Roles of follicular helper T and T helper 17 cells in Sjögren’s syndrome development

Abstract

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disorder that affects mainly salivary and lacrimal glands, but its cause remains largely unknown. Clinical data indicating that SS occurs in a substantial proportion of patients with lupus and rheumatoid arthritis point to common pathogenic mechanisms underlying these diseases.

To address this idea, we asked first whether SS develops in the lupus-prone mouse strain sanroque. Owing to hyper-activation of follicular helper T (Tfh) cells, female sanroque mice developed lupus-like symptoms at approximately 20 weeks of age but there were no signs of SS at that time. However, symptoms typical of SS were evident at approximately 40 weeks of age, as judged by reduced saliva flow rate, sialadenitis, and IgG deposits in the salivary glands. Increases in serum titers of SS-related autoantibodies and numbers of autoantibody-secreting cells in cervical lymph nodes preceded the pathologic manifestations of SS and were accompanied by expansion of Tfh cells and their downstream effector cells. Thus, our results suggest that chronic dysregulation of Tfh cells in salivary gland-draining lymph nodes is sufficient to drive the development of SS in lupus-prone mice.

Next, we examined whether SKG mice, a cardinal model of T helper 17 (Th17) cellmediated arthritis, also develop a secondary form of SS-like disorder. We found that SKG mice developed xerostomia 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 curdlan-injected SKG mice contained elevated titers of IgG (predominantly IgG1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca2+ 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.

This study provides evidence that Tfh and Th17 cells play critical roles in the development of autoantibody-mediated secondary SS. Autoantibodies produced under the help with Tfh and Th17 cells may elicit either inflammatory damage of salivary gland tissue or non-inflammatory blocking of salivation signals. This study also suggests sanroque and SKG mice as secondary SS models.