Pércio S. Gulko, MD Lab Head pgulko@nshs.edu

Pércio S. Gulko, MD, is finding genes that regulate the susceptibility to rheumatoid arthritis and the severity of the symptoms. While a number of new therapies have emerged with encouraging results in recent years, disease remission and cure are still rarely achieved. The identification of RA susceptibility and severity genes, and the understanding of their function, are anticipated to generate novel targets for the development of more effective therapies, as well as new tools for diagnosis and prognostication.
In order to accomplish his team’s goals of gene identification, they have been using a combination of strategies involving genetic analysis, functional studies of inflammatory cells, and gene expression studies of the joint cells (synovial fibroblasts). These studies led to the identification of several new chromosomal regions that regulate arthritis severity, and well as the discovery of novel regulators of the inflammatory response, such as Cia4 and Cia6. Furthermore, his group has determined that one specific arthritis locus, Cia5a, regulates numbers of a unique type of regulatory T cells that are capable of suppressing the immune responses.

This discovery has the potential of generating a novel way of treating arthritis by increasing numbers of these cells. Recent results from his laboratory have identified a novel genetic pathway that regulates the invasive properties of the synovial fibroblast, a cell that is considered to be central to the joint damage and destruction seen in RA. They are now in the process of modulating this new pathway and determining whether it would be a good target for therapy.

Ultimately, they aim to bring these laboratory discoveries into the clinic to improve the lives of patients with rheumatoid arthritis. His group has shown that one arthritis locus, Cia5d, regulates disease severity and the invasive properties of the synovial fibroblasts, including the activation of MMP-2 and MMP-14, two proteases implicated in joint destruction. Another locus, Cia5a, regulates numbers on a subset of Treg cells, and two other arthritis severity loci, Cia4 and Cia6, have been implicated in the regulation of neutrophil migration into inflammatory sites.

Ultimately, these genes, and others currently being studied, should generate novel and targets for the development of new and better treatments for rheumatoid arthritis and other erosive forms of arthritis such as psoriatic arthritis.

Identification of genes regulating arthritis; identification and characterization of the collagen and pristine-induced arthritis regulatory loci Cia10 and Cia27).

This project aims to identify the two specific non-MHC genes (Cia10 and Cia27) regulating arthritis in two experimental model of rheumatoid arthritis and to determine how these genes operate to cause disease. Congenic models are being generated, and sub-phenotypes of the autoimmune response are being identified and will be used to specify pathways regulated by the arthritis genes. These loci are related to those regulating rheumatoid arthritis, and our findings will likely be relevant to human disease.

Identification of arthritis genes in DAxF344 models.

This grant aims to identify the genes accounting for Cia3d, Ci5a, Cia5d and Cia6, non-MHC loci identified in an intercross between DA and F344. Congenic models were previously established and studied. 

Identification of a gender-specific arthritis locus.

This grant aims to identify and functionally characterize Cia12, a new major non-MHC locus that regulates arthritis in females but not in males. Congenic models are being generated, and subphenotypes of the immune response, are being characterized. This study will determine which gender-effects account for the sex-specific effect of this locus in arthritis. 

		Name:   Max Brenner, MD, PhD Position:   Postdoctoral Scientist Research:   Studies the genetics of rheumatoid arthritis. Email:   mbrenner@nshs.edu
		Name:   Petrus Linge, MD Position:   Ph.D Candidate Research:   Studies the genetics of rheumatoid arthritis. Email:   plinge@nshs.edu
		Name:   Teresin Laragione , PhD Position:   Research Scientist Research:   Studies the genetics of rheumatoid arthritis. Email:   tlaragio@nshs.edu
		Name: Emma Jenkins, PhD Position: Research Scientist Email: ejenkins1@nshs.edu
		Name:   Adriana Mello, BS Position:   Research Assistant Research:   Studies the genetics of rheumatoid arthritis. Email:   amello@nshs.edu
		Name: Kevin Kwan Position: Research Assistant Email: kevikwan@@gmail.com

Publications

Johannesson M, Lopez-Aumatell R, Stridh P, Diez M, Tuncel J, Blazquez G, Martinez E, Canete A, Vicens-Costa E, Graham D, Copley RR, Hernandez-Pliego P, Beyeen AD, Öckinger J, Fernandez C, Gulko PS, Brenner M, Tobeña A, Guitart-Masip M, Gimenez-Llort L, Dominiczak A, Holmdahl R, Gauguier D, Olsson T, Mott R, Valdar W, Redei E, Fernandez-Teruel A, Flint J. A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Res 2008 (in press).

Laragione T, Brenner M, Li W, Gulko PS. Cia5d regulates a new fibroblast-like synoviocyte invasion-associated gene expression signature. Arthritis Res Ther. 2008 Aug 15;10(4):R92. [Epub ahead of print]. PMCID: PMC2575606.

Laragione T, Brenner M, Mello A, Symons M, Gulko PS. The arthritis severity locus Cia5d is a novel genetic regulator of the invasive properties of synovial fibroblasts Arthritis Rheum. 2008 Aug;58(8):2296-306. NIHMSID # 77691.

Gulko PS. Contribution of genetic studies in rodent models of autoimmune arthritis to understanding and treatment of rheumatoid arthritis. Genes and Immunity 2007, 8: 523-531.

Chan A, Akhtar M, Brenner M, Zheng Y, Gulko PS, Symons M. The GTPase Rac Regulates the Proliferation and Invasion of Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients. Mol. Med. 2007, 13:297-304.

Brenner M, Laragione T, Yarlett NC, Gulko PS. Genetic regulation of T regulatory, CD4, and CD8 cell numbers by the arthritis severity loci Cia5a, Cia5d and the MHC in the rat. Mol. Med. 2007, 13:277-287.

Brenner M, Laragione T, Mello A, Gulko PS. Cia25 on rat chromosome 12 regulates severity of autoimmune arthritis induced with pristane and collagen. Ann Rheum Dis 2007, 66:952-957.

Laragione, T, Yarlett NC, Brenner M, Mello A, Sherry B, Miller EJ, Metz CN, Gulko PS. The arthritis severity quantitative trait loci (QTL) Cia4 and Cia6 regulate neutrophil migration into inflammatory sites and levels of TNFα and nitric oxide. Journal of Immunology 2007, 178:2344-2351.
 
Laragione, T, Yarlett NC, Brenner M, Mello A, Miller EJ, Metz CN, Sherry B, Gulko PS. The arthritis severity quantitative trait locus (QTL) Cia7 regulates neutrophil migration into inflammatory sites. Genes and Immunity 2007 Mar;8(2):147-53.

Brenner M, Laragione T, Yarlett NC, Li W, Mello A, Gulko PS. Cia27 is a novel non-MHC arthritis severity locus on rat hromosome 10 syntenic to the rheumatoid arthritis 17q22-q25 locus. Genes and Immunity 2006, May 4; [Epub ahead of print].

Batliwalla FM, Li W, Ritchlin CT, Xiao X, Brenner M, Laragione T, Shao T, Durham R, Kemshetti S, Schwarz E, Coe R, Kern M, Baechler EC, Behrens TW, Gregersen PK, Gulko PS. Microarray analyses of peripheral blood cells identifies unique gene expression signature in psoriatic arthritis. Mol Med. 2005 Jan-Dec;11(1-12):21-9.

Brenner M, Braun C, Oster M, Gulko PS. Thermal signature analysis as a novel method for evaluating inflammatory arthritis activity. Ann Rheum Dis Sep 8; [Epub ahead of print], 2005.

Brenner M, Meng HC, Yarlett NC, Joe B, Griffiths MM, Remmers EF, Wilder RL, Gulko PS. The non-MHC quantitative trait locus Cia5 contains three major arthritis genes that differentially regulate disease severity, pannus formation and joint damage in collagen- and pristane-induced arthritis. Journal of Immunology, 174(12):7894-902, 2005.

Batliwalla FM, Baechler EC, Xiao X, Li W, Balasubramanian S, Khalili H, Damle A, Ortmann WA, Perrone A, Kantor AB, Gulko PS, Kern M, Furie R, Behrens T, Gregersen PK. Peripheral Blood Gene Expression Profiling in Rheumatoid Arthritis. Genes and Immunity, 2005 Aug;6(5):388-97.
Brenner M, Meng HC, Yarlett NC, Griffiths MM, Remmers EF, Wilder RL, Gulko PS. The non-MHC quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation and joint damage. Arthritis Rheum 52(1):322-32, 2005.

Meng HC, Griffiths MM, Remmers EF, Kawahito Y, Li W, Neisa R, Cannon GW, Wilder RL, Gulko PS. Identification Of Two NovelFemale-Specific Non-MHC Loci Regulating Collagen-Induced Arthritis Severity And Chronicity, And Evidence For Epistasis. Arthritis Rheum 50 (8):2695-2705, 2004.

Pillemer S, Gulko PS, Ligier S, Yarboro C, Gourley M, Goldbach-Mansky R, Siegel R, Hirsch R, Pucino F, Tilley B, Wilder RL. Pilot Clinical Trial Of Intravenous Doxycycline Versus Placebo For Rheumatoid Arthritis. J Rheumatol 30:41-3, 2003.

Remmers EF, Joe B, Griffiths MM, Dobbins DE, Dracheva SV, Hashiramoto A, Furuya T, Salstrom JL, Wang J, Gulko PS, Cannon GW, Wilder RL. Collagen-induced arthritis QTLs isolated in congenic rats modulate experimental arthritis: Non-MHC QTL effects differ in males and females. Arthritis Rheum 46:2225-2234, 2002.

Joe B, Cannon GW, Griffiths MM, Dobbins DE, Gulko PS, Wilder RL, Remmers EF. Evaluation of Mycobacterial adjuvant-induced arthritis (Mbt-AIA) severity QTLs isolated in mono-congenic and poly-congenic rats: Identification of a new regulatory locus on rat chromosome 10, and evidence that Mbt-AIA loci overlap rheumatoid arthritis susceptibility loci. Arthritis Rheum 46:1075-85, 2002.

Slager SL, Carleu L, Chung, WK, Jackson T, Winchester RJ, Hodge SE, Gulko PS. The IDDM13 region containing the insulin-like growth factor binding protein-5 (IGFBP5) gene on chromosome 2q33-q36 and the susceptibility to rheumatoid arthritis. Genes Immun 3:110-3, 2002.

Wilder RL, Griffiths MM, Cannon GW, Caspi R, Gulko PS, Remmers ER. Genetic factors involved in central nervous system/immune interaction. Adv Exp Med Biol 493:59-67, 2001.

Joe B, Remmers EF, Dobbins DE, Salstrom JL, Furuya T, Dracheva S, Gulko PS, Cannon GW, Griffiths MM, Wilder RL. Genetic dissection of collagen-induced arthritis in Chromosome 10 quantitative trait locus speed congenic rats: evidence for more than one regulatory locus and sex influences. Immunogenetics 51:930-944, 2000.

Dracheva SV, Remmers EF, Chen S, Chang L, Gulko PS, Kawahito Y, Longman RE, Wang J, Du Y, Shepard J, Ge L, Joe B, Kotake, S, Salstrom JL, Furuya T, Hoffman J, Cannon GW, Griffiths MM, Wilder RL. An integrated genetic linkage map with 1137 markers constructed from five F2 crosses of autoimmune disease-prone and -resistant inbred rat strains. Genomics 63:202-226, 1999.

El-Gabalawy HS, Goldbach-Mansky R, Smith D, Arayssi T, Bale S, Gulko P, Yarboro C, Wilder RL, Klippel JH, Schumacher HR Jr. Association of HLA alleles and clinical features in patients with synovitis of recent onset. Arthritis Rheum 42:1696-705, 1999.

Shepard JS, Remmers EF, Chen S, Chang L, Kawahito Y, Gulko PS, Joe B, Longman RE, Dracheva S, Ge L, WangJ,ReeseVR, Cannon GW, Griffiths MM, Wilder RL. A genetic linkage map of rat chromosome 15 derived from 5 F2 crosses. Mamm Genome 10: 186-188, 1999.

Dracheva S, Remmers EF, Gulko PS, Kawahito Y, Longman RE, Reese V, Cannon GW, Griffiths MM,  Wilder RL. Identification of a new non-MHC quantitative trait locus on chromosome 7 controlling disease severity of collagen-induced arthritis (CIA) in rats. Immunogenetics 49:787-91, 1999.

Kawahito Y, Cannon GW, Gulko PS, Remmers EF, Longman RE, Reese VR, Wang J, Griffiths MM, Wilder RL. Localization of quantitative trait loci regulating adjuvant-induced arthritis in rats: evidence for genetic factors for common autoimmune diseases. J Immunol 161:4411-4419, 1998.

Gulko PS, Kawahito Y, Remmers EF, Reese VR, Wang J, Dracheva SV, Longman RE, Shepard JS, Cannon GW, Sawitzke AD, Wilder RL, Griffiths MM. Identification of a new non-MHC locus on chromosome 2 controlling disease severity in collagen-induced arthritis in rats. Arthritis Rheum 41:2122-2131, 1998.

Wilder RL, Remmers EF, Gulko PS, Kawahito Y, Longman R, et al. National Institutes of Health Rat Genetic Database. http://www.nih.gov/niams/scientific/ratgbase/index.htm, 1997 (most recent update October 2000).

Gulko PS; Reveille JD; Koopman WJ; Burgard SL; Bartolucci AA; Alarcón GS: Survival Impact of Autoantibodies in Systemic Lupus Erythematosus. J Rheumatol 21:224-228, 1994.

Gulko PS; Reveille JD; Koopman WJ; Burgard SL; Bartolucci AA; Alarcón GS: Anticardiolipin Antibodies in Systemic Lupus Erythematosus: clinical correlates, HLA associations and impact on Survival. J Rheumatol 20:1684-93, 1993.

INVITED ARTICLES OR BOOK CHAPTERS (selected)

Gregersen PK, Plenge RM, Gulko PS. Genetics of rheumatoid arthritis. In Rheumatoid arthritis: the new frontiers in pathogenesis and treatment (second edition). Firestein G, Panayi G, Wollheim F. (editors), Oxford Press, New York, pp. 3-14, 2006.

Gulko PS, Gregersen PK. Genetics of Rheumatoid arthritis. In The Yearbook in Rheumatoid Arthritis 2002. Cope, A.P. and Scott, D.L. (editors), Clinical Publishing Services, England, pp 3-22, 2002.

Gulko PS, Winchester RJ. Rheumatoid Arthritis. In Samter’s Textbook of Immunologic Diseases. Austen, K. F., Frank, M.M., Atkinson, J.P. and Cantor (editors), Lippincott, Williams & Wilkins, Baltimore, pp.427-463, 2001.

Gulko PS, Seki T, Winchester RJ. Fibroblast synoviocytes: their intrinsic and modified phenotypes and their potential role in the pathogenesis of rheumatoid arthritis. In Rheumatoid arthritis: the new frontiers in pathogenesis and treatment (first edition). Firestein G, Panayi G, Wollheim F. (editors), Oxford Press, New York, pp. 113-135, 2000.

Wilder RL, Remmers EF, Kawahito Y, Gulko PS, Cannon GW, Griffiths MM. Genetic factors regulating experimental arthritis in mice and rats. In Current Directions in Autoimmunity, Theofilopoulos AN (ed), Basel, Karger, vol.1, pp121-165, 1999.