Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase.
Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candidate gene for regulation of Lyme arthritis and reveal Lyme arthritis to be independent of NADPH oxidase activity, distinguishing it from other models of rheumatoid arthritis.
Crandall
Hillary
H
Department of Pathology, University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT 84132. janis.weis@path.utah.edu.
Ma
Ying
Y
Dunn
Diane M
DM
Sundsbak
Rhianna S
RS
Zachary
James F
JF
Olofsson
Peter
P
Holmdahl
Rikard
R
Weis
John H
JH
Weiss
Robert B
RB
Teuscher
Cory
C
Weis
Janis J
JJ
D000818:Animals; D025065:Borrelia burgdorferi / Q000276:immunology; D002874:Chromosome Mapping; D008040:Genetic Linkage; D008193:Lyme Disease / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D019255:NADPH Oxidases / Q000378:metabolism*; D010586:Phagocytes / Q000201:enzymology*; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D012720:Severity of Illness Index
D010750:Phosphoproteins; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1