A naturally occurring polymorphism in the protein neutrophil cytosolic factor (Ncf1) regulates the severity of arthritis through a previously unknown mechanism involving arthritogenic T cells, explains an article published in the January issue of Nature Genetics. Holmdahl and colleagues used positional cloning to identify the Ncf1 gene in a particular locus that is associated with arthritis severity. Ncf1, also known as phagocyte oxidase, is a component of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex, which produces reactive oxygen species (ROS). The authors went on to show that pharmacological treatment with drugs that activated the NADPH oxidase complex, thereby producing higher levels of ROS, were able to ameliorate arthritis in rats. Arthritis in the rat model is very similar to rheumatoid arthritis (RA) in humans, so this work suggests new therapeutic pathways to target.

RA is a chronic inflammatory disease that affects peripheral joints; synovial inflammation in these joints leads to cartilage destruction, bone erosion and ultimately joint deformity and loss of joint function. Inheritance of RA is polygenic and influenced by environmental factors. The authors have found, using the rat arthritis model, that different gene regions control different phases of the disease, such as the onset, and severity of the acute and chronic phases.

Ncf1 is expressed in all phagocytic cells, and following phosphorylation it forms part of the NADPH oxidase complex in the cell membrane. This complex has a central role in host defence against bacterial infections through the production of ROS. Holmdahl and colleagues showed that the Ncf1 disease-related polymorphism led to differences in enzyme activity, rather than to quantitative differences in expression, and to a lower oxygen burst, which resulted in more severe arthritis.

High levels of ROS in the joints are believed to be involved in inflammation-mediated joint destruction; however, the possibility that these high ROS levels might actually reduce arthritis severity through earlier events is not usually considered. The authors showed that Ncf1 is involved in the early phase of arthritis due to the generation of disease-causing autoimmune arthritogenic T helper cells. Furthermore, T cells originating from a rat with the disease-related polymorphism could transfer severe arthritis to rats without the Ncf1 polymorphism.

The involvement of Ncf1 in the generation of arthritogenic T cells explains the paradox that a decreased, rather than an increased, oxygen burst is associated with arthritis. Activation of the NADPH oxidase complex is characteristic of activated macrophages and other immune cells that trigger T cells into action. The authors speculate that the production of ROS during T-cell interaction with another immune cell induces apoptosis, which limits the expansion of T cells responding to self-components; a reduction in the ROS allows arthritogenic T cells to escape death.