Identification of new quantitative trait loci in mice with collagen-induced arthritis
Kristin Bauer MSc
Institute for Immunology, University of Rostock, Rostock, Germany
Ms Bauer and Mr. Yu contributed equally to this work.
Search for more papers by this authorXinhua Yu MSc
Institute for Immunology, University of Rostock, Rostock, Germany
Ms Bauer and Mr. Yu contributed equally to this work.
Search for more papers by this authorPatrik Wernhoff PhD
Institute for Immunology, University of Rostock, Rostock, Germany
Search for more papers by this authorDirk Koczan PhD
Institute for Immunology, University of Rostock, Rostock, Germany
Search for more papers by this authorHans-Juergen Thiesen MD
Institute for Immunology, University of Rostock, Rostock, Germany
Search for more papers by this authorCorresponding Author
Saleh M. Ibrahim MD, PhD
Institute for Immunology, University of Rostock, Rostock, Germany
Institute of Immunology, Rostock University, Schillingallee 70, 18055 Rostock, GermanySearch for more papers by this authorKristin Bauer MSc
Institute for Immunology, University of Rostock, Rostock, Germany
Ms Bauer and Mr. Yu contributed equally to this work.
Search for more papers by this authorXinhua Yu MSc
Institute for Immunology, University of Rostock, Rostock, Germany
Ms Bauer and Mr. Yu contributed equally to this work.
Search for more papers by this authorPatrik Wernhoff PhD
Institute for Immunology, University of Rostock, Rostock, Germany
Search for more papers by this authorDirk Koczan PhD
Institute for Immunology, University of Rostock, Rostock, Germany
Search for more papers by this authorHans-Juergen Thiesen MD
Institute for Immunology, University of Rostock, Rostock, Germany
Search for more papers by this authorCorresponding Author
Saleh M. Ibrahim MD, PhD
Institute for Immunology, University of Rostock, Rostock, Germany
Institute of Immunology, Rostock University, Schillingallee 70, 18055 Rostock, GermanySearch for more papers by this authorAbstract
Objective
Collagen-induced arthritis (CIA) in the mouse is one of the most widely used autoimmune experimental models, with many features similar to rheumatoid arthritis. This study sought to identify potential genetic regulatory mechanisms of CIA in major histocompatibility complex–matched (H2-q) F2 hybrid mice.
Methods
We used 126 polymorphic markers to perform simple sequence-length polymorphism analysis on 290 F2 hybrids of arthritis-susceptible (DBA/1J) and arthritis-resistant (FVB/N) inbred mouse strains. The major clinical traits (disease severity and onset) were assessed, and serum antibodies specific to type II collagen (CII) were determined by enzyme-linked immunosorbent assay in 270 F2 mice. Lymph nodes from 94 F2 mice were used to test the ratio of CD4 to CD8 by fluorescence-activated cell sorter analysis, and cell proliferation was determined by XTT test.
Results
Two quantitative trait loci (QTLs) identified in previous studies were confirmed; these were severity-controlling Cia2 and onset-controlling Cia4 on chromosome 2. Moreover, we identified 5 new QTLs, 1 for CII-specific IgG2a antibodies on chromosome 5, 2 controlling the CII-specific IgG1 antibody response on chromosomes 10 and 13, 1 for the CD4:CD8 ratio on chromosome 2, and 1 for cell proliferation (measured by XTT test) on chromosome 16. Complement component C5 was identified as the probable main candidate gene for the QTLs Cia2 and Cia4. F2 mice carrying a 2-basepair deletion of C5, the FVB/N allele, had low incidence and less severe disease as compared with those carrying the DBA/1J allele.
Conclusion
This genome scan provides additional evidence confirming the role of C5 as a probable candidate gene for Cia2 and Cia4 loci, and identifies new QTLs controlling new traits in autoimmune arthritis.
REFERENCES
- 1 Silman AJ. Epidemiology of rheumatoid arthritis. APMIS 1994; 102: 721–8.
- 2 Wordsworth P, Bell J. Polygenic susceptibility in rheumatoid arthritis. Ann Rheum Dis 1991; 50: 343–6.
- 3 MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000; 43: 30–7.
- 4 Wordsworth BP, Lanchbury JS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci U S A 1989; 86: 10049–53.
- 5 McIndoe RA, Bohlman B, Chi E, Schuster E, Lindhardt M, Hood L. Localization of non-MHC collagen-induced arthritis susceptibility loci in DBA/1J mice. Proc Natl Acad Sci U S A 1999; 96: 2210–4.
- 6 Yang HT, Jirholt J, Svensson L, Sundvall M, Jansson L, Pettersson U, et al. Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat. J Immunol 1999; 163: 2916–21.
- 7
Johansson AC,
Sundler M,
Kjellen P,
Johannesson M,
Cook A,
Lindqvist AK, et al.
Genetic control of collagen-induced arthritis in a cross with NOD and C57BL/10 mice is dependent on gene regions encoding complement factor 5 and FcγRIIb and is not associated with loci controlling diabetes.
Eur J Immunol
2001;
31:
1847–56.
10.1002/1521-4141(200106)31:6<1847::AID-IMMU1847>3.0.CO;2-F CAS PubMed Web of Science® Google Scholar
- 8
Jirholt J,
Cook A,
Emahazion T,
Sundvall M,
Jansson L,
Nordquist N, et al.
Genetic linkage analysis of collagen-induced arthritis in the mouse.
Eur J Immunol
1998;
28:
3321–8.
10.1002/(SICI)1521-4141(199810)28:10<3321::AID-IMMU3321>3.0.CO;2-M CAS PubMed Web of Science® Google Scholar
- 9 Adarichev VA, Valdez JC, Bardos T, Finnegan A, Mikecz K, Glant TT. Combined autoimmune models of arthritis reveal shared and independent qualitative (binary) and quantitative trait loci. J Immunol 2003; 170: 2283–92.
- 10 Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A. Simplified mammalian DANN isolation procedure. Nucleic Acids Res 1991; 19: 4293.
- 11 Myrick C, DiGuisto R, DeWolfe J, Bowen E, Kappler J, Marrack P, et al. Linkage analysis of variations in CD4:CD8 T cell subsets between C57BL/6 and DBA/2. Genes Immun 2002; 3: 144–50.
- 12 Manly KF, Cudmore RH Jr, Meer JM. Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 2001; 12: 930–2.
- 13 Broman KW, Wu H, Sen S, Churchill GA. R/qtl: QTL mapping in experimental crosses. Bioinformatics 2003; 19: 889–90.
- 14 Sen S, Churchill GA. A statistical framework for quantitative traitmapping. Genetics 2001; 159: 371–82.
- 15 Wetsel RA, Fleischer DT, Haviland DL. Deficiency of the murine fifth complement component (C5): a 2-base pair gene deletion in a 5′-exon. J Biol Chem 1990; 265: 2435–40.
- 16 Wang Y, Kristan J, Hao L, Lenkoski CS, Shen Y, Matis LA. A role for complement in antibody-mediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J Immunol 2000; 164: 4340–7.
- 17 Spinella DG, Jeffers JR, Reife RA, Stuart JM. The role of C5 and T-cell receptor Vb genes in susceptibility to collagen-induced arthritis. Immunogenetics 1991; 34: 23–7.
- 18 Reife RA, Loutis N, Watson WC, Hasty KA, Stuart JM. SWR mice are resistant to collagen-induced arthritis but produce potentially arthritogenic antibodies. Arthritis Rheum 1991; 34: 776–81.
- 19 Watson WC, Brown PS, Pitcock JA, Townes AS. Passive transfer studies with type II collagen antibody in B10.D2/old and new line and C57BL/6 normal and beige (Chediak-Higashi) strains: evidence of important roles for C5 and multiple inflammatory cell types in the development of erosive arthritis. Arthritis Rheum 1987; 30: 460–5.
- 20 Mori L, de Libero G. Genetic control of susceptibility to collagen-induced arthritis in T cell receptor β-chain transgenic mice. Arthritis Rheum 1998; 41: 256–62.
- 21 Ji H, Gauguier D, Ohmura K, Gonzales A, Duchatelle V, Danoy P, et al. Genetic influences on the end-stage effector phase of arthritis. J Exp Med 2001; 194: 321–30.
- 22 Butterfield RJ, Blankenhorn EP, Roper RJ, Zachary JF, Doerge RW, Teuscher C. Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Am J Pathol 2000; 157: 637–45.
- 23 Vidal S, Kono DH, Theofilopoulos AN. Loci predisposing to autoimmunity in MRL-Fas lpr and C57BL/6-Faslpr mice. J Clin Invest 1998; 101: 696–702.
- 24 Mikulowska A, Metz CN, Bucala R, Holmdahl R. Macrophage migration inhibitory factor is involved in the pathogenesis of collagen type II-induced arthritis in mice. J Immunol 1997; 158: 5514–7.
- 25 Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002; 298: 1395–401.
- 26 Otto JM, Cs-Szabo G, Gallagher J, Velins S, Mikecz K, Buzas EI, et al. Identification of multiple loci linked to inflammation and autoantibody production by a genome scan of a murine model of rheumatoid arthritis. Arthritis Rheum 1999; 42: 2524–31.
- 27 Watson WC, Townes AS. Genetic susceptibility to murine collagen II autoimmune arthritis: proposed relationship to the IgG2 autoantibody subclass response, complement C5, major histocompatibility complex (MHC) and non-MHC loci. J Exp Med 1985; 162: 1878–91.
- 28 Ruschpler P, Lorenz P, Eichler W, Koczan D, Hanel C, Scholz R, et al. High CXCR3 expression in synovial mast cells associated with CXCL9 and CXCL10 expression in inflammatory synovial tissues of patients with rheumatoid arthritis. Arthritis Res Ther 2003; 5: R241–52.
- 29 Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsetti A, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 1998; 187: 129–34.
- 30 Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997; 277: 2005–7.
- 31 Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 1998; 187: 875–83.
- 32 Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM, Mellado M, Acevedo A, Garcia MI, et al. CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest 2001; 81: 409–18.
- 33 Luross JA, Williams NA. The genetic and immunopathological processes underlying collagen-induced arthritis. Immunology 2001; 103: 407–16.
- 34 Adarichev VA, Valdez JC, Bardos T, Finnegan A, Mikecz K, Glant TT. Combined autoimmune models of arthritis reveal shared and independent qualitative (binary) and quantitative trait loci. J Immunol 2003; 170: 2283–92.
- 35 Weis JJ, McCracken BA, Ma Y, Fairbairn D, Roper RJ, Morrison TB, et al. Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of lyme disease. J Immunol 1999; 162: 948–56.
- 36 Griffiths MM, Remmers EF. Genetic analysis of collagen-induced arthritis in rats: a polygenic model for rheumatoid arthritis predicts a common framework of cross-species inflammatory/autoimmune disease loci. Immunol Rev 2001; 184: 172–83.
- 37 Griffiths MM, Wang J, Joe B, Dracheva S, Kawahito Y, Shepard JS, et al. Identification of four new quantitative trait loci regulating arthritis severity and one new quantitative trait locus regulating autoantibody production in rats with collagen-induced arthritis. Arthritis Rheum 2000; 43: 1278–89.
- 38 Otto JM, Chandrasekeran R, Vermes C, Mikecz K, Finnegan A, Rickert SE, et al. A genome scan using a novel genetic cross identifies new susceptibility loci and traits in a mouse model of rheumatoid arthritis. J Immunol 2000; 165: 5278–86.
- 39 Myrick C, DiGuisto R, DeWolfe J, Bowen E, Kappler J, Marrack P, et al. Linkage analysis of variations in CD4:CD8 T cell subsets between C57BL6 and DBA/2. Genes Immun 2002; 3: 144–50.
- 40 Deftos ML, He YW, Ojala EW, Bevan MJ. Correlating notch signaling with thymocyte maturation. Immunity 1998; 9: 777–86.
- 41 Karlsson J, Zhao X, Lonskaya I, Neptin M, Holmdahl R, Andersson A. Novel quantitative trait loci controlling development of experimental autoimmune encephalomyelitis and proportion of lymphocyte subpopulations. J Immunol 2003; 170: 1019–26.
- 42 Butterfield RJ, Blankenhorn EP, Roper RJ, Zachary JF, Doerge RW, Sudweeks J, et al. Genetic analysis of disease subtypes and sexual dimorphisms in mouse experimental allergic encephalomyelitis (EAE): relapsing/remitting and monophasic remitting/nonrelapsing EAE are immunogenetically distinct. J Immunol 1999; 162: 3096–102.
