Effects of ITGAM Genetic Variation on Mac-1-Mediated Functions of B Cells
Abstract
Two single-nucleotide polymorphisms (SNPs) in ITGAM, the gene encoding CD11b, associate with the risk of havinglupus. One of these SNPs causes a 77Arg right arrow 77His amino acid change in the extracellular domain of CD11b and the other SNPcauses a1146Pro right arrow 1146Ser change in its cytoplasmic domain. The goal of this project is to understand how these SNP associatedamino acid changes might affect the function of CD11b and explain their association with lupus. Using Epstein-Barr virus (EBV) transformed B cells and B cells from SLE patients, we will test the hypothesis that the 77His and 1146Ser variants alter CD11b mediated intracellular signaling in B cells, thereby change CD11b membrane mobility, clustering, and cytoskeletal association in ways that impact B cell biology and foster the development of lupus. To date we have made 2 major and new findings: First, we found that the SNP variant 1146Ser residue is a target for phosphorylation by at least two kinases (ERK and GSK3beta). Second, the presence of the SNP variant 1146Ser residue is associated with increased surface expression of CD11b by EBV-B cells. We expect these changes in CD11b will have a major impact on CD11b signaling in EBV-transformed and primary B cells, helping understand why this SNP is associated with the risk of developing lupus.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1123919
Entities
People
- Alexander J. Szalai
Organizations
- University of Alabama