Background/Purpose: Primary Sjögren’s syndrome (PSS) is a chronic inflammatory disease affecting exocrine glands including salivary and lacrimal glands that leads to dry eyes and mouth along with various systemic manifestations. While in established disease, systemic adaptive immune system activation is a key process in PSS and autoantibodies against nuclear proteins (Ro, La) are formed, the initiating events that target the exocrine glands in PSS are yet to be identified. A glandular epithelial deregulation is thought to be the critical initiator of PSS pathogenesis. In the steady state, innate immune cells patrolling salivary glands are under the influence of the autonomic system and readily react after sensing damage of the tissue. The goal of this work is to evaluate the early epithelial changes induced by the stimulation of salivary secretion under the action of specific beta-adrenergic agonists.

Methods: We employed a mouse model of sialadenitis provoked by the induction of an abrupt secretion of hypercalcemic saliva in mice treated with calcium gluconate (300µmol/Kg) followed by one dose of the β1-adrenergic agonist denopamine (14µmol/Kg) or the β2 agonist fenoterol (1.4 mg/Kg) after 30 minutes. Repeated salivary secretion stimulation for 3 weeks caused early histopatological changes suggestive of a sialadenitis confirmed by image mass cytometry (IMC) of submandibular glands (SMG). Evaluation of sera for autoantibodies and salivary and lacrimal tissues by IMC after a recovery phase of 8 weeks revealed an association of salivary epithelial damage and autoimmunity against Ro and La autoantigens.

Results: Beta adrenergic stimulation of hypercalcemic mice caused cellular swelling (increased cellular size) and an absolute loss of epithelial nuclei of the mucous acini of SMG of mice that persisted until the end of the recovery phase. The multiplexed IMC analysis revealed a strong downregulation of TGF-ß in the mucous acini accompanied with the upregulation of the ribosomal protein S6 along with an early accumulation of CD20 positive B-cells. After the recovery phase, the mice with ß-adrenergic stimulation displayed a significant reduction of tear production and developed autoantibodies against Ro, La and the N-terminus peptide of the M3 muscarinic receptor.

Conclusion: The ribosomal protein S6 is part of the translation machinery and is activated by phosphorylation via the mammalian target of rapamycin (mTOR) pathway and TGF-ß is a potent inhibitor of the mTOR pathway. We conclude that subtle damage of salivary epithelial cells concur in the activation of the mTOR pathway which is involved in the regulation of cell size, growth, proliferation and autophagy. These early changes in the mucous acini are sufficient to initiate B-cell infiltration and autoantibody response conditioning the appearance of Sjögren´s Syndrome-like manifestations in our murine model.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/early-histopathological-changes-of-the-salivary-glands-associated-with-the-development-of-primary-sjogrens-syndrome/