A new finding by the Johns Hopkins Division of Rheumatology provides insight into how the immune system may increase joint damage in rheumatoid arthritis (RA). By studying blood samples from patients with RA, Darrah et.al found a unique antibody that binds to an enzyme, called PAD4, known to be involved in the disease. This newly discovered antibody turns the enzyme on and is found in the blood of patients with the most severe form of RA, in which bone destruction is found.
PAD4 is an enzyme that normally modifies proteins in the body to change their function. For reasons that are still unclear, proteins modified by PAD4 and enzymes like it, become targets of the immune system in RA. PAD4 can be thought of as a fuel pump, providing fuel for the fire that is the ongoing disease in RA. The more active the enzyme is, the more fuel (or modified protein) that is available to the immune system, and the fire becomes larger and hotter (i.e. worse disease). In contrast, if PAD4 enzymes are less active, there is less fuel present and the fire will be smaller.
In experiments looking at the ability of the enzyme to function, the group found that in the presence of the antibody, the PAD4 enzyme could function 500-times better under conditions normally found in the body. In other words, these antibodies turned on the fuel pump, increasing the amount of fuel available to activate the immune system and may explain why patients with this antibody have the worst disease. This newly discovered antibody may therefore identify patients who would benefit the most from being treated with aggressive therapy or from the addition of medications that inhibit PAD4 enzyme activity.