How could the Ncfl gene be involved in the development of arthritis? To our advantage, a huge effort in investigation and characterization had already been made regarding the Ncfl gene and the encoded Ncf1 protein. The fact that a lot of information was already available simplified the process of finding phenotypes associated with the genotype. The Ncf1 protein is part of the NADPH oxidase complex expressed in phagocytic cells. The complex is composed of five subunits, of which two, Cyba (gp91phox) and Cybb (p22 phox), resides in the membrane where they form a heterodimeric flavohemoprotein—cytochrome b558. The other three subunits—Ncf1, Ncf2 (p67phox) and Ncf4 (p40phox)—are in the resting state forming a complex in the cytosol, but when activated by any of a wide variety of stimuli, the Ncf1 protein gets heavily phosphorylated and the complex migrates to the membrane to form the activated complex . The Ncf1 protein is the sub-
unit responsible for transporting the cytosolic complex to the endosomal membrane or the cell membrane during activation . The NADPH oxidase complex functions as an electron donor in the oxidative burst process activated in response to pathogenic invaders, ultimately generating reactive oxygen species (ROS) . To investigate the functional consequences of the identified Ncfl polymorphism, we tested the ability of rat peritoneal cells to produce ROS. The surprising results showed that the arthritis-susceptible DA rat had a lower burst than the resistant DA. Ncf1E3 congenic rat . One allele containing the functional Ncfl was enough to correct for the deficiency in ox-idative burst and protect from disease since the congenic heterozygous for the Ncf1E3 allele had a milder disease than the homozygous DA rat. These results contradict the general belief that oxidative burst promotes inflammation and suggest that the oxidative burst is involved in a previously unknown pathway controlling inflammation. In fact, transfer of spleen-derived T cells from the congenic DA. Ncf1E3 rat to the parental DA and vice versa showed that the Ncfl polymorphism operated before activation of the T cells, indicating that it plays a role in the control of autoimmune activation.
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