Sjögren’s syndrome is a chronic disease that causes the immune system to attack moisture-producing glands. Two of the most common symptoms are dry eyes and dry mouth resulting from decreases in production of tears and saliva. That may not seem serious, but for those with the disease, it greatly impacts their quality of life. Sjögren’s can lead to scarring of the corneas and can be so severe that patients produce no tears. In the mouth, lack of saliva can lead to severe cavities, broken teeth and infections. It also changes the way things taste and can make it hard to speak, eat or swallow. Sjogren’s can also affect virtually any organ in the body. Other symptoms may include common ones such as fatigue, arthritis, and neurological problems, or more rare complications such as lymphoma. The disease is common but often unrecognized and affects about 3 million Americans.
In my lab, the main goal is to understand what causes Sjögren’s syndrome and to develop new ways to treat the disease. Our work focuses mostly on identifying the genetic roots of the disease. We’ve established a clinic with doctors who perform specialized testing and gather genetic samples from patients. With a large collection of samples from Sjögren’s patients, we can perform experiments to determine which genes they have in common and find out what role those genes play in the disease.
We are also working on another part of the Sjögren’s puzzle known as gene expression. This involves comparing how genes function between people with Sjögren’s and people who don’t have the disease. Using the latest technologies, we determine which genes are active and to what level they are working. With this information, we can identify patterns of genes that are behaving abnormally and then focus on why these specific genes lead to disease.
Our work in genetics also extends to lupus, another disease in which an unbalanced immune system gets confused and turns against a person’s own body. By doing large-scale screens of lupus patients’ DNA, we can identify common genes and how they’re related to the disease. Our goal, as with Sjögren’s, is to use this information to help devise better ways to treat patients suffering from this debilitating disease.
My laboratory is primarily interested in identifying and characterizing genes that predispose to systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). SLE and SS are complex rheumatic autoimmune diseases caused by the joint action of multiple genes and influenced by environmental factors. We use multidisciplinary approaches to study SLE and SS that draw on tools and concepts from immunology, genetics, biostatistics, bioinformatics, molecular biology, biochemistry, and microbiology to understand the underlying disease mechanisms.
Sjögren’s syndrome is a common, chronic, systemic disorder in which immune responses preferentially target moisture-producing glands. Dysfunction of salivary and lacrimal glands leads to the common symptoms of dry eyes and dry mouth, although multiple organ systems can also be involved and cause significant morbidity. SS may occur alone (in about 50% of patients) or in conjunction with other rheumatic autoimmune diseases such as SLE or rheumatoid arthritis. One major focus in our lab is to characterize gene expression profiles in SS using microarray technology. This powerful approach allows us to monitor the expression of thousands of genes simultaneously and identify key molecular pathways that are disregulated in patients compared to healthy controls. These studies clearly show that activation of interferon-inducible pathways are important in SS. Current studies are aimed at identifying additional pathways associated with SS and definung correlations with important clinical manifestations. A related goal is to identify genetic polymorphisms that contribute to disregulation of these pathways. For these studies and others, we have established an OMRF Sjögren’s Research Clinic. Patients and controls are extensively evaluated for clinical and laboratory features of SS. The comprehensive nature of data collection through this effort makes it a unique and extremely valuable resource for numerous studies in our lab and through collaborative efforts.
SLE is a systemic autoimmune disease with a wide spectrum of clinical manifestations involving inflammation in the joints, kidneys, brain, and other organs. Our lab has played a major role in a longstanding effort devoted to identifying genes involved in SLE. Recent projects include genome wide association studies using high-density single nucleotide polymorphism (SNP) analysis, fine mapping of several newly discovered SLE genes, functional studies aimed at understanding how these genes contribute to disease mechanism, and using a variety of alternative analytical approaches to expand the growing list of SLE genes.
B.S., Oklahoma State University, 1987
Ph.D., University of Oklahoma Health Sciences Center, 1995
Post-doctoral training, Case Western Reserve University, Cleveland, OH
Honors and Awards
1990 Award for Outstanding Scientific Paper, Bretton Symposium on Autoimmunity, Brest, France
1992 Student Travel Award, American College of Rheumatology 56th Annual Scientific Meeting
1992-1995 OMRF Predoctoral Fellowship Award
1994 Course Scholarship, “Genetic Analysis Methods for Medical Researchers,” Duke University, Durham, NC
1995 Graduate Student Association Award for Outstanding Academic Achievement, OUHSC
1999-2000 NIH Postdoctoral Fellowship Award, Case Western Reserve University, Cleveland, OH
1999 Healthcare Provider of the Year, Oklahoma Lupus Association, Inc.
1999 New Investigator Award, Clinical Immunology Society
2002-2007 NIH Educational Loan Repayment Award
2003-2007 J.V. Satterfield Arthritis Investigator Award, National Arthritis Foundation
2004 Outstanding Graduate Student Abstract Award, Department of Medicine Research Day, University of Minnesota, Minneapolis, MN
2004 Sjögren’s Syndrome Foundation Outstanding Abstract Award, Honorable Mention, American College of Rhematology 68th Annual Meeting
2006 Sjögren’s Syndrome Foundation Ethel Baxter Award for Outstanding Abstract
2008 Sjögren’s Syndrome Foundation Healthcare Professional Leadership Award
2008 Merrick Award for Outstanding Research, OMRF
2014 Edward L. and Thelma Gaylord Prize for Scientific Achievement
Editorial board, Genes and Immunity (1998-2003)
Member, Arthritis Foundation North Central Chapter Board of Directors (2006-2007)
Member, Oklahoma Lupus Association, Inc. (1997-2000)
Member, SLEGEN (SLE Genetics Consortium)
Guest Editor, Genes and Immunity, special issue: SLE Genetics
Coordinator, SGENE (Sjögren’s Genetics Network)
Member, OMRF Fleming Scholar Selection Committee, 2009
NIH Special Emphasis Panels (NIAMS, NIAID, NIDCR) – 2002 to present
Ad hoc reviewer: Genes and Immunity, The Journal of Rheumatology, Molecular Immunology, Arthritis and Rheumatism, Arthritis Research, American Journal of Human Genetics, Scandinavian Journal of Immunology, Human Genetics, The Journal of Laboratory and Clinical Medicine
Sjögren’s Syndrome Foundation Abstract Review Committee, American College of Rheumatology Annual Scientific Meeting, 2005 to present
Co-Chair, Sjögren’s Syndrome Study Group, American College of Rheumatology Annual Scientific Meeting, 2007-2008
American College of Rheumatology
American Society of Human Genetics
International Genetic Epidemiology Society
Sjögren’s Syndrome Foundation
Joined OMRF Scientific Staff in 2007.
Kottyan LC, Maddox A, Braxton JR, Stucke EM, Mukkada V, Putnam PE, Abonia JP, Chehade M, Wood RA, Pesek RD, Vickery BP, Furuta GT, Dawson P, Sampson HA, Martin LJ, Kelly JA, Kimberly RP, Sivils K, Gaffney PM, Kaufman K, Harley JB, Rothenberg ME. Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis. Genes Immun. 2018 Jun 8. [Epub ahead of print] PMID: 29904099
Bagavant H, Dunkleberger ML, Wolska N, Sroka M, Rasmussen A, Adrianto I, Montgomery C, Sivils K, Guthridge JM, James JA, Merrill JT, Deshmukh US. Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients. Clin Exp Rheumatol. 2018 Jun 25. [Epub ahead of print] PMID: 29998833
Patel Z, Lu X, Miller D, Forney CR, Lee J, Lynch A, Schroeder C, Parks L, Magnusen AF, Chen X, Pujato M, Maddox A, Zoller EE, Namjou B, Brunner HI, Henrickson M, Huggins JL, Williams AH, Ziegler JT, Comeau ME, Marion MC, Glenn SB, Adler A, Shen N, Nath SK, Stevens AM, Freedman BI, Pons-Estel BA, Tsao BP, Jacob CO, Kamen DL, Brown EE, Gilkeson GS, Alarcón GS, Martin J, Reveille JD, Anaya JM, James JA, Sivils KL, Criswell LA, Vilá LM, Petri M, Scofield RH, Kimberly RP, Edberg JC, Ramsey-Goldman R, Bang SY, Lee HS, Bae SC, Boackle SA, Cunninghame Graham D, Vyse TJ, Merrill JT, Niewold TB, Ainsworth HC, Silverman ED, Weisman MH, Wallace DJ, Raj P, Guthridge JM, Gaffney PM, Kelly JA, Alarcón-Riquelme ME, Langefeld CD, Wakeland EK, Kaufman KM, Weirauch MT, Harley JB, Kottyan LC. A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet. 2018 Apr 18. [Epub ahead of print] PMID: 29912393
Leehan KM, Pezant NP, Rasmussen A, Grundahl K, Moore JS, Radfar L, Lewis DM, Stone DU, Lessard CJ, Rhodus NL, Segal BM, Scofield RH, Sivils KL, Montgomery C, Farris AD. Minor salivary gland fibrosis in Sjögren's syndrome is elevated, associated with focus score and not solely a consequence of aging. Clin Exp Rheumatol. 2017 Oct 23. PMID:29148407
Leehan KM, Pezant NP, Rasmussen A, Grundahl K, Moore JS, Radfar L, Lewis DM, Stone DU, Lessard CJ, Rhodus NL, Segal BM, Kaufman CE, Scofield RH, Sivils KL, Montgomery C, Farris AD. Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren's syndrome. Autoimmunity. 2017 Oct 8:1-7. PMID:28988489
Glauzy S, Boccitto M, Bannock JM, Delmotte FR, Saadoun D, Cacoub P, Ice JA, Sivils KL, James JA, Wolin SL, Meffre E. Antigen-driven lymphoproliferations in Sjögren's Syndrome patients accumulate in complement receptor 2/CD21-/low B cells. Arthritis Rheumatol. 2017 Oct 26. PMID:29073352
Langefeld CD, Ainsworth HC, Cunninghame Graham DS, ...Guthridge JM, Huggins JL, James JA, ... Merrill JT, Miranda P, Moctezuma JF, Nath SK, ... Sivils KL, ... Alarcón-Riquelme ME, ..., Gaffney PM, Vyse TJ. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017 Jul 17;8:16021. PMCID: PMC5520018
Li H, Reksten TR, Ice JA, ...Sivils KL. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet. 2017 Jun 22;13(6):e1006820. PMCID:PMC5501660
Reksten TR, Lessard CJ, Sivils KL. Genetics in Sjögren Syndrome. Rheum Dis Clin North Am. 2016 Aug;42(3):435-47. Epub 2016 Jun 21. Review. PMID:27431346
Arthritis & Clinical Immunology Research Program, MS 24
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104
Phone: (405) 271-2534
Fax: (405) 271-3045
News from the Sivils lab
OMRF has received a $10 million grant from the National Institutes of Health to study the autoimmune disease lupus. The five-year award comes from the National Institute of Allergy and Infectious Diseases at the NIH. The grant will support research on the genetic origins of lupus, which affects up to an estimated 2 million Americans […]
You may never have heard of Sjögren’s syndrome, but you may very well know someone suffering from the illness. Sjögren’s (pronounced SHOW-grins) is a chronic autoimmune disease in which the body’s white blood cells attack the moisture-producing glands. The hallmark symptoms are dry eyes and dry mouth, but Sjögren’s may also cause dysfunction of other […]
Four Oklahomans joined the Oklahoma Medical Research Foundation’s Board of Directors at OMRF’s semiannual board meeting Wednesday. Also at the meeting, three OMRF scientists were honored. Joining the board are Dave Bialis, Ramsey Drake and Cliff Hudson of Oklahoma City and Harold Hamm of Enid. Bialis is president of Cox Oklahoma. His civic involvement includes […]
An international consortium of scientists led by OMRF investigator John B. Harley, M.D., Ph.D., has identified multiple genes linked to lupus, a devastating autoimmune disease that affects as many as 2 million Americans and 15 million people worldwide. The group’s findings appear online in two related articles in the Feb. edition of the journal Nature […]
The Oklahoma Medical Research Foundation is seeking participants for Sjögren’s syndrome research studies. Scientists are seeking healthy individuals as well as those who have been diagnosed with or have symptoms of Sjögren’s syndrome. Sjögren’s syndrome is an “autoimmune” disease in which the immune system attacks a person’s own moisture-producing glands, such as those that produce […]
The Oklahoma Medical Research Foundation today announced the addition of four scientists to the faculty of its Arthritis & Immunology Research Program. The four new faculty members are Patrick Gaffney, M.D., Kathy Moser, Ph.D., Jonathan Wren, Ph.D., and Igor Dozmorov, Ph.D. “Their recruitment gives us a depth of scientific commitment and expertise that is unparalleled […]