transforming-growth-factor-beta and Keratoconjunctivitis-Sicca

Keratoconjunctivitis sicca is a common ocular surface disease that develops in patients with aqueous tear deficiency. Recent advances have been made in diagnosis, pathogenesis, and therapy of this condition. Advances in diagnosis include improved understanding of the specificity of the tests used for diagnosis, elucidation of the mechanism of the ocular surface rose bengal and fluorescein staining that occurs in this condition, and the expanded use of impression cytology. Advances in pathogenesis include the concept that keratoconjunctivitis sicca is a condition of abnormal growth and differentiation and immune activation of the ocular surface epithelium. These findings indicate that keratoconjunctivitis sicca may represent a chronic wound-healing response to a poorly lubricated and inflamed ocular surface. Advances in therapy include improved nonpreserved artificial tears and therapies targeted at decreasing ocular surface inflammation.

Topics: Animals; Cornea; Diagnosis, Differential; Epidermal Growth Factor; Growth Substances; Humans; Immunosuppressive Agents; Keratoconjunctivitis Sicca; Ophthalmic Solutions; Recombinant Proteins; Transforming Growth Factor beta; Treatment Outcome

TGF-β is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-β1 in tears and elevated TGF-β1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-β type II receptor (CD4-DNTGFβRII) mice. These mice have a truncated TGF-β receptor in CD4(+) T cells, rendering them unresponsive to TGF-β.. DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFβRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFβRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4(+) T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFβRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, RORγT, IFN-γ and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFβRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.. Our results showed that disruption of TGF-β signaling in CD4(+) T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress.

Topics: Adoptive Transfer; Aging; Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Movement; Cell Proliferation; Conjunctiva; Dry Eye Syndromes; Epithelium; Eye; Genes, Dominant; Homeodomain Proteins; Humans; Inflammation; Keratoconjunctivitis Sicca; Mice; Mice, Knockout; Mucous Membrane; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Chemokine; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

To compare epidermal growth factor (EGF) concentration in tear fluid and levels of inflammatory cytokines in the conjunctival epithelium of patients with Sjögren's syndrome keratoconjunctivitis sicca with those of normal controls.. Schirmer 1 tear testing, corneal fluorescein staining and conjunctival impression cytology for quantitation of goblet cell density were performed in ten patients with Sjögren's syndrome-associated keratoconjunctivitis sicca and ten asymptomatic normal controls. ELISA was used to detect the concentration of EGF in tear fluid and interleukin 6 in lysates of conjunctival cytology specimens obtained from all subjects. The levels of RNA transcripts encoding inflammatory cytokines [interleukin 1alpha_(IL-1alpha), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha_(TNF-alpha), and transforming growth factor beta1 (TGF-beta1)] as well as a housekeeping gene (G3PDH) were evaluated in conjunctival cytology specimens taken from all subjects by semiquantitative competitive reverse transcriptase polymerase chain reaction (RT-PCR).. Decreased tear fluid EGF concentration was noted in Sjögren's syndrome patients (mean 0.68 +/- 0.59 ng/ml) compared to controls (mean 1.66 +/- 0.45 ng/ml, P = 0.004). Significantly increased levels of IL-1alpha, IL-6, IL-8, TNF-alpha and TGF-beta1 RNA transcripts were found in the conjunctival epithelium of Sjögren's syndrome patients compared to controls (P < 0.05), while the level of G3PDH was similar in both groups. The concentration of IL-6 protein was significantly higher in Sjögren's syndrome conjunctiva samples (P = 0.012). Tear EGF concentration correlated with Schirmer 1 scores (rho 0.767, P < 0.001), corneal fluorescein staining scores (rho -0.562, P = 0.01), conjunctival goblet cell density (rho 0.661, P = 0.001) and the levels of IL-1alpha_and IL-8 RNA in the conjunctival epithelium (rho -0.677 and -0.747, respectively, P = 0.001). Both IL-1alpha_and IL-8 RNA in the conjunctival epithelium increased as Schirmer 1 scores decreased (P

Topics: Adult; Aged; Cell Count; Conjunctiva; Cytokines; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epithelial Cells; Female; Humans; Interleukins; Keratoconjunctivitis Sicca; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sjogren's Syndrome; Tears; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha