Enhanced autoimmunity, arthritis, and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene

Abstract

The Ncf1 gene was recently identified as a strong regulator of severe arthritis in rat. This finding was surprising, because the disease-promoting allele mediated a lower level of reactive oxygen species in NADPH oxidase-expressing cells. We have now investigated a splice mutation of the Ncf1 gene in B10.Q mice, causing a truncated and nonfunctional Ncf1 protein. We found that the mutated Ncf1 led to a more severe and chronic relapsing collageninduced arthritis. Enhanced IgG and delayed-type hypersensitivity responses against type II collagen were seen, indicating increased activity of autoreactive T cells. Interestingly, female Ncf1-mutated mice spontaneously developed severe arthritis during the postpartum period. The arthritis was accompanied by an increased antibody response to type II collagen, with the same fine specificity as in collagen-induced arthritis. The enhancing effect of the mutated Ncf1 could also be shown to be more general in that it enhanced myelin oligodendrocyte glycoprotein protein-induced experimental autoimmune encephalomyelitis, a model for multiple sclerosis. These results show that Ncf1, a gene important for oxidative burst, regulates the susceptibility and severity of both arthritis and encephalomyelitis and modulates, directly or indirectly, the level of T cell-dependent autoimmune responses. rodent ͉ T lymphocytes ͉ NADPH

Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors

“…Furthermore, our recent studies demonstrated Ncf1 (coding p47 phox subunit of the NA-DPH oxidase complex, which is a multicomponent electron carrier that is responsible for the reduction of oxygen, resulting in the production of ROS) polymorphism as one of the major genetic factors that control arthritis severity and chronicity, regulating autoimmune reactions and impaired tolerance to CII. [27][28][29] In addition, we have also observed a high frequency of arthritis after CII immunization without any adjuvant in a transgenic mice expressing a CII-specific TCR V␤12 chain that recognizes the immunodominant glycosylated CII260Ϫ270 peptide that is dependent on eosinophilic inflammation. 30 Hence, in the present study, we tested various mouse strains using PNiPAAm-CII immunization to find genetic restriction of arthritis development in the absence of a classical adjuvant.…”

“…Earlier we identified Ncf1 as an arthritis susceptibility gene in rats and mice, 27,28 which provided evidence for the importance of the dysfunctional NADPH oxidase complex and reduced reactive oxygen species (ROS) production in arthritis development. The Ncf1 protein (also known as p47 phox ) is an essential organizing subunit of the NADPH oxidase complex that is responsible for the production of ROS in phagocytic cells (NOX2).…”

“…B10.Q mice with a mutated Ncf1 gene (B10.Q.Ncf1*/*) have been described previously. 28 The V␤12 transgenic mouse was generated on an SWR background 31 and has been backcrossed to DBA/1J for more than 15N generations. B10.P/Rhd mice were bred at the animal facility of the division of Medical Inflammation Research at Lund University.…”

“…44 Reduced ROS production due to a polymorphism in the neutrophil cytosolic factor 1 (Ncf1) gene is associated with autoimmunity and arthritis severity in murine models with arthritis induced by CII emulsified in CFA adjuvant. 28 Hence, we tested Ncf1 mutated mice with CII and PNiPAAm. Of the Ncf1 mutated mice, 90% developed severe arthritis (Figure 4 A and B) with a high level of anti-CII antibody response ( Figure 4C), but there was no preference for any particular IgG subclass (Figure 4D).…”

Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice

“…19 However, the lower levels of Gstm1 and Gstm2 in the congenic strain might play a protective role during the induction phase of CIA, since reduced oxidative burst response has been shown to promote activation of arthritogenic T cells, both in pristane-induced arthritis (PIA) in rats 20 and in CIA in mice. 21 Tspan-2, which is one of the candidates for Cia21, 5 is also a possible candidate for the insulin-dependent diabetes loci 10, Idd10, mapped to the same region. 22 The gene was upregulated in spleen in the Cia5 congenic compared to the parental strain 12 days after immunization.…”