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NADPH Oxidase: Kills microbes and now causing Lupus?

This post was chosen as an Editor's Selection for ResearchBlogging.org

Lupus, or systemic lupus erythematosus (SLE), is a systemic autoimmune disease that causes chronic inflammation and extensive immune dysregulation in multiple organs, resulting life-spanning unpredictable periods of illness and possible death. The only relief from SLE is anti-inflammatory medications that correlate with side effects such as increased susceptibility to bacterial infections, malnutriention, and cancers.

There has been evidence that SLE has a genetic component, but not one single gene can be linked with SLE. In fact, many genes have been linkedto the development of SLE. In effort to further elucidate the genetic components correlated with SLE, Chaim Jacob, et al. used previous research on SLE-related genes and created an intelligent computational screen looking for new genes associated with the development of early and late onset SLE.

They identified a mutation in the NCF2 gene of patients who have SLE that causes a reduction in cellular NADPH oxidase function. This mutation was seen in two independent populations – a childhood-onset SLE cohort and a large adult-onset SLE cohort.

NADPH oxidase is a membrane-bound enzyme complex that resides in the outer membranes of cells and in phagosomes. The phagosome is an intracellular vesicle that is designed to destroy microbes by producing antimicrobial agents, oxygen and nitrogen radicals, lowered pH, and nutrient-deprivation. NADPH oxidase is employed in the phagosome to produce reactive oxygen and nitrogen species (ROS and NOS) that can disrupt the membrane or protein structures of invading bacteria or viruses.

The NCF2 mutation was a single base-pair change (H389 position from histidine to glutamine) that reduced the binding efficiency of NCF2 protein to Vav1 (pictured below). Vav1 is a protein involved in regulation of NADPH oxidase-dependent ROS production. The lowered binding efficiency of NCF2 with Vav1 resulted in a 2-fold reduction of Vav1-dependent ROS production.

Why would decreased NADPH oxidase function affect development of SLE?

Recently, it was seen that NADPH oxidase-dependent ROS production has been associated with cellular mechanisms that are not related to clearing microbial infections. In fact, NADPH oxidase assembly has been seen in non-phagocytic cells (cells that do not form phagosomes). These non-phagocytic NADPH oxidase have very low level of ROS production, however it has been shown that the production can be up-regulated in response to high glucose and hyperlipidemia (lipids in the blood) indicating they may be playing a role in the development of diabetes.

Since Chaim Jacob, et al. preformed their ROS production measurements in K526 cells (tumor cells/non-phagocytic cells), it would be interesting if the decrease in ROS production was specific to non-phagocytic cells. Therefore, ROS production may be in response to up-regulation of NADPH oxidase assembly in response to particular cytokines or immune molecules in the blood. This is very intriguing in that ROS production may be acting as an immunomodulatory mechanism that could be influencing SLE disease development. I vote more research needs to be conducted to elucidate the specifics of ROS production and immune modulation.


Jacob CO, Eisenstein M, Dinauer MC, Ming W, Liu Q, John S, Quismorio FP Jr, Reiff A, Myones BL, Kaufman KM, McCurdy D, Harley JB, Silverman E, Kimberly RP, Vyse TJ, Gaffney PM, Moser KL, Klein-Gitelman M, Wagner-Weiner L, Langefeld CD, Armstrong DL, & Zidovetzki R (2012). Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proceedings of the National Academy of Sciences of the United States of America, 109 (2) PMID: 22203994

Li, J. (2003). ROS Generation by Nonphagocytic NADPH Oxidase: Potential Relevance in Diabetic Nephropathy Journal of the American Society of Nephrology, 14 (90003), 221-226 DOI: 10.1097/01.ASN.0000077406.67663.E7

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Reader Comments (3)

"ROS production may be in response to up-regulation of NADPH oxidase assembly in response to particular cytokines or immune molecules in the blood."

Taking this one step further, is it possible chronic infection can trigger this process? Is there any documented correlation between infection and Lupus?

January 17, 2012 | Unregistered CommenterCamp Other

Do you know if there are any plans to continue research in the vein you describe?

January 19, 2012 | Unregistered CommenterSarah Scoles

This helped me out SO much with a school assignment. Thanks for writing

January 25, 2012 | Unregistered CommenterAnonymous

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