PXK and Lupus: Defining novel immunobiology for an SLE risk gene. S. E. Vaughn1,2,3, I. T. W. Harley3, C. Foley4, L. C. Kottyan1,2, K. M. Kaufman1,2,5, J. B. Harley1,2,3,5, SLEGEN 1) Immunobiology Graduate Program, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH; 2) Center for Autoimmune Genomics and Etiology, Division of Rheumatology, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH; 3) Medical Scientist Training Program, University of Cincinnati, Cincinnati, OH; 4) Spellman University, Atlanta, GA; 5) US Department of Veterans Affairs Medical Center, Cincinnati, OH.
Systemic Lupus Erythematous (SLE) is a systemic autoimmune disease with a strong genetic component. Over 50 risk genes have been associated with SLE, many with no immediate biological connection to disease. We previously identified one such gene, PXK, as being a candidate gene associated with SLE in women of European descent. These findings have since been replicated. PXK has additionally been identified as a risk gene for RA as well, suggesting that PXK may have a broad role in the pathobiology of autoimmune disease. In this work we undertake the fine mapping of the PXK genetic locus in an effort to refine the association signal. We identify one independent effect in the region occurring strictly in individuals of European ancestry. In an attempt to capture more of the potential variation in the region, we performed imputation, which confirmed our findings of a single associated region found only in Europeans. In tandem with refinement of the genetic signal, we also attempt to identify the SLE relevant biological import of PXK by examining the role it plays in B cells. Public datasets reveal that PXK is highly expressed in the blood, specifically in B cell subsets. PXK has been shown to participate in receptor internalization, and we find using ImageStream technology that PXK colocalizes with the B cell receptor (BCR) upon BCR internalization. Finally, we show that the BCR is more rapidly internalized in cells carrying the PXK SLE-associated allele. These results suggest that PXK may play an important role in the regulation of BCR signaling and B cell differentiation and survival. As B cell regulation is crucial to SLE pathogenesis, understanding the specific changes induced by SLE-associated variants in PXK will provide important insight into SLE pathogenesis.
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