In the late 1970s, researchers discovered that certain male mice carried a lupus-promoting gene on their Y chromosome (the male chromosome). They referred to it as the ‘Y-linked autoimmune accelerator,’ or Yaa. Since then, although mice carrying the accelerator have been used extensively in lupus research, no one knew what the gene was.
With LRI funding, Dr. Bolland discovered an important clue in 2002. She found that the accelerator not only made lupus worse, but that it also changed the type of autoantibodies produced. (Normally, mice that are genetically susceptible to lupus make autoantibodies to DNA-containing antigens. But mice carrying the accelerator make autoantibodies predominantly to nucleoproteins, which are RNA-containing antigens.)
Her findings identifying several genetic loci that contribute to various features of lupus were published in the Journal of Experimental Medicine, a highly selective and broadly read immunology journal. The discoveries have had a significant impact on the field of lupus research.
In related work, she showed that a strain of lupus-susceptible mice carry an extra copy of an immune receptor for virus RNA (TLR7), which explains why these mice develop autoantibodies to self-RNA.
And in landmark research published in Science in 2006, Bolland reveals certain key characteristics of the “Y-linked autoimmune accelerator gene” that may well help explain why some people develop such severe lupus.
She reports that having this gene makes B cells produce twice as much of the receptor that makes them sensitive to RNA—single stranded DNA—and therefore more likely to mount a harmful reaction to self-RNA. Bolland’s study shows that this actually happens in mice as opposed to just the test tube.
The Science paper is also important in showing that relatively minor genetic alterations can have a major effect on disease. “We expected the important genetic changes to be major mutations but now we are finding that a small change can have a big impact on disease,” she explained.
“Bolland’s findings show that one extra copy of the gene is enough to predispose to severe autoimmunity—direct evidence that minor genetic mutations, small differences in expression, are important…The study provides new understanding of how this gene works and insight into the genetic basis of lupus, in other words, why lupus runs in families. And it also highlights TLR7 as another potential target for lupus therapies.”
– Mark Shlomchik, M.D., Ph.D., professor of laboratory medicine and immunobiology at Yale University School of Medicine.
As Chief of the Autoimmunity and Functional Genomics section at NIAID’s Laboratory of Immunogenetics, Dr. Bolland oversees numerous scientists—7 or more at any given time—who are fully focused on mouse models of lupus.
Bolland S, Yim YS, Tus K, Wakeland EK, Ravetch JV. Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice. J Exp Med. 2002 May 6; 195(9):1167-74.
Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 2006 Jun 16;312(5780):1669-72. Epub 2006 May 18.
Subsequent funding from the National Institutes of Health made it possible for Bolland to expand on her original Lupus Research Institute research, and she now conducts lupus research at the National Institute of Allergy and Infectious Diseases.
Rev. July 2010