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Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation, demyelination, and axonal damage. Increased levels of reactive oxygen species (ROS), produced by macrophages and leading to oxidative stress, have been implicated as mediators of demyelination and axonal injury in both MS and experimental autoimmune encephalomyelitis, the murine model of the disease. On the other hand, reduced ROS levels can increase susceptibility to autoimmunity. In this work, we screened for association with MS 11 single nucleotide polymorphisms (SNPs) and two microsatellite markers in the five genes (<i>NCF1</i>, <i>NCF2</i>, <i>NCF4</i>, <i>CYBA</i>, and <i>CYBB</i>) of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) system, the enzymatic pathway producing ROS in the brain and neural tissues, in 347 Finnish patients with MS and 714 unaffected family members. This analysis showed suggestive association signals for <i>NCF1</i> and <i>CYBB</i> (lowest <i>p</i> = 0.038 and <i>p</i> = 0.013, respectively). Functional relevance for disease predisposition was further supported for the <i>CYBB</i> gene, by microarray analysis in CD4^+/&#8722; mononuclear cells of 21 individuals from five Finnish multiplex MS families, as well as by real-time RT-PCRs performed on RNA extracted from peripheral blood mononuclear cells of an Italian replication cohort of 21 MS cases and 21 controls. Our results showed a sex-specific differential expression of <i>CYBB</i>, suggesting that this gene, and more in general the NOX2 system, deserve to be further investigated for their possible role in MS.