Positional identification of Ncf1 as a gene that regulates arthritis severity in rats

The identification of genes underlying quantitative-trait loci (QTL) for complex diseases, such as rheumatoid arthritis, is a challenging and difficult task for the human genome project. Through positional cloning of the Pia4 QTL in rats, we found that a naturally occurring polymorphism of Ncf1 (encoding neutrophil cytosolic factor 1, a component of the NADPH oxidase complex) regulates arthritis severity. The disease-related allele of Ncf1 has reduced oxidative burst response and promotes activation of arthritogenic T cells. Pharmacological treatment with substances that activate the NADPH oxidase complex is shown to ameliorate arthritis. Hence, Ncf1 is associated with a new autoimmune mechanism leading to severe destructive arthritis, notably similar to rheumatoid arthritis in humans.

[1]  B. Åkerström.  Immunological analysis of alpha 1-microglobulin in different mammalian and chicken serum. alpha 1-Microglobulin is 5-8 kilodaltons larger in primates. , 1985, The Journal of biological chemistry.

[2]  S. Desiderio,et al.  BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  I. Orme,et al.  Transient Loss of Resistance to Pulmonary Tuberculosis in p47phox−/− Mice , 2000, Infection and Immunity.

[4]  K. Johnson.  An Update. , 1984, Journal of food protection.

[5]  R. Holmdahl,et al.  Arthritis induced in rats with non‐immunogenic adjuvants as models for rheumatoid arthritis , 2001, Immunological reviews.

[6]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[7]  R. Holmdahl,et al.  Increased serum levels of cartilage oligomeric matrix protein in chronic erosive arthritis in rats , 1998, Arthritis and rheumatism.

[8]  R. Sha’afi,et al.  Activation of MAP kinase-activated protein kinase 2 in human neutrophils after phorbol ester or fMLP peptide stimulation. , 1996, Blood.

[9]  A. Monaco,et al.  Construction and characterization of a 10-fold genome equivalent rat P1-derived artificial chromosome library. , 1998, Genomics.

[10]  K. Rittinger,et al.  Architecture of the p40-p47-p67 phox Complex in the Resting State of the NADPH Oxidase , 2002, The Journal of Biological Chemistry.

[11]  M. Yaffe,et al.  The PX domains of p47phox and p40phox bind to lipid products of PI(3)K , 2001, Nature Cell Biology.

[12]  Zheng,et al.  The preventive effects of incomplete Freund’s adjuvant and other vehicles on the development of adjuvant‐induced arthritis in Lewis rats , 1999, Immunology.

[13]  Webb Miller,et al.  Generation and Comparative Analysis of ∼3.3 Mb of Mouse Genomic Sequence Orthologous to the Region of Human Chromosome 7q11.23 Implicated in Williams Syndrome , 2002 .

[14]  R. Holmdahl,et al.  Vaccination and genetic experiments demonstrate that adjuvant-oil-induced arthritis and homologous type II collagen-induced arthritis in the same rat strain are different diseases. , 1992, Clinical and experimental immunology.

[15]  A. Karlsson,et al.  Respiratory burst in human neutrophils. , 1999, Journal of immunological methods.

[16]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[17]  A. Kang,et al.  Autoimmunity to type II collagen an experimental model of arthritis , 1977, The Journal of experimental medicine.

[18]  A. Shiose,et al.  Arachidonic Acid and Phosphorylation Synergistically Induce a Conformational Change of p47 phox to Activate the Phagocyte NADPH Oxidase* , 2000, The Journal of Biological Chemistry.

[19]  U. Francke,et al.  A mouse single-copy gene, Gtf2i, the homolog of human GTF2I, that is duplicated in the Williams-Beuren syndrome deletion region. , 1998, Genomics.

[20]  A S Rigby,et al.  Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. , 2000, Arthritis and rheumatism.

[21]  C I Amos,et al.  A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. , 2001, American journal of human genetics.

[22]  H. Erlandsson‐Harris,et al.  Polyclonal Th1 cells transfer oil‐induced arthritis , 1997, Immunology.

[23]  R. Jonsson,et al.  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. , 1996, The American journal of pathology.

[24]  B. Babior.  NADPH oxidase: an update. , 1999, Blood.

[25]  J. Dixon,et al.  Phoxy Lipids Revealing PX Domains as Phosphoinositide Binding Modules , 2001, Cell.

[26]  J. Palmblad,et al.  Activity of the Leukocyte Nadph Oxidase in Whole Neutrophils and Cell-Free Neutrophil Preparations Stimulated with Long-Chain Polyunsaturated Fatty Acids , 2001, Inflammation.

[27]  E. Remmers,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. , 2000, Arthritis and rheumatism.

[28]  M. Woods,et al.  Suppression of adjuvant-induced arthritis in DA rats by incomplete Freund's adjuvant. , 1993, Arthritis and rheumatism.

[29]  M. A. Hossain,et al.  Complete Freund's adjuvant suppresses the development and progression of pristane-induced arthritis in rats. , 2002, Clinical immunology.

[30]  T. Ito,et al.  Functional modules and expression of mouse p40(phox) and p67(phox), SH3-domain-containing proteins involved in the phagocyte NADPH oxidase complex. , 1998, European journal of biochemistry.

[31]  Jeffrey W Touchman,et al.  Generation and comparative analysis of approximately 3.3 Mb of mouse genomic sequence orthologous to the region of human chromosome 7q11.23 implicated in Williams syndrome. , 2002, Genome research.

[32]  E. Remmers,et al.  Identification of genomic regions controlling experimental autoimmune uveoretinitis in rats. , 1999, International immunology.

[33]  R. Holmdahl,et al.  Genetic links between the acute‐phase response and arthritis development in rats , 2002, Arthritis and rheumatism.

[34]  E. Wakeland,et al.  Lessons from the NZM2410 Model and Related Strains , 2000, International reviews of immunology.

[35]  R. Doerge,et al.  Identification of quantitative trait loci governing arthritis severity and humoral responses in the murine model of Lyme disease. , 1999, Journal of immunology.

[36]  K Lindpaintner,et al.  High-throughput scanning of the rat genome using interspersed repetitive sequence-PCR markers. , 2000, Genomics.

[37]  R. C. van der Veen,et al.  Superoxide Prevents Nitric Oxide-Mediated Suppression of Helper T Lymphocytes: Decreased Autoimmune Encephalomyelitis in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Knockout Mice1 , 2000, The Journal of Immunology.

[38]  K. Bergsteinsdottir,et al.  Evidence for Common Autoimmune Disease Genes Controlling Onset, Severity, and Chronicity Based on Experimental Models for Multiple Sclerosis and Rheumatoid Arthritis1 , 2000, The Journal of Immunology.

[39]  E. Ligeti,et al.  Chronic granulomatous disease: more than the lack of superoxide? , 2001, Journal of leukocyte biology.

[40]  P. Marrack,et al.  Immunological adjuvants promote activated T cell survival via induction of Bcl-3 , 2001, Nature Immunology.

[41]  S. Holland,et al.  The p47phox mouse knock-out model of chronic granulomatous disease , 1995, The Journal of experimental medicine.

[42]  F. Levi-Schaffer,et al.  Role of reactive oxygen species (ROS) in apoptosis induction , 2000, Apoptosis.

[43]  Hidekazu Hiroaki,et al.  Solution structure of the PX domain, a target of the SH3 domain , 2001, Nature Structural Biology.

[44]  T. Olsson,et al.  Genome-wide linkage analysis of chronic relapsing experimental autoimmune encephalomyelitis in the rat identifies a major susceptibility locus on chromosome 9. , 1999, Journal of immunology.

[45]  H. Malech,et al.  Recombinant 47-kilodalton cytosol factor restores NADPH oxidase in chronic granulomatous disease. , 1989, Science.

[46]  L. Zhan,et al.  P47phox ‐deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J‐m db/db and db/+ , 2000, Journal of leukocyte biology.

[47]  D. Heinegård,et al.  Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. , 1992, British journal of rheumatology.

[48]  D. Bentley,et al.  Autosomal recessive chronic granulomatous disease caused by deletion at a dinucleotide repeat. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[49]  J. Donelson,et al.  Cloning of the cDNA and functional expression of the 47-kilodalton cytosolic component of human neutrophil respiratory burst oxidase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[50]  R. Holmdahl,et al.  Genetic control of arthritis onset, severity and chronicity in a model for rheumatoid arthritis in rats , 1998, Nature Genetics.

[51]  R. Holmdahl,et al.  Complex genetic control in a rat model for rheumatoid arthritis. , 2000, Journal of autoimmunity.

[52]  M. Mahowald,et al.  The cellular basis of adjuvant arthritis. II. Characterization of the cells mediating passive transfer. , 1983, Cellular immunology.

[53]  G. Gyapay,et al.  New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study. , 1998, Proceedings of the National Academy of Sciences of the United States of America.