RESUMO
Lymphocytic infiltration of the lacrimal gland and ocular surface in autoimmune diseases such as Sjögren's syndrome (SS) causes an aqueous-deficient dry eye that is associated with significant morbidity. Previous studies from our laboratory and others have established autoimmune regulator (Aire)-deficient mice as a useful model to examine exocrinopathy and ocular surface disease associated with SS. Consistent with human SS, autoreactive CD4(+) T cells play an indispensible role in the development of exocrine and ocular surface disease in Aire knockout mice. We report that in addition to CD4(+) T cells, a large number of macrophages infiltrate the corneal stroma, limbus, and lacrimal glands of diseased mice. Adoptive transfer of autoreactive CD4(+) T cells from Aire knockout mice led to local infiltration of macrophages and ocular surface damage in immunodeficient recipients. Depletion of local macrophages, through subconjunctival injection of clodronate liposome, attenuated lissamine green staining and improved ocular phenotype. Alternatively, systemic depletion of macrophages had no effect on ocular phenotype but led to significant improvements in lacrimal gland exocrinopathy and tear secretion. Our results suggested that autoreactive CD4(+) T cells provoked macrophage infiltration to the eye and lacrimal gland, where they played a functional role in directing the development of autoimmune dry eye.
Assuntos
Movimento Celular/imunologia , Síndromes do Olho Seco/complicações , Olho/patologia , Macrófagos/imunologia , Macrófagos/patologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/imunologia , Ácido Clodrônico , Substância Própria/patologia , Síndromes do Olho Seco/imunologia , Olho/imunologia , Humanos , Limbo da Córnea/patologia , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Knockout , Fenótipo , Síndrome de Sjogren/patologia , Lágrimas/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjögren's syndrome (SS)-associated SQM, we identified CD4(+) T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4(+) T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4(+) T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4(+) T cells. In the eye, IL-1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4(+) T-cell infiltration was only observed in the presence of IL-1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4(+) T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4(+) T cells, we observed SQM hallmarks in local tissues-corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4(+) T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study indicated a central role for IL-1 in orchestrating a functional interplay between immune cells and resident cells of SS-targeted tissues in the pathogenesis of SQM.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Ceratoconjuntivite Seca/etiologia , Receptores de Interleucina-1/metabolismo , Síndrome de Sjogren/complicações , Transferência Adotiva , Animais , Células Caliciformes/patologia , Interleucina-1/metabolismo , Ceratoconjuntivite Seca/metabolismo , Ceratoconjuntivite Seca/patologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/metabolismo , Metaplasia/imunologia , Metaplasia/metabolismo , Camundongos , Camundongos Knockout , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/patologia , Transdução de Sinais , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologiaRESUMO
Chronic inflammation of the ocular surface in Sjögren's syndrome (SS) is associated with a vision-threatening, phenotypic change of the ocular surface, which converts from a nonkeratinized, stratified squamous epithelium to a nonsecretory, keratinized epithelium. This pathological process is known as squamous metaplasia. Based on a significant correlation between ocular surface interleukin (IL)-1beta expression and squamous metaplasia in patients with SS, we investigated the role of IL-1 in the pathogenesis of squamous metaplasia in an animal model that mimics the clinical characteristics of SS. Using autoimmune-regulator (aire)-deficient mice, we assessed lacrimal gland and ocular surface immunopathology by quantifying the infiltration of major histocompatibility complex class II(+) (I-A(d+)) dendritic cells and CD4(+) T cells. We examined squamous metaplasia using a biomarker of keratinization, small proline-rich protein 1B. We used lissamine green staining as a readout for ocular surface epitheliopathy and Alcian blue/periodic acid-Schiff histochemical analysis to characterize goblet cell muco-glycoconjugates. Within 8 weeks, the eyes of aire-deficient mice were pathologically keratinized with significant epithelial damage and altered mucin glycosylation. Although knockdown of IL-1 receptor 1 did not attenuate lymphocytic infiltration of the lacrimal gland or eye, it significantly reduced ocular surface keratinization, epitheliopathy, and muco-glycoconjugate acidification. These data demonstrate a phenotypic modulation role for IL-1 in the pathogenesis of squamous metaplasia and suggest that IL-1 receptor 1-targeted therapies may be beneficial for treating ocular surface disease associated with SS.