Pilot Project

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Linked publications, trials & patents

Abstract

SUMMARY ACE Pilot Project; PI – Caielli, S. Human monocytes (Mo) are bone marrow–derived leukocytes with important functions in pathogen sensing and innate immunity during bacterial, viral, and fungal infections. Single-cell transcriptomic data suggests that blood Mo are likely heterogeneous. During infections, circulating Mo rapidly leave the bloodstream and migrate to tissues where, after pathogen sensing and/or other stimuli, they differentiate into macrophages (Mo-Macs) or dendritic cells (Mo-DCs). Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to nuclear antigens. A more comprehensive understanding of SLE pathogenesis is long overdue as, in the past 50 years, only three new drugs have been approved for SLE treatment. Genome-wide association studies (GWAS) have identified many susceptibility loci for SLE, confirming that SLE patients display predisposing genetic factors. Such factors affect the immune system when challenged with environmental factors and alter the functions of different immune cell compartments in SLE patients. The myeloid cell compartment is altered in SLE. Yet, Mo from a subset of patients behave like activated DCs by inducing allogeneic CD4+ T cells to proliferate in vitro. Furthermore, exposure of normal monocytes to SLE serum results in the generation of DCs, which is dependent on Type I IFN. Recently, by analyzing the transcriptomes of ~276k single PBMCs from 33 children with SLE, we were able to identify novel alterations in SLE blood Mo such as the expansion, in patients with active disease, of a subset of Mo co-expressing IL1B and ISGs (IL1B+ ISGs+ Mo). Here we wil study whether circulating IL1B+ ISGs+ Mo, upon differentiation into DCs, function as pathologic mediators in SLE by promoting i) the generation of inflammatory CD4+ and/or CD8+ T helper cells and/or ii) the differentiation of B cells into antibodies-secreting cells. The studies outlined in this proposal will expand on the paradigm shifting observation that a fraction of CD14+ CD16- Mo from SLE patients co-express IL-1b and ISGs (IL1B+ ISGs+ Mo) and thus might play a pathogenic role in disease progression and/or exacerbation, therefore representing a potential novel therapeutic target and/or biomarker.