Inositol 1,4,5-trisphosphate receptors are autoantibody target antigens in patients with Sjögren's syndrome and other systemic rheumatic diseases

Abstract

IP(3)R2 and IP(3)R3 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 IP(3)Rs 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 IP(3)R1, IP(3)R2, and IP(3)R3 made from full-length cDNA, and core, T604, and EL for epitope mapping. Antibodies to IP(3)R1 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-IP(3)R2 antibodies in rheumatoid arthritis was found to be higher than those found in Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Anti-IP(3)R2 antibodies found in rheumatoid arthritis primarily recognized residues 578-2171 of the internal coupling and regulatory domain. On the other hand, anti-IP(3)R1 found in Sjögren's syndrome recognized residues 224-604 of the core protein IP(3)R1. Anti-IP(3)R1 antibodies were present in 48.6% of primary Sjögren's syndrome and in 3.0% of normal healthy subjects. Anti-IP(3)R2 antibodies were detected most frequently in rheumatoid arthritis. Locations of the antigenic epitopes were found to differ among the disease conditions.

IP3R deficit underlies loss of salivary fluid secretion in Sjögren’s Syndrome

“…While there are some discrepancies in the reported findings 39 40 41 , it is feasible to hypothesize that if there were high levels of circulating anti-M3R in vivo in the vicinity of the receptors in the gland, it could dampen the cellular response to neurotransmitter stimulation. Additionally, antibodies to IP3R have also been detected in sera from primary Sjögren’s 17 of 35 (48.6%), secondary Sjögren’s 13 of 39 (33%), and rheumatoid arthritis 34 of 124 (27.4%) 42 . However, it is unclear whether autoantibodies can induce permanent effects on the acinar cells which would lead to dampening of their response to (CCh) in vitro , as seen in the present study.…”

IP3 receptor/Ca2+ channel: from discovery to new signaling concepts

“…IP 3 R2‐R3 KO mice show symptoms of dry mouth and dry eye (unpublished observations) that are similar to the characteristics of Sjogren’s syndrome. An analysis of sera from patients with Sjogren’s syndrome revealed that anti‐IP 3 R antibodies were present at a rate of close to 50%, as detected using western blotting (Miyachi et al. 2007).…”

“…2007). Antibodies against IP 3 Rs are also present in more than 30% of sera samples from patients with systemic rheumatic disease (Miyachi et al. 2007), suggesting that IP 3 Rs play an important role in exocrine secretion and that immunoscreening could be used as a diagnostic tool for Sjogren’s syndrome and systemic rheumatic diseases.…”

Antibodies to inositol 1,4,5-triphosphate receptor 1 in patients with cerebellar disease

“…Because in a previous study 6 it was shown that 48.6% (17/35) of patients with primary Sjögren syndrome harbored antibodies against IP3R1, we assayed 45 patients with primary Sjögren syndrome with our specific CBA; they were all negative. This discrepancy is likely attributed to different specificity and sensitivity of the methods used or possibly to the difference of diagnostic criteria used in defining disease among the examined patients.…”