2001 Biomarkers, General Immune System Function.Human Lupus Biology
With her first LRI grant, in 2001, Dr. Crow investigated the novel hypothesis that the products of viral-like “junk” DNA found between genes, called transposons, might stimulate the production of interferon-alpha—and in this way contribute to autoimmunity.
Dr. Crow’s findings, including increased expression of transcripts encoded by long interspersed nuclear elements (LINE-1) in peripheral blood of some people with lupus, led to funding of an NIH R21 grant and further development of this provocative research direction. Recent data are linking LINE-1 transcripts to production of interferon-alpha. A manuscript describing these data was in preparation in 2010.
With her second LRI grant, in 2004, Dr. Crow set out to identify and validate patterns of gene activity that could be used as actual biomarkers of lupus flare.
Her lab initiated a longitudinal study to examine three patterns of gene activity—interferon signature, inflammatory signature, and TLR/VEGF signature—to see if these might serve as effective biomarkers.
“By identifying good markers that measure the early phase of disease activity and, in particular, flares, we can one day intervene earlier with new or existing drugs and treat a patient before disease becomes clinically active,” Dr. Crow explained. “To know if a drug works, we have to assess how active the disease is and how that activity changes in response to the drug.”
Among other discoveries generated by LRI funding, Dr. Crow developed an informative assay of serum interferon activity that has been essential in defining genetic contributions to interferon pathway activation and autoimmunity.
Thanks to a large lupus patient and family registry developed with the assistance of organizations such as the S.L.E. Lupus Foundation, her laboratory demonstrated that production of interferon is a heritable trait that might be used to predict those at risk of developing the disease in the first place. Dr. Crow continues to investigate the genetic variants that account for different patterns of disease with collaborator Dr. Timothy Niewold at the University of Chicago (also an LRI investigator).
With her colleague Dr. Kyriakos Kirou, a rheumatologist at the Hospital for Special Surgery, Dr. Crow is continuing the longitudinal study of lupus patients to unravel the molecular pathways involved in innate immune system activation in lupus and the determinants of increased disease activity. A goal of this work is to gain new understanding of pathogenic mechanisms and markers of disease activity that will guide patient management as innovative new therapies are developed.
Notably, in an expanded study that continues the work supported by the LRI, Dr. Crow has analyzed an extensive dataset based on longitudinal microarray and proteomics assays. A recent analysis of the data has resulted in development of a molecular score that is associated with lupus flare. The score is based on expression of three representative genes from molecular pathways that contribute to lupus pathogenesis.
Coordinate overexpression of interferon-alpha-induced genes in systemic lupus erythematosus. Kirou KA, Lee C, George S, Louca K, Papagiannis IG, Peterson MG, Ly N, Woodward RN, Fry KE, Lau AY, Prentice JG, Wohlgemuth JG, Crow MK. Arthritis Rheum. 2004 50(12):3958-67.
Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Kirou KA, Lee C, George S, Louca K, Peterson MG, Crow MK. Arthritis Rheum. 2005 52(5):1491-503.
Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Hua J, Kirou K, Lee C, Crow MK. Arthritis Rheum. 2006 54(6):1906-1916.
High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus. Niewold TB, Hua J, Lehman TJ, Harley JB, Crow MK. Genes Immun, 2007 Sep;8(6):492-502. Epub 2007 Jun 21.
Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Niewold TB, Kelley JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Arthritis Rheum 2008; 58:2481-7.
The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high IFN-alpha activity and low tumor necrosis factor-alpha levels in patients with lupus. Kariuki SN, Crow MK, Niewold TB. Arthritis Rheum 2008; 58:2818-23.
Cutting edge: Autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB. J Immunol 2009; 182:34-8.
Age- and gender-specific modulation of serum osteopontin and interferon-αby osteopontin genotype in systemic lupus erythematosus. Kariuki SN, Moore KA, Kirou KA, Crow MK, Utset TO, Niewold TB. Genes and Immunity 2009; 10:487-94.
Developments in the clinical understanding of lupus. Crow MK. Arthritis Res Ther, 2009; 11:245.
Long Interspersed Nuclear Elements (LINE-1): potential triggers of systemic autoimmune disease. Crow MK. Autoimmunity 2009; 43:7-16.
Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Crow MK. Rheum Dis Clin North Am, 2010; 36:173-86.
Dr. Crow won a $1.820 million NIH R01 grant to continue her work on activation of the interferon pathway in lupus, as well as a $50,000 grant from the Mary Kirkland Center for Lupus Research grant (at the Hospital for Special Surgery). She also received a total of $275,000 from the Alliance for Lupus Research (ALR) to expand on her LRI findings and in 2010, a collaborative research grant from Novo Nordisk providing more than $400,000 of support for lupus biomarker research was in progress.
Rev. July 2010