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.
Olofsson
Peter
P
Section for Medical Inflammation Research and Department of Cell and Molecular Biology, Sölvegatan 19, I11 BMC, Lund University, S-22184 Lund, Sweden.
Holmberg
Jens
J
Tordsson
Jesper
J
Lu
Shemin
S
Akerström
Bo
B
Holmdahl
Rikard
R
D019264:Adoptive Transfer; D000483:Alleles; D000818:Animals; D020296:Animals, Congenic; D000835:Animals, Wild; D001168:Arthritis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D018450:Disease Progression; D004789:Enzyme Activation; D005787:Gene Frequency; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D016897:Respiratory Burst
D010750:Phosphoproteins; D012333:RNA, Messenger; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1