A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity

Olsson, Lina; Lindqvist, Anna-Karin; Källberg, Henrik; Padyukov, Leonid; Burkhardt, Harald; Alfredsson, Lars; Klareskog, Lars; Holmdahl, Rikard

doi:10.1186/ar2299

Cited by 89 publications

(69 citation statements)

References 67 publications

(82 reference statements)

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“…Examples of such disease-modifying mutations are neutrophil cytosolic factor 1 (Ncf1; also known as p47 phox ) and Ncf4 in patients with rheumatoid arthritis and NCF2 in patients with systemic lupus erythematosus and inflammatory bowel disease. [49][50][51][52] Our data also add a caveat for ROS-targeted interventions, whereas IL-1 receptor blockade could be a promising strategy in patients with active ANCA vasculitis.…”

Section: Discussionmentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

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ANCA-activated phagocytes cause vasculitis and necrotizing crescentic GN (NCGN). ANCA-induced phagocyte NADPH oxidase (Phox) may contribute by generating tissue-damaging reactive oxygen species. We tested an alternative hypothesis, in which Phox restrains inflammation by downregulating caspase-1, thereby reducing IL-1b generation and limiting NCGN. In an antimyeloperoxidase (anti-MPO) antibody-mediated disease model, mice transplanted with either gp91 phox -deficient or p47 phox -deficient bone marrow showed accelerated disease with increased crescents, necrosis, glomerular monocytes, and renal IL-1b levels compared with mice transplanted with wild-type bone marrow. IL-1b receptor blockade abrogated aggravated NCGN in gp91 phox -deficient mice. In vitro, challenge with anti-MPO antibody strongly enhanced caspase-1 activity and IL-1b generation in gp91 phox -deficient and p47 phox -deficient monocytes compared with wild-type monocytes. This enhanced IL-1b generation was abrogated when caspase-1 was blocked. ANCA-induced superoxide and IL-1b generation were inversely related in human monocytes. Furthermore, transplantation of gp91 phox /caspase-1 double-deficient bone marrow rescued the accelerated NCGN phenotype in gp91 phox bone marrow-deficient mice. These results suggest that Phox-generated reactive oxygen species downregulate caspase-1, thereby keeping the inflammasome in check and limiting ANCA-induced inflammation. IL-1 receptor blockade may provide a promising strategy in NCGN, whereas our data question the benefit of antioxidants.

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Section: Discussionmentioning

confidence: 99%

Phagocyte NADPH Oxidase Restrains the Inflammasome in ANCA-Induced GN

Schreiber

Luft

Kettritz

2015

Journal of the American Society of Nephrology

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“…3E). We reasoned that this may result from the generation of other potential immunogenic epitopes (MOG [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90] and MOG 101-120 ) in these mice, even though we found them to be insufficient to induce EAE on their own. Nonetheless, consistent with the findings that NOX2-deficient BMMfs are less efficient in the generation of the I-A b -immunodominant MOG epitope MOG …”

Section: Cybbmentioning

confidence: 99%

“…In brief, 8-to 10-wk-old female WT, Cybb 2/2 , and Ncf mice were anesthetized with ketamine-xylazine and injected s.c. with an emulsion of 50 mg MOG (24 of 25 WT, 11 of 37 NOX2-deficient), 200 mg MOG [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90] , 200 mg MOG 101-120 , or 200 mg rMOG in CFA (0.5 mg/ml Mycobacterium butyricum in paraffin oil) (BD Difco, Franklin Lakes NJ) in a total volume of 200 ml split between each flank. Pertussis toxin (300 ng) (List Biological Laboratories, Campbell, CA) was injected i.p.…”

Section: Induction Of Eaementioning

confidence: 99%

“…(pH 7, in saline) on day 0 and day 2. MOG [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90] and MOG 101-120 were not sufficient to induce EAE in any genotype. Mice were weighed and clinically scored each day for 40 d. In brief, scores were: 0, asymptomatic; 0.5, tail weakness; 1, limp tail; 1.5, hindlimb limping; 2, hindlimb weakness; 2.5, partial hindlimb paralysis; 3, complete hindlimb paralysis; 3.5, hindlimb paralysis with forelimb weakness; 4, forelimb paralysis; 4.5-5, morbidity/death (10).…”

Section: Induction Of Eaementioning

confidence: 99%

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NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing

Allan

Tailor

Balce

et al. 2014

The Journal of Immunology

106

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The chemistries within phagosomes of APCs mediate microbial destruction as well as generate peptides for presentation on MHC class II. The antimicrobial effector NADPH oxidase (NOX2), which generates superoxide within maturing phagosomes, has also been shown to regulate activities of cysteine cathepsins through modulation of the lumenal redox potential. Using real-time analyses of lumenal microenvironmental parameters, in conjunction with hydrolysis pattern assessment of phagocytosed proteins, we demonstrated that NOX2 activity not only affects levels of phagosomal proteolysis as previously shown, but also the pattern of proteolytic digestion. Additionally, it was found that NOX2 deficiency adversely affected the ability of bone marrow–derived macrophages, but not dendritic cells, to process and present the I-Ab–immunodominant peptide of the autoantigen myelin oligodendrocyte glycoprotein (MOG). Computational and experimental analyses indicated that the I-Ab binding region of the immunodominant peptide of MOG is susceptible to cleavage by the NOX2-controlled cysteine cathepsins L and S in a redox-dependent manner. Consistent with these findings, I-Ab mice that were deficient in the p47phox or gp91phox subunits of NOX2 were partially protected from MOG-induced experimental autoimmune encephalomyelitis and displayed compromised reactivation of MOG-specific CD4+ T cells in the CNS, despite eliciting a normal primary CD4+ T cell response to the inoculated MOG Ag. Taken together, this study demonstrates that the redox microenvironment within the phagosomes of APCs is a determinant in MHC class II repertoire production in a cell-specific and Ag-specific manner, which can ultimately impact susceptibility to CD4+ T cell–driven autoimmune disease processes.

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“…SNPs in NCF4 (rs729749), NCF2 (rs789181) and RAC2 (rs1476002) genes were found to be mildly associated with RA only in men. 28 Moreover, the association of COX-2 polymorphisms with disease risk and response to NSAID varies between sexes, 29,30 most likely as a result of sexual dimorphism in PGE 2 metabolism. Systemic biosynthesis of PGE 2 differs markedly between males and females in human, as in mice.…”

Section: Discussionmentioning

confidence: 99%