Tolerogenic dendritic cells in human lupus
Plasmacytoid dendritic cells (PDCs) are a major source of type I interferon (IFN), and are important pathogenic effector cells in systemic lupus erythematosus (SLE). Though many studies have characterized factors that amplify inflammatory pathways in SLE, the study of negative regulators is equally important and has not been as extensively explored. In this proposal, we plan to study the expression and function of two important immune regulators of PDCs, immunoglobulin like transcript 7 (ILT-7) and blood dendritic cell antigen 2 (BDCA2) to induce tolerogenic PDCs in human SLE.
We have two Specific Aims:
Aim 1: Assess the functional consequence of decreased expression of ILT-7 and BDCA2 on SLE patient PDCs, and relationship to disease phenotypes.
Aim 2: Determine capacity of ILT-7 and BDCA2 to induce tolerogenic DCs in SLE patients, both separately and in combination.
The data we generate will identify important patient sub-groups to be targeted, and define which intracellular signaling pathways are interrupted. Aim2 will potentially support a novel dual inhibition therapeutic strategy which would combine ILT-7 and BDCA2 ligation, as it seems unlikely that ligating a single suppressive receptor on the PDC surface will lead to a tolerogenic outcome.