Autoantibody-Mediated Dysfunction of Salivary Glands Leads to Xerostomia in SKG Mice

Abstract

Sjögren's syndrome (SS) is a chronic heterogeneous disease that mainly affects exocrine glands, leading to sicca syndromes such as xerostomia. Despite the second highest prevalence rate among systemic autoimmune diseases, its pathophysiology remains largely unknown. Here we report that SKG mice, a cardinal model of Th17 cell-mediated arthritis, also develop a secondary form of SS-like disorder upon systemic exposure to purified curdlan, a type of β-glucan. The reduced production of saliva was not caused by focal immune cell infiltrates but was associated with IgG deposits in salivary glands. Sera from curdlaninjected SKG mice contained elevated titers of IgG (predominantly IgG 1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca 2+ signaling in salivary acinar cells. These results suggest that the Th17 cells that are elicited in SKG mice promote the production of salivary gland-specific autoantibodies including anti-M3R IgG; the antibodies are then deposited on acinar cells and inhibit M3R-mediated signaling required for salivation, finally leading to hypofunction of the salivary glands. This type II hypersensitivity reaction may explain the origin of secondary SS occurring without focal leukocyte infiltrates.

Induction of Anti-Aquaporin 5 Autoantibody Production by Immunization with a Peptide Derived from the Aquaporin of Prevotella melaninogenica Leads to Reduced Salivary Flow in Mice

“…Despite the reduced salivary flow rate, no histologic abnormality was observed in the salivary glands of the mice with anti-AQP5E autoantibodies. Similarly, no immune cell infiltration was reported in curdlan-injected SKG mice despite increased IgG deposition in the salivary glands and reduced salivary flow rates ( 32 ). The authors attributed this finding to the fact that IgG1 was the major isotype of autoantibody produced and that murine IgG1 is ineffective in complement and FcR activation.…”

An Inflammatory Loop Between Spleen-Derived Myeloid Cells and CD4+ T Cells Leads to Accumulation of Long-Lived Plasma Cells That Exacerbates Lupus Autoimmunity

“…To deplete CD11b + Gr-1 + cells, ~15 week-old sanroque mice were injected intraperitoneally with 10 mg/kg body weight gemcitabine (Sigma-Aldrich) or its vehicle PBS every 2 day over 7 days. Alternatively, SKG mice were injected intraperitoneally with anti-Gr-1 Ab (Bio X cell) or isotype-matched control Ab at a dose of 0.4 mg/mouse every day for 4 weeks starting at day 1 after curdlan administration ( 40 ). The protocol was approved by the Institutional Animal Care and Use Committee.…”