concomitant with clinical remission. ITGAM is also overexpressed in human SLE renal biopsies. Since ITGAM has multiple pro-inflammatory functions we therefore hypothesize that the ITGAM polymorphism associated with SLE results in a gain of function such that there is increased adhesion, pro-inflammatory or pro-coagulant function of monocytes. To test this hypothesis we will utilize a unique very large normal subject registry containing DNA from normal subjects who express a willingness to be re-contacted to participate in various research protocols. We will select homozygous R/R and H/H individuals for our study. To identify functional differences in the two polymorphic ITGAM alleles we will establish whether the R77H ITGAM polymorphism alters expression or ligand binding characteristics of CD11b. We will determine whether the polymorphism affects the function of monocytes expressing CD11b with respect to their phagocytosis, adhesion, migration and their production of inflammatory molecules. Finally, we will establish transfected cell lines bearing the polymorphic alleles to better study adhesion under flow conditions and downstream signal transduction events. These studies should help us identify the functional significance of the ITGAM polymorphism and may allow us to understand how this polymorphism affects the susceptibility to and severity of SLE.
The goal of this proposal is to determine the functional significance of the R77H coding region polymorphism in the ITGAM gene that is associated with human SLE. ITGAM encodes the alpha chain of the CD11b adhesion molecule expressed on leukocytes and monocytes. The approach will be to use peripheral blood normal individuals homozygous for the two allelic forms of ITGAM to analyze the expression of CD11b and the function of monocytes with respect to adhesion, migration and expression of pro-inflammatory molecules.
|Liu, Zheng; Davidson, Anne (2012) Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med 18:871-82|