Immune Modulation in Ocular Mucous Membrane Pemphigoid

Dart, John K.G.; Saw, Valerie P J

doi:10.1007/978-3-642-54350-0_2

Cited by 2 publications

(4 citation statements)

References 61 publications

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“…The pathogenesis of inflammation and scarring in OMMP is incompletely understood (3,23,47), and our findings implicating the role of pathogenic fibroblast autoregulation, mediated by ALDH/RA, in this process are new. We have shown both that ALDH overexpression can be identified in the conjunctiva and that we can screen for the effects of ALDH inhibition using in vitro-cultured fibroblast assays from phenotyped patients.…”

Section: Discussionmentioning

confidence: 68%

“…In vivo topical eye drops of ovalbumin (OVA) were applied, with or without disulfiram, to the ocular surface of previously OVA-sensitized mice over 7 days, and both inflammation and fibrosis were scored daily. In vitro mouse primary conjunctival fibroblasts were explanted and cultured to validate the role of Biopsies were obtained from patients with MMP confirmed by direct immunofluorescence (DIF) microscopy, which is required for the gold standard diagnosis of MMP (47). Most patients donated biopsies from both eyes.…”

Section: Resultsmentioning

confidence: 99%

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Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

Ahadome¹,

Abraham²,

Rayapureddi³

et al. 2016

JCI Insight

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Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

Ahadome¹,

Abraham²,

Rayapureddi³

et al. 2016

JCI Insight

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“…36 In this publication I have restricted the description of treatments to a summary of the role of immunomodulatory techniques and the evidence for their use in ocular MMP, with guidelines for their use.…”

Section: Treatment Summarymentioning

confidence: 99%

“…We have proposed three sets of criteria for the diagnosis of ocular MMP: 4,35,36 a. Patients with positive conjunctival DIF or positive DIF from another site meet currently agreed criteria.…”

Section: Recommended Diagnostic Criteria For Ocular Mmpmentioning

confidence: 99%

The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on

Dart

2017

Eye

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This review is in two sections. The first section summarises 35 conditions, both common and infrequent, causing cicatrising conjunctivitis. Guidelines for making a diagnosis are given together with the use of diagnostic tests, including direct and indirect immunofluorescence, and their interpretation. The second section evaluates our knowledge of ocular mucous membrane pemphigoid, which is the commonest cause of cicatrizing conjunctivitis in most developed countries. The clinical characteristics, demographics, and clinical signs of the disease are described. This is followed by a review and re-evaluation of the pathogenesis of conjunctival inflammation in mucous membrane pemphigoid (MMP), resulting in a revised hypothesis of the autoimmune mechanisms causing inflammation in ocular MMP. The relationship between inflammation and scarring in MMP conjunctiva is described. Recent research, describing the role of aldehyde dehydrogenase (ALDH) and retinoic acid (RA) in both the initiation and perpetuation of profibrotic activity in MMP conjunctival fibroblasts is summarised and the potential for antifibrotic therapy, using ALDH inhibition, is discussed. The importance of the management of the ocular surface in MMP is briefly summarised. This is followed with the rationale for the use of systemic immunomodulatory therapy, currently the standard of care for patients with active ocular MMP. The evidence for the use of these drugs is summarised and guidelines given for their use. Finally, the areas for research and innovation in the next decade are reviewed including the need for better diagnostics, markers of disease activity, and the potential for biological and topical therapies for both inflammation and scarring.

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Immune Modulation in Ocular Mucous Membrane Pemphigoid

Cited by 2 publications

References 61 publications

Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring

The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on

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