Nature's Choice of Genes Controlling Chronic Inflammation
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.
KeywordsRheumatoid Arthritis Major Histocompatibility Complex Celiac Disease Major Histocompatibility Complex Class Oxidative Burst
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).
- 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
- 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
- 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
- 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