Nathan Nelson-Maney

Project Summary:

Diffuse alveolar hemorrhage (DAH), characterized by rapid bleeding in the lungs, is among the most severe clinical manifestations of Systemic Lupus erythematosus (SLE), with a mortality rate greater than 50%. The cause of DAH remains unknown and no targeted therapy is available.

Mice treated with pristane develop many features of human SLE including self-reactive antibodies and kidney inflammation. Interestingly, pristane-induced lupus is also the only animal model that develops DAH. Using this model, we found a critical role of the interferon regulatory factor 8 (Irf8) in the development of DAH.

Irf8 is a transcription factor normally involved in the differentiation of monocytes, dendritic cells and B cells. Irf8-deficient mice are protected from the development of DAH and lupus-associated antibodies induced by pristane treatment.

The goal of our work is to understand the how Irf8 contributes to the pathogenesis of DAH. Aim 1 will define cell population(s) expressing Irf8 in the lungs before and after pristane treatment. Aim 2 will address the role of Irf8 in the function of B cells, which have been implicated in the development of DAH.

These studies will enhance our understanding of the pathogenesis of DAH and provide the rationale for therapeutic targeting of Irf8 in lupus.