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Immunopathogenesis of stem cells in autoimmune‐mediated keratinizing squamous metaplasia of the ocular surface mucosa
Author(s) -
Chen Ying-Ting,
Chen Feeling Y.T.,
Vijmasi Trinka,
Lazarev Stanislav,
Gallup Marianne,
McNamara Nancy A
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1034.1
Subject(s) - autoimmune regulator , squamous metaplasia , biology , progenitor cell , immunology , pax6 , pathology , conjunctiva , immune system , stem cell , epithelium , medicine , microbiology and biotechnology , autoimmunity , transcription factor , biochemistry , gene
Ocular keratinizing squamous metaplasia (SQM) is a blinding consequence associated with autoimmune dry eye disease. Traditionally viewed as an adaptive tissue response to chronic ocular dryness, we hypothesize SQM is an immune‐mediated stem cell disorder. Using autoimmune regulator ( Aire ) KO mouse, we characterized the histological, phenotypical, and immunological alterations associated with chronic CD4 + T cell‐mediated autoimmune SQM. Our studies revealed (i) hyperplasia of the ocular mucosal epithelium (105±25 in KO vs. 46±14 μm in WT); (ii) a shift from corneal to epidermal CK phenotype; (iii) a decrease in MUC5AC‐secreting goblet cells, and (iv) keratinization with impaired barrier function of the ocular mucosal surface. Epithelial progenitor cells (ePC) in SQM are characterized by focal aggregation of infiltrating autoreactive CD4 + T cells target two distinct ocular progenitor niches: the limbus and the conjunctival GC‐rich zone. BrdU labeling in Aire KO mice revealed a hyperproliferative growth kinetic in p63 + ePCs while quantitation of Pax6, the master regulator governing ocular lineage differentiation showed a 51±15% decrease in Aire‐KO vs WT mice ( p <0.01). Clonal analysis of Aire‐KO ePCs revealed reduced CFE with paraclonal dormancy. Collectively, our data suggest a role for dysregulation of Pax6/p63 ePC transcriptional activity in the development of autoimmune SQM.