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Hans Haecker, MD PhD


University of Utah, School of Medicine



Innate immune cell mechanisms controlling inflammation in Systemic Lupus Erythematosus

The pathogenetic mechanisms that drive Systemic Lupus Erythematosus (SLE) are still merely understood. Recent genome-wide association studies have linked Tnipl, which encodes ABINI, with SLE. We identified ABINI as signaling component of Toll-like receptors (TLR), and studies of ABIN1-deficient mice revealed a lupus-like inflammatory disease with striking similarity to SLE. Innate immune cells use TLRs physiologically to initiate immune responses by pro-inflammatory mechanisms; however, data from SLE patients indicate that TLR-mediated inflammation may also contribute to disease. We show in this application (i) that disease in ABINI -deficient mice is mediated via MyD88, the master regulator of TLRs and (ii) that disease proceeds independent of T- and B-cells, Thus, this model is uniquely suited to investigate TLR-mediated, innate immune cell mechanisms contributing to inflammation* By using a defined set of genetic and biochemical experiments, we propose here to define (i) the role of suspected culprits, i.e. TLR7, TLR9 and type I interferons, (ii) the impact of specific ABINI -target genes, i.e. C/EBPß, G-CSF and INOS, (iii) the contribution of neutrophils and (iv) the molecular mechanism of ABINI -mediated gene regulation. We expect that information obtained will help to identify pathogenetically important factors contributing to inflammation, and hopefully identify promising therapeutic targets for SLE.

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