title: Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells.
abstract: In both humans and animal models, the development of Sjögren syndrome (SS) and non-SS keratoconjunctivitis sicca (KCS) increases with age. Here, we investigated the ocular surface and lacrimal gland (LG) phenotype of NOD.B10.H2bmice at 7-14, 45-50, and 96-100 weeks. Aged mice develop increased corneal permeability, CD4+T-cell infiltration, and conjunctival goblet cell loss. Aged mice have LG atrophy with increased lymphocyte infiltration and inflammatory cytokine levels. An increase in the frequency of CD4+Foxp3+T regulatory cells (Tregs) was observed with age in the cervical lymph node (CLN), spleen, and LG. These CD4+CD25+cells lose suppressive ability, while maintaining expression of Foxp3 (forkhead box P3) and producing interleukin-17 (IL-17) and interferon-γ (IFN-γ). An increase of Foxp3+IL-17+or Foxp3+IFN-γ+cells was observed in the LG and LG-draining CLN. In adoptive transfer experiments, recipients of either purified Tregs or purified T effector cells from aged donors developed lacrimal keratoconjunctivitis, whereas recipients of young Tregs or young T effector cells failed to develop disease. Overall, these results suggest inflammatory cytokine-producing CD4+Foxp3+cells participate in the pathogenesis of age-related ocular surface disease.
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Coursey
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bian
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zaheer
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Pflugfelder
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Volpe
authors.affiliation: Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: de Paiva
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005123:Eye / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007638:Keratoconjunctivitis Sicca / Q000276:immunology*; D007765:Lacrimal Apparatus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D012859:Sjogren's Syndrome / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D007371:Interferon-gamma