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Nature's Choice of Genes Controlling Chronic Inflammation

  • R. Holmdahl
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/4)

Abstract

Inflammation is a physiological response that may go uncontrolled and thereby develop in a chronic way. This seems to happen in many common diseases of autoimmune, degenerative, or allergic character. Rheumatoid arthritis (RA) is by definition a chronic disease with an autoimmune inflammatory attack on diarthrodial cartilaginous joints. The development of new treatment neutralizing cytokines involved in the inflammatory attack has given relief and gives the promise of more effective treatment of already established disease. It is now time to set our eyes on a new vision to develop preventive and curative treatment based on knowledge of the unique and causative pathogenic mechanisms. To do this we believe it is important to identify the natural-selected polymorphisms that are associated with disease. These have proven to be extremely difficult to identify in complex diseases such as RA, but using animal models, this work is closer to reality. Animal models have recently been developed mimicking various aspects of the human disease. We will present an example in which a genetic polymorphism associated with the development of arthritis has been identified. On the basis of this finding, a new pathway involving control of immune tolerance by reactive oxidative species has been identified and a new class of antiinflammatory agents activating the induced oxidative burst protein complex is suggested.

Keywords

Rheumatoid Arthritis Major Histocompatibility Complex Celiac Disease Major Histocompatibility Complex Class Oxidative Burst 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

I am grateful for support from several foundations that have made this work possible: the Anna Greta Crafoord, King Gustaf V:s 80-year, the Swedish Science Research Council, the Strategic Research Foundation, and the EU project NeuroproMiSe—LSHM-CT-2005-018637 and LSHM-CT-2005-005223 (Euraps).

References

  1. Aho K, Palosuo T, Raunio V, Puska P, Aromaa A, Salonen JT (1985) When does rheumatoid disease start? Arthritis Rheum 28:485–489CrossRefPubMedGoogle Scholar
  2. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330–337CrossRefPubMedGoogle Scholar
  3. Bijlsma JW, van den Brink HR (1992) Estrogens and rheumatoid arthritis. Am J Reprod Immunol 28:231–234PubMedGoogle Scholar
  4. Gelderman KA, Hultqvist M, Holmberg J, Olofsson P, Holmdahl R (2006) T-cell surface redox levels determine T-cell reactivity and arthritis susceptibility. Proc Natl Acad Sci USA 103:12831–12836CrossRefPubMedGoogle Scholar
  5. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30:1205–1213CrossRefPubMedGoogle Scholar
  6. Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6:508–519CrossRefPubMedGoogle Scholar
  7. Huang CK, Zhan L, Hannigan MO, Ai Y, Leto TL (2000) P47(phox)-deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J-m db/db and db/+. J Leukoc Biol 67:210–215PubMedGoogle Scholar
  8. Hultqvist M, Olofsson P, Holmberg J, Backstrom BT, Tordsson J, Holmdahl R (2004) Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene. Proc Natl Acad Sci USA 101:12646–12651CrossRefPubMedGoogle Scholar
  9. Hultqvist M, Olofsson P, Gelderman KA, Holmberg J, Holmdahl R (2006) A new arthritis therapy with oxidative burst inducers. PLoS Med 3:e348CrossRefPubMedGoogle Scholar
  10. Jansson L, Holmdahl R (1998) Estrogen-mediated immunosuppression in autoimmune diseases. Inflamm Res 47:290–301CrossRefPubMedGoogle Scholar
  11. John S, Amos C, Shephard N, Chen W, Butterworth A, Etzel C, Jawaheer D, Seldin M, Silman A, Gregersen P, Worthington J (2006) Linkage analysis of rheumatoid arthritis in US and UK families reveals interactions between HLA-DRB1 and loci on chromosomes 6q and 16p. Arthritis Rheum 54:1482–1490CrossRefPubMedGoogle Scholar
  12. Jones EY, Fugger L, Strominger JL, Siebold C (2006) MHC class II proteins and disease: a structural perspective. Nat Rev Immunol 6:271–282CrossRefPubMedGoogle Scholar
  13. Karlsson J, Zhao X, Lonskaya I, Neptin M, Holmdahl R, Andersson A (2003) Novel quantitative trait loci controlling development of experimental autoimmune encephalomyelitis and proportion of lymphocyte subpopulations. J Immunol 170:1019–1026PubMedGoogle Scholar
  14. MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43:30–37CrossRefPubMedGoogle Scholar
  15. Mattsson R, Mattsson A, Holmdahl R, Whyte A, Rook GA (1991) Maintained pregnancy levels of oestrogen afford complete protection from post-partum exacerbation of collagen-induced arthritis. Clin Exp Immunol 85:41–47CrossRefPubMedGoogle Scholar
  16. Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ, Ambati J (2006) Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA 103:2328–2333CrossRefPubMedGoogle Scholar
  17. Olofsson P, Holmberg J, Tordsson J, Lu S, Akerstrom B, Holmdahl R (2003) Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet 33:25–32CrossRefPubMedGoogle Scholar
  18. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, Sundin U, van Venrooij WJ (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749CrossRefPubMedGoogle Scholar
  19. Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101:273–281CrossRefPubMedGoogle Scholar
  20. Sollid LM (2002) Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2:647–655CrossRefPubMedGoogle Scholar
  21. Sollid LM, Jabri B (2005) Is celiac disease an autoimmune disorder? Curr Opin Immunol 17:595–600CrossRefPubMedGoogle Scholar
  22. Stastny P (1978) Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 298:869–871CrossRefPubMedGoogle Scholar
  23. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402CrossRefPubMedGoogle Scholar
  24. Symmons D, Turner G, Webb R, Asten P, Barrett E, Lunt M, Scott D, Silman A (2002) The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford) 41:793–800CrossRefGoogle Scholar
  25. Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P, Nika K, Tautz L, Tasken K, Cucca F, Mustelin T, Bottini N (2005) Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 37:1317–1319CrossRefPubMedGoogle Scholar
  26. Vingsbo C, Sahlstrand P, Brun JG, Jonsson R, Saxne T, Holmdahl R (1996) Pristane-induced arthritis in rats: a new model for rheumatoid arthritis with a chronic disease course influenced by both major histocompatibility complex and non-major histocompatibility complex genes. Am J Pathol 149:1675–1683PubMedGoogle Scholar
  27. Vingsbo-Lundberg C, Nordquist N, Olofsson P, Sundvall M, Saxne T, Pettersson U, Holmdahl R (1998) Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats. Nat Genet 20:401–404CrossRefPubMedGoogle Scholar
  28. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Medical Inflammation ResearchLundSweden

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