A Role for NADPH Oxidase in Antigen Presentation

Abstract

The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expressed in phagocytes is a multi-subunit enzyme complex that generates superoxide (O2.−). This radical is an important precursor of hydrogen peroxide (H2O2) and other reactive oxygen species needed for microbicidal activity during innate immune responses. Inherited defects in NADPH oxidase give rise to chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and granulomatous inflammation. Interestingly, CGD, CGD carrier status, and oxidase gene polymorphisms have all been associated with autoinflammatory and autoimmune disorders, suggesting a potential role for NADPH oxidase in regulating adaptive immune responses. Here, NADPH oxidase function in antigen processing and presentation is reviewed. NADPH oxidase influences dendritic cell (DC) crosspresentation by major histocompatibility complex class I molecules through regulation of the phagosomal microenvironment, while in B lymphocytes, NADPH oxidase alters epitope selection by major histocompatibility complex class II molecules.

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

“…Because the Th arm of the immune system relies on the faithful reproduction of MHC-II-restricted peptides from any given Ag during education, activation, and effector function (all performed by different APCs), subtle changes to Ag processing chemistries could lead to a breakdown in tolerance or conversely deficiencies in the Th cell response. Interestingly, NOX2 deficiencies in humans (chronic granulomatous disease) have been associated with altered susceptibilities to a number of autoimmune disorders, including systemic lupus erythematous, rheumatoid arthritis, colitis, and Crohn's disease (67)(68)(69)(70)(71)(72)(73). In this study, we demonstrate that the redox state of phagosomes is a determinant of Ag processing fidelity and its modification by NOX2 can ultimately impact Th cell-driven disease processes.…”

“…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 …”

“…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.…”

“…(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).…”

NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs

“…The NADPH oxidase complex catalyzes electron transfer from NADPH to molecular oxygen and thus generates superoxide, the precursor of H 2 O 2 and other ROS (29,46). Genetic defects in NADPH oxidase cause chronic granulomatous disease, an inherited primary immunodeficiency associated with autoinflammation and autoimmunity (47)(48)(49).…”