Evidence of Corneal Lymphangiogenesis in Dry Eye Disease

Goyal, Sunali; Chauhan, Sunil; Annan, Jaafar El; Nallasamy, Nambi; Zhang, Qiang; Dana, Reza

doi:10.1001/archophthalmol.2010.124

Cited by 100 publications

(91 citation statements)

References 25 publications

(38 reference statements)

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“…[8][9][10][11] A recent study on lung cancer showed an association between intratumoral IL-17-postitive cell frequency and lymphatics density, suggesting that IL-17 may play a role in the metastasis of lung cancer by promoting lymphangiogenesis. 22 In addition, in a preclinical model of Th17-dominant autoimmune DED, 2,23 we have recently reported the occurrence of corneal lymphangiogenesis, 24 and significantly elevated homing of MHC II hi CD11b ϩ antigen-presenting cells to the lymphoid tissues 24 where they induce autoreactive T-cell responses. 2 We therefore next tested the relevance of IL-17-mediated lymphangiogenesis using a mouse model of autoimmune DED 2,23 by investigating whether in vivo IL-17 blockade could inhibit corneal lymphangiogenesis and progression of the disease.…”

Section: Resultsmentioning

confidence: 99%

A novel pro-lymphangiogenic function for Th17/IL-17

Chauhan

Jin

Goyal

et al. 2011

Blood

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100

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Section: Resultsmentioning

confidence: 99%

A novel pro-lymphangiogenic function for Th17/IL-17

Chauhan

Jin

Goyal

et al. 2011

Blood

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100

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“…21,25 These cytokines activate resident APCs and promote the corneal infiltration of additional CD11b þ cells. 26,27 Activated APCs subsequently stimulate an adaptive immune response, as evidenced by the proliferation of CD4 þ T cells in the draining lymphatics. 1,28 Furthermore, APCs prime pathogenic ocular surface-specific CD4 þ T cells (e.g., T helper 17 cells), supporting the theory that DED has an autoimmune component.…”

Section: Discussionmentioning

confidence: 99%

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Lee¹,

Hattori²,

Park³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED).METHODS. Seven to 8-week-old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1b, IL-6, TNF, and CCL2), corneal infiltration of CD11b 3 Recent studies have demonstrated that corneal epithelial cells respond to hyperosmolar stress by producing proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs).4,5 Furthermore, hyperosmolar stress and proinflammatory cytokines such as interferon (IFN)-c promote epithelial cell apoptosis. [5][6][7][8] Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize highly conserved microbial structures and products.9,10 To date, 12 murine TLRs have been identified, and TLRs are expressed by a variety of cell types, including epithelial cells, dendritic cells, macrophages, and lymphocytes.10-13 TLR stimulation leads to the activation of nuclear factor-kappaB (NF-jB) that upregulates the production of proinflammatory cytokines and antimicrobial proteins.10,14 The NF-jB signaling pathway is important for the induction of innate and adaptive immune responses. 10,14 TLR4 recognizes the Gram-negative bacterial cell wall component lipopolysaccharide (LPS) in association with cofactors such as CD14, LPS-binding protein (LBP), and myeloid differentiation factor-2 (MD-2). 15,16 It has also been suggested that TLR4 is a receptor for endogenous ligands associated with noninfectious diseases such as myocardial ischemia-reperfusion injury and central nervous system autoimmune disease. 17,18 We hypothesized that DED-induced corneal inflammation and injury may lead to the production of endogenous TLR4 ligands that activate the immune system. Therefore, we investigated the corneal expression of TLR4 and sought to determine the expression pattern of TLR4 in DED. MATERIALS AND METHODS AnimalsSeven to 8-week-old female C57BL/6 mice (Charles River Laboratories, Wilmington, MA) were used for these experiments. The experimental protocol was approved by the Institutional Animal Care and Use Committee, and all animals were managed according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Dry Eye ModelDED was induced by placing mice in a controlled environment chamber (CEC) and administering scopolamine (Sigma-Aldrich, St. Louis, MO) to maximize ocular surface dryness, as previously described. 19,20 Mice placed in the CEC were exposed to a relative humidity < 25%, temperature of 20 to 228C, and airflow of 15 L/min, 2...

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“…During the development of experimental dry eye, it is possible that ocular surface Ags gain access to other lymph nodes, for instance: 1) by soluble transport of Ags into the conduit system of other lymph nodes, where resident DCs may gain access for presentation to Ag-specific T cells (44); or 2) DCs activated within the ocular surface tissues may transport the Ag to other lymph nodes, or to other DCs, to fuel the autoimmune response (45). As noted, DS induces lymphoangiogenesis on the ocular surface, which likely facilitates APC and/or Ag drainage during experimental dry eye (17). Indeed, subconjunctival administration of Evans blue showed intense lymphatic drainage from the ocular surface to the CLNs, but also mild drainage to axillary nodes, supporting a role for other lymph nodes in the priming of ocular surface-specific CD4 + T cells.…”

Section: Cd11bmentioning

confidence: 99%

“…MHC class II (MHC II) molecules are required for presentation of antigenic epitopes to CD4 + T cells and are also upregulated on APCs localized within the ocular surface tissues in animal models (15) and in patients with dry eye (16). Homing of CD11c + CD11b + MHC II + APCs from the ocular surface to the CLN is dependent on CCR7-CCL21 signaling (13); more recently, homing of mature MHC II + APCs to the draining CLNs was shown to be associated with enhanced lymphoangiogenesis on the ocular surface during DS-induced experimental dry eye (17). Nonetheless, the absolute role of APCs in the initiation and progression of dry eye has not been evaluated.…”

mentioning

confidence: 99%

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

Schaumburg

Siemasko

Paiva

et al. 2011

The Journal of Immunology

134

126

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As specialized sentinels between the innate and adaptive immune response, APCs are essential for activation of Ag-specific lymphocytes, pathogen clearance, and generation of immunological memory. The process is tightly regulated; however, excessive or atypical stimuli may ignite activation of APCs in a way that allows self-Ag presentation to autoreactive T cells in the context of the necessary costimulatory signals, ultimately resulting in autoimmunity. Studies in both animal models and patients suggest that dry eye is a chronic CD4+ T cell-mediated ocular surface autoimmune-based inflammatory disease. Using a desiccating stress-induced mouse model of dry eye, we establish the fundamental role of APCs for both the generation and maintenance of ocular-specific autoreactive CD4+ T cells. Subconjunctival administration of liposome-encapsulated clodronate efficiently diminished resident ocular surface APCs, inhibited the generation of autoreactive CD4+ T cells, and blocked their ability to cause disease. APC-dependent CD4+ T cell activation required intact draining cervical lymph nodes, as cervical lymphadenectomy also inhibited CD4+ T cell-mediated dry eye disease. In addition, local depletion of peripheral conjunctival APCs blocked the ability of dry eye-specific CD4+ T cells to accumulate within the ocular surface tissues, suggesting that fully primed and targeted dry eye-specific CD4+ T cells require secondary activation by resident ocular surface APCs for maintenance and effector function. These data demonstrate that APCs are necessary for the initiation and development of experimental dry eye and support the standing hypothesis that dry eye is a self-Ag–driven autoimmune disease.

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Evidence of Corneal Lymphangiogenesis in Dry Eye Disease

Cited by 100 publications

References 25 publications

A novel pro-lymphangiogenic function for Th17/IL-17

A novel pro-lymphangiogenic function for Th17/IL-17

Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

Ocular Surface APCs Are Necessary for Autoreactive T Cell-Mediated Experimental Autoimmune Lacrimal Keratoconjunctivitis

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