Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

doi:10.1073/pnas.0607984103

Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase

*Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900;
^‡Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; and
^§Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and
^¶Center for Immunology, University of California, Irvine, CA 92697-4120

Contributed by Lewis C. Cantley, September 13, 2006

Abstract

Sjögren's syndrome (SS) is an autoimmune disease that is characterized by infiltration of exocrine tissues, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Here, we show that mice with T cell-specific loss of class IA phosphoinositide 3-kinase function develop organ-specific autoimmunity that resembles the human disease SS. Most mutant mice aged 3–8 months develop corneal opacity and eye lesions due to irritation and constant scratching. These mice display cardinal signs of primary SS such as marked lymphocytic infiltration of the lacrimal glands, antinuclear antibodies in the serum, and elevated titer of anti-SS-A antibody, in the absence of kidney pathology. Immunofluorescence studies show the presence of numerous CD4⁺ T cells with a smaller number of CD8⁺ T cells and B cells in the lacrimal glands. CD4⁺ T cells from these mice exhibit aberrant differentiation in vitro. These results indicate that aberrant T cells with impaired class IA phosphoinositide 3-kinase signaling can lead to organ-specific autoimmunity. In addition, the mouse model described here represents a tool to study the pathogenesis and treatment of SS.

Footnotes

^‖To whom correspondence may be addressed. E-mail: lewis_cantley{at}hms.harvard.edu
**To whom correspondence may be addressed at:
Department of Molecular Biology and Biochemistry, 3242 McGaugh Hall, University of California, Irvine, CA 92697-3900.
E-mail: dfruman{at}uci.edu
↵ ^†Present address: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852.
Author contributions: J.S.O., J.A.D., M.G.K., T.E.L., and D.A.F. designed research; J.S.O., J.A.D., and M.G.K. performed research; J.L. and L.C.C. contributed new reagents/analytic tools; J.S.O., J.A.D., M.G.K., and D.A.F. analyzed data; and J.S.O. and D.A.F. wrote the paper.
The authors declare no conflict of interest.
Abbreviations:

ANA,

antinuclear antibody;

PI3K,

phosphoinositide 3-kinase;

SS,

Sjögren's syndrome;

pSS,

primary SS.