STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjogren's syndrome.
Primary Sjögren's Syndrome (pSS) is an autoimmune disease involving salivary and other exocrine glands that leads to progressive lymphocytic infiltration into the gland, tissue damage, and secretory defects. The mechanism underlying this disease remains poorly understood. Here we report that mice with T-cell-targeted deletion of Stromal Interaction Molecule (STIM) 1 and STIM2 [double-knockout (DKO)] mice develop spontaneous and severe pSS-like autoimmune disease, displaying major hallmarks of the disease. In DKO mice, diffuse lymphocytic infiltration was seen in submandibular glands, a major target of pSS, by age 6 wk, progressing to severe inflammation by age 12 wk. Sjögren's syndrome-specific autoantibodies (SSA/Ro and SSB/La) were detected in the serum, and progressive salivary gland destruction and loss of fluid secretion were also seen. Importantly, we report that peripheral blood mononuclear cells as well as lymphocytic infiltrates in submandibular glands from patients with pSS demonstrated significant reductions in STIM1 and STIM2 proteins. Store-operated calcium entry was also reduced in peripheral blood mononuclear cells from pSS patients compared with those from healthy controls. Thus, deficiency of STIM1 and STIM2 proteins in T cells, and consequent defects in Ca(2+) signaling, are associated with salivary gland autoimmunopathy in DKO mice and pSS patients. These data reveal a previously unreported link between STIM1 and STIM2 proteins and pSS.
Secretory Physiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Kwong Tai
KT
Cheng
Ilias
I
Alevizos
Xibao
X
Liu
Wiliam D
WD
Swaim
Hongen
H
Yin
Stefan
S
Feske
Masatsugu
M
Oh-hora
Indu S
IS
Ambudkar
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D012859:Sjogren's Syndrome / Q000235:genetics*; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D013363:Submandibular Gland / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000378:metabolism*
D001323:Autoantibodies; D015220:Calcium Channels; D008562:Membrane Glycoproteins; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium