Inositol 1,4,5-Trisphosphate Receptors Are Autoantibody Target Antigens in Patients with Sjögren's Syndrome and Other Systemic Rheumatic Diseases.

IP3R2 and IP3R3 double knock-out mice present with exocrine dysfunctions such as secretion deficits of saliva and pancreatic juice. Therefore, we investigated whether the presence of antibodies to IP3Rs could be found in patients with Sjögren's syndrome, and the location of the epitopes. Subjects included 35 primary Sjögren's syndrome, 39 secondary Sjögren's syndrome, 144 rheumatoid arthritis, and 96 other connective tissue disease patients. As controls, 33 healthy subjects were included. Immunoblot was conducted using recombinant proteins IP3R1, IP3R2, and IP3R3 made from full-length cDNA, and core, T604, and EL for epitope mapping. Antibodies to IP3R1 in sera from patients with primary Sjögren's syndrome, secondary Sjögren's syndrome, and rheumatoid arthritis were found to be positive in 17 of 35 (48.6%), 13 of 39 (33%), and 34 of 124 (27.4%) cases, respectively. These frequencies were significantly higher than the 1 of 33 (3.0%) found in normal healthy subjects. The frequency of anti-IP3R2 antibodies in rheumatoid arthritis was found to be higher than those found in Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Anti-IP3R2 antibodies found in rheumatoid arthritis primarily recognized residues 578–2171 of the internal coupling and regulatory domain. On the other hand, anti-IP3R1 found in Sjögren's syndrome recognized residues 224–604 of the core protein IP3R1. Anti-IP3R1 antibodies were present in 48.6% of primary Sjögren's syndrome and in 3.0% of normal healthy subjects. Anti-IP3R2 antibodies were detected most frequently in rheumatoid arthritis. Locations of the antigenic epitopes were found to differ among the disease conditions.