Glucose-regulated protein 78 kDa (GRP78) is a molecular chaperone that is ubiquitously expressed in the endoplasmic reticulum of mammalian cells. GRP78 can be citrullinated at its 27 arginine residues by protein deiminases (PADs). The accumulation of citrullinated proteins in vivo leads to the production of anti-citrullinated protein antibodies (ACPAs) which perpetuate the inflammatory process. In vitro, ACPAs bind to citrullinated GRP78 expressed on the cell surface of peripheral blood mononuclear cells PMBCs and U937 cells leading to the production of TNF-α. In a mouse model of collagen-induced arthritis (CIA), anti-citrullinated GRP78 antibodies are found in the serum. Pre-immunization with citrullinated GRP78 prior to CIA induction shortens the time to joint inflammation and increases arthritis scores compared with non-citrullinated GRP78-immunized and non-immunized control mice. In autoimmune diseases such as rheumatoid arthritis, patient-derived serum contains higher levels of anti-citrullinated GRP78 antibodies than serum derived from patients with systemic lupus erythematosus and healthy controls.
