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Two Loci on Chromosome 15 Control Experimentally Induced Arthritis through the Differential Regulation of IL-6 and Lymphocyte Proliferation¹

Tibor T. Glant^*, Sándor Szántó^*,, Aniko Vegvari^*,, Zoltan Szabo^*,, Katalin Kis-Toth^*,, Katalin Mikecz^*, and Vyacheslav A. Adarichev^2,*,

^* Section of Molecular Medicine, Department of Orthopedic Surgery, and Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612; Department of Internal Medicine 3, Health Science Center, University of Debrecen, Debrecen, Hungary; and Albert Einstein College of Medicine of Yeshiva University, Department of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461

Using genetic linkage analysis of proteoglycan-induced arthritis (PGIA), a murine model for rheumatoid arthritis, we identified two loci, Pgia8 and Pgia9, on chromosome 15 (chr15) that appear to be implicated in disease susceptibility. Immunization of congenic strains carrying the entire chr15 and separately each of the two loci of DBA/2 arthritis-resistant origin in susceptible BALB/c background confirmed locations of two loci on chr15: the major Pgia9 and lesser Pgia8 locus. Distal part of chr15 (Pgia9) showed a major suppressive effect on PGIA susceptibility in females (40%, p < 0.001), whereas the effect of this locus in congenic males was still significant but weaker. Proximal part of chr15 (Pgia8) demonstrated mild and transient effect upon arthritis; this effect was PGIA-promoting in males and suppressive in females. Pgia8 and Pgia9 loci demonstrated an additive mode of inheritance, since when they were both incorporated in consomic chr15 strain, the total effect was a sum of the two loci. Using F₂ population of the intercross of wild-type and chr15 consomic strain, we confirmed and refined quantitative trait locus positions and identified a strong correlation between disease susceptibility and lymphocyte-producing cytokines of TNF- and IL-6. Both Pgia8 and Pgia9 loci on chr15 appear to control IL-6 production in spleen cultures of arthritic mice, providing an important link to the mechanism of autoimmune inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants AR051101, AR045652 and AR040310. V.A.A. is a recipient of the Sontag Foundation and the Arthritis National Research Foundation Awards.

² Address correspondence and reprint requests to Dr. Vyacheslav A. Adarichev, Albert Einstein College of Medicine of Yeshiva University, Department of Medicine, 1300 Morris Park Avenue, Forchheimer, Room 405, Bronx, NY 10461. E-mail address: vadarich{at}aecom.yu.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; chr15, chromosome 15; LRS, likelihood ratio statistic; Ncf, neutrophil cytosolic factor; PG, proteoglycan; PGIA, PG-induced arthritis; PIA, pristane-induced arthritis; QTL, quantitative trait locus (loci).