IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse

Alam, Jehan; Yazdanpanah, Ghasem; Ratnapriya, Rinki; Borcherding, Nicholas; Paiva, Cintia S. de; Li, Dequan; Souza, Rodrigo G. de; Yu, Zhiyuan; Pflugfelder, Stephen C.

doi:10.3389/fmed.2022.849990

Cited by 18 publications

(18 citation statements)

References 56 publications

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“…Removal of the major extraorbital lacrimal gland induces severe aqueous deficient dry eye and is the basis for a well-characterized animal model 18 – 20 . We analyzed retention of an antibody to IL-17A because intraperitoneal injection of antibodies to IL-17A has been shown to reduce dry eye signs in mouse models 21 – 23 . The antibody was labeled with Alexa Fluor 488, and the presence on the ocular surface was followed by fluorescence photography.…”

Section: Resultsmentioning

confidence: 99%

Extending the use of biologics to mucous membranes by attachment of a binding domain

Shanks

Romanowski

et al. 2023

Commun Biol

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Biologics are almost exclusively administered systemically, but localized delivery is preferable as it minimizes off-target exposure and allows more aggressive treatments. Topical application of biologics to epithelia is generally ineffective because most are covered with fluids and biologics are washed out too quickly to have significant therapeutic effects. Here we explore the idea that attaching a binding domain can serve as an “anchor” to extend the residency time of biologics on wet epithelia, allowing their effective use even with infrequent applications. We use topical application to the ocular surface as a challenging test since foreign substances are washed out especially efficiently by tear flow and blinking. Our results demonstrate that conjugation of antibodies to wheat germ agglutinin, which binds GlcNAc and sialic acid that are ubiquitously present in tissues, increases their half-life 350-fold upon application to the ocular surface in a mouse model of dry eye, a common and onerous disease in humans. Importantly, antibodies to IL-17A, IL-23, and IL-1β conjugated to the agglutinin reduces manifestations of dry eye, even when applied just once daily. In contrast, unconjugated antibodies are ineffective. Attaching an anchor to biologics is a simple means to overcome washout and to extend their therapeutic use.

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Section: Resultsmentioning

confidence: 99%

Extending the use of biologics to mucous membranes by attachment of a binding domain

Shanks

Romanowski

et al. 2023

Commun Biol

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“…Further, Chauhan et al were able to show that DED inflammation was lower in mice treated with anti-IL–17A antibodies. 7 , 56 Almost at the same time, Alam et al 39 found that the Pinkie mouse strain with a loss-of-function RXRα mutation has increased signs of DED and a 4-fold greater percentage of conjunctival γδ T cells with a higher expression of IL-17 under homeostatic conditions. Notably, disruption of the IL-17A signal has been associated with the development and progression of various autoimmune or autoinflammatory diseases, such as rheumatic diseases.…”

Section: Discussionmentioning

confidence: 96%

“… 31 , 33 , 35 – 37 Interestingly, γδ T cells are abundantly distributed in the conjunctiva and highly express IL-17A in response to conjunctival commensals, and of these approximately one-half are Vγ4 + subset. 23 Meanwhile, mice with a loss-of-function RXRα mutation exhibited a 4-fold greater percentage of conjunctival γδ T cells with increased expression of IL-17, 39 and the development and progression of DED seem to be highly dependent on IL-17A. 9 , 13 , 38 However, the contribution of γδ T cells itself in the conjunctiva to the occurrence of DED is not known.…”

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confidence: 99%

Conjunctiva Resident γδ T Cells Expressed High Level of IL-17A and Promoted the Severity of Dry Eye

Zhu

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Conjunctival inflammation promotes ocular surface disorders in dry eye disease (DED). Here we identified γδ T cells as the predominant source of IL-17A in the murine conjunctiva and assessed their contribution to the pathogenesis of DED. Methods We enrolled 22 patients with DED, and analyzed the proportion of γδ T cells in the conjunctival epithelial samples by flow cytometry. Adult C57Bl/6 wild-type and TCRδ − / − mice were used to induce DED models to investigate the role of γδ T cells. The characteristics of immune cell infiltration and the expression of immune-related cytokines or markers in mouse conjunctiva were analyzed by flow cytometry, Western blot, and quantitative polymerase chain reaction. Results The proportion of γδ T cells in the human DED conjunctiva is significantly higher in patients with severe corneal epithelial defects than in mild ones, which is consistently observed in the murine DED model. Further, a high level of IL-17A but not IFN-γ is detected in the conjunctiva of mice. The increased murine IL-17A–producing cells on the conjunctiva are identified as γδ T cells predominantly and Th17 cells to a lesser extent. Ablation of γδ T cells by antibody depletion or genetic deletion of TCRδ alleviates ocular surface damage in the murine DED model. Conclusions Our studies evaluate human and experimental murine DED for evidence of γδ T-cell–mediated inflammation and highlight a potential therapeutic synergy by targeting IL-17 and γδ T cells in DED treatment.

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“…Using the RXRα Pinkie mouse model, which develops many characteristics of DED including goblet cell loss, it was recently reported that IL-17+ γδ T cells found in the conjunctiva contribute to MMP-9 production and goblet cell loss, both of which could be blocked with an anti-IL-17 monoclonal antibody. 74 IL-17 is an important contributor to SS pathogenesis. 75 – 77 Additionally, activation of P2X7R, which is elevated in the lacrimal glands of NOD.H-2 h4 DKO mice ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Early Dry Eye Disease Onset in a NOD.H-2^h4 Mouse Model of Sjögren's Syndrome

Jasmer

Camden

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose To develop a mouse model of human dry eye disease (DED) for investigation of sex differences in autoimmune-associated dry eye pathology. Methods Ocular surface disease was assessed by quantifying corneal epithelial damage with lissamine green stain in the NOD.H-2 h4 ,IFNγ − / − ,CD28 − / − (NOD.H-2 h4 DKO) mouse model of Sjögren's syndrome (SS). Lacrimal gland function was assessed by tear volume quantification with phenol red thread and lacrimal gland inflammation (i.e., dacryoadenitis) was assessed by quantification of immune cell foci, flow cytometric analysis of immune cell composition, and expression of proinflammatory markers. Results The NOD.H-2 h4 DKO mouse model of SS exhibits greater age-dependent increases in corneal damage than in NOD.H-2 h4 parental mice and demonstrates an earlier disease onset in females compared to males. The severity of ocular surface disease correlates with loss of goblet cell density, increased conjunctivitis, and dacryoadenitis that is more pronounced in NOD.H-2 h4 DKO than NOD.H-2 h4 mice. B cells dominate lacrimal infiltrates in 16-week-old NOD.H-2 h4 and NOD.H-2 h4 DKO mice, but T helper cells and macrophages are also present. Lacrimal gland expression of proinflammatory genes, including the P2X7 and P2Y 2 purinergic receptors, is greater in NOD.H-2 h4 DKO than NOD.H-2 h4 mice and correlates with dacryoadenitis. Conclusions Our results demonstrate for the first time that autoimmune dry eye disease occurs in both sexes of NOD.H-2 h4 DKO and NOD.H-2 h4 mice, with earlier onset in female NOD.H-2 h4 DKO mice when compared to males of the same strain. This study demonstrates that both NOD.H-2 h4 and NOD.H-2 h4 DKO mice are novel models that closely resemble SS-related and sex-dependent DED.

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IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse

Cited by 18 publications

References 56 publications

Extending the use of biologics to mucous membranes by attachment of a binding domain

Extending the use of biologics to mucous membranes by attachment of a binding domain

Conjunctiva Resident γδ T Cells Expressed High Level of IL-17A and Promoted the Severity of Dry Eye

Early Dry Eye Disease Onset in a NOD.H-2^h4 Mouse Model of Sjögren's Syndrome

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IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse

Cited by 18 publications

References 56 publications

Extending the use of biologics to mucous membranes by attachment of a binding domain

Extending the use of biologics to mucous membranes by attachment of a binding domain

Conjunctiva Resident γδ T Cells Expressed High Level of IL-17A and Promoted the Severity of Dry Eye

Early Dry Eye Disease Onset in a NOD.H-2h4 Mouse Model of Sjögren's Syndrome

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Early Dry Eye Disease Onset in a NOD.H-2^h4 Mouse Model of Sjögren's Syndrome