# Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $534,120

## Abstract

Project Summary
Sjögren’s syndrome (SjS) is characterized by impaired production of saliva and tears affecting ~1-3 million
people in the US potentially leading to severe complications such as lymphoma. The causes of SjS are
complex and poorly understood. SjS is considered an autoimmune disease in which the body's immune
system turns against itself and causes gland inflammation and destruction. This premise is supported by the
presence of autoantibodies, infiltration of salivary glands by immune cells and increased levels of inflammatory
mediators in most patients. However, whether immune cell infiltration and autoantibodies cause SjS or are the
consequence of gland destruction and/or dysfunction is unknown. Our preliminary data reveal an unexpected
link between SjS and calcium signals in cells of the immune system and salivary glands. Calcium ions within
cells control the function of immune and salivary gland cells. Calcium enters cells through specialized channels
that form pores in the cell's membrane. An important calcium channel in both immune and salivary gland cells
is the CRAC channel, which mediates calcium influx. We found that deletion of genes encoding the CRAC
channel in T cells, a cell type that mediates immunity to infection, abolishes calcium signals and causes SjS-
like disease in mice. This phenotype is even stronger when CRAC channels are deleted in a specific T cell
subset, so-called T regulatory (Treg) cells, that suppresses other immune cells and thereby prevents
autoimmune diseases. These mice develop a disease that recapitulates many features of human SjS. Calcium
signals also control the function of many secretory glands. We recently demonstrated that CRAC channels
regulate sweat production by controlling the function of chloride channels and thus water secretion in sweat
glands cells. Our data further show that mice lacking CRAC channels in salivary glands have impaired saliva
production. This is relevant to SjS as patients can develop dry mouth and eyes before their glands become
inflamed and infiltrated by immune cells, suggesting that altered salivary gland function precedes immune
activation. We hypothesize that impaired calcium signals in salivary gland cells predisposes mice and human
patients to develop SjS by impairing the production of saliva and oral innate immune responses, ultimately
resulting in gland inflammation and immune cell infiltration. The MAIN GOALS of this proposal are to
understand the role of calcium signals in the development and progression of SjS. (1) We will characterize how
calcium influx enables Treg cells to function and prevent the onset of SjS. (2) We will determine how calcium
influx regulates salivary gland function and oral immune responses, thereby preventing SjS. To this end, we
will study two mouse models of SjS that we generated. (3) We will analyze salivary glands and lymphocytes of
human SjS patients for calcium influx and the expression of CRAC channel proteins. The proposed st...

## Key facts

- **NIH application ID:** 9980846
- **Project number:** 5R01DE027981-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** STEFAN FESKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $534,120
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980846

## Citation

> US National Institutes of Health, RePORTER application 9980846, Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome (5R01DE027981-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9980846. Licensed CC0.

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