Prizewinning Insights Into the Future of Lupus Research

What causes the immune system to misfire so disastrously in disorders like lupus? For insights that helped lead the way to solutions named rituximab and belimumab, Mark Shlomchik MD PhD has been named the first recipient of the new $200,000 Insight Prize awarded by a trio of related institutions: the Alliance for Lupus Research, the Lupus Foundation of America, and the Lupus Research Institute.

In this brief recording, hear about the studies that led Dr. Shlomchik and his collaborators to revelations about the actions of B cells that are counteracted by these groundbreaking biologics. He also addresses the significance of the Toll-like receptors, and how they complicate intracellular trash collection inside individuals who are genetically susceptible to lupus and other autoimmune diseases.

He concludes by revealing where he and his team hope to advance next, with the benefit of the Prize. If all goes well, their work may lead a new understanding of the puzzling association between lupus flares and infections.

Dr. Shlomchik will shortly become Chair of Immunology at the University of Pittsburgh. He is leaving the post of Professor of Medicine and of Immunobiology and Associate Director of the Transfusion Service at Yale School of Medicine.

The questions:

•  Could you begin by telling us about research that has led to your winning this award, please?

•  In the text about your award in the press release, it talks about a surprising result having to do with NADPH oxidase. Can you tell us a little bit about that?

•  So what will you be able to do in the future as a result of this reward?

Key quotes:

"It wasn't just antibody secretion by [B] cells. Activating T cells and secreting cytokines could also be important, and this presaged the notion of targeting B cells as a therapeutic modality."

"We came to the insight that DNA and RNA, which are the essential major targets in lupus and actually in several auto-immune diseases, carry with themselves the kind of danger signals that are also present in viruses and bacteria."

"The question arises, where is this stuff coming from? We and many others have felt that it comes from dead and dying cells that may not be so efficiently cleared in diseases like lupus."

"When we got this result, we went back into the human literature, and sure enough the literature is full of case reports, mostly actually of the mothers of these boys with chronic granulomatous disease, having a much higher incidence of autoimmunity ... We think there's something like a 10- to 20-fold increase in lupus-like illnesses in the mothers of these boys."

"So now what we really want to understand is, Why is it that when neutrophils can't die through NADPH oxidase does this really promote disease? Because this is a new and unexpected clue to the nature of lupus."

Prizewinning Insights Into the Future of Lupus Research

For your reference:

Campbell AM, Kashgarian M, and Shlomchik MJ
NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosusSci Transl Med. (2012) Oct 24;4:157ra141.

Ahuja A, Teichmann LL, Wang H et alAn acquired defect in IgG-dependent phagocytosis explains the impairment in antibody-mediated cellular depletion in lupusJ Immunol. (2011) 187(7):3888-9384

Nickerson KM, Christensen SR, Shupe J et alTLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus.J Immunol. (2010) 184:1840-1848

Shlomchik MJ
Activating systemic autoimmunity: B's, T's, and tollsCurr Opin Immunol. (2009) 21:626-633