Systemic lupus erythematosus (SLE) is a life threatening disease affecting ~1.5 million Americans, wherein autoantibodies attack the body and trigger disabling and destructive inflammation. Non-specific immunosuppression reduces SLE morbidity and mortality but often has severe side effects. Specific therapies for SLE with fewer side effects are being developed but so far only one has been FDA approved (belimumab). The need for more specific therapies will remain great and unmet until SLE pathogenesis is better understood. Over 80 different genes are known to be statistically linked with SLE risk, but little is known about the mechanisms by which these variants alter gene expression or function and how they affect SLE pathogenesis. Our proposed research directly addresses this knowledge gap. Single-nucleotide polymorphisms (SNPs) in a gene called ITGAM strongly associate with SLE risk. ITGAM encodes the CD11b subunit of Mac-1, a receptor expressed mainly by cells of the myeloid lineage. Mac-1 has numerous ligands and by engaging them on different cells, this receptor can regulate many and diverse immunological functions. Notably, Mac-1 is an important receptor on dendritic cells (DCs), a cell type wherein Mac-1 expression has been linked to proper DC development and inhibition of full DC-mediated T cell activation. DCs have long been implicated in the initiation, progression, and modulation of SLE. Our long-term goal is to understand how ITGAM genetic variation changes Mac-1 function on myeloid cells in a way that propels SLE. The two objectives of this application, a major step towards our long-term goal, are (i) to establish that an SLE associated ITGAM 77His variant alters Mac-1 biology on human peripheral blood monocyte-derived DCs and (ii) to determine if this SLE associated ITGAM variant alters DC mediated tolerance in vivo in humanized mice. Our proposed research is based on the rationale that we can link this SLE associated genetic variant with alterations in Mac-1 mediated DC functions that have immunological consequences that propel SLE. Accordingly, our central hypothesis is that the 77His variant perturbs DC-mediated regulation of T cell-mediated adaptive immunity.
In Aim 1 we will use human DCs to test the hypothesis that presence of 77His alters Mac-1 function on DCs in a manner sufficient to interfere with the cells' ability to trigger a normal T-cell response.
For Aim 2 we have generated unique humanized mice expressing the SLE associated CD11b 77His variant. These will be used to determine if the impact of 77His on DC biology is sufficient to affect peripheral tolerance in vivo. The working hypothesis here is that mice expressing the SLE associated 77His variant will show defects in DC-mediated tolerance mechanisms. Successful pursuit of this work will provide a new functional genomics interpretation for the recognized associations of this ITGAM variant with SLE, which could have a positive impact on human health.
to public health: About 1.5 million people in the U.S.A. have systemic lupus erythematosus (SLE), a disease whose susceptibility is increased by slight variations in a gene called ITGAM. By deciphering the reasons for this genetic risk, our research will pave the way towards new diagnostics and drugs for this life- threatening disease.
