Paul Hoover, MD
2018 Career Development Awardee
Brigham and Women’s Hospital, Inc.
Study: Dissecting the role of myeloid cells in lupus nephritis
Lupus nephritis (LN) is a severe, potentially life-threatening complication of systemic lupus erythematosus (SLE). Drug development is stalled because little is known about the cell-types and pathways driving disease. Recently, the NIH-sponsored AMP-PEARL consortium discovered 22 immune cell-types infiltrating kidney tissue from 24 disaggregated patient biopsies using single-cell RNA-sequencing. Thus, key follow-up questions remain: What is the spatial organization of the immune landscape? What biological principles underpin this organization? Does in situ immune cell organization drive clinical outcomes? The central hypothesis of this proposal is that the immune cell infiltrate in LN tissue is highly organized and promotes kidney remodeling. Given our lab’s expertise, this proposal dissects the organizational landscape, role, and clinical associations of the five newly discovered myeloid subsets in formalin fixed paraffin embedded tissue in a new, larger 40 LN patient cohort, independent from AMP. In aim 1, we propose rigorously characterizing in situ LN myeloid organization by mapping spatial relationships between new myeloid subsets, immune infiltrate, and kidney lesions. We will also map the CXCL12-CXC4 intercellular communication loop, a strong signature in AMP data and LN mouse model immune cell migration, to determine its contribution to monocyte-mediated immune cell recruitment to areas of kidney remodeling. In Aim 2, with assistance from BWH’s bioinformatics core, we will determine whether in situ LN myeloid organization is associated with clinical outcomes in our patient cohort. The cohort is composed 40 LN patients with archived kidney tissue (class III, IV, V) who presented with varying disease severity undergoing their first biopsy (naïve to potent immune-modulators). We expect this proposal to define the in situ organizational landscape between myeloid subsets in clinical samples, identify which organizational parameters are clinically relevant, and illuminate underlying organizing principles for future investigations.