Dataset Information

Tissue Remodeling in Ocular Mucous Membrane Pemphigoid.

ABSTRACT:

Purpose

Ocular mucous membrane pemphigoid (OcMMP) is a rare eye disease characterized by relapsing-remitting or persisting long-lasting inflammatory events associated with progressive scarring. Despite long-term immunomodulating therapy, abnormal fibrosis keeps worsening in patients with OcMMP. This study investigates the fibrotic process in patients with OcMMP, as well as the critical role of the epithelium in modulating the local fibrosis.

Methods

In this prospective, observational pilot study, patients affected by long-lasting OcMMP were compared with age- and gender-matched healthy controls. Clinical grading was assessed, and conjunctival biopsy and impression cytology were performed. Conjunctival samples were used for quantifying the expression of transcripts regulating the inflammatory and fibrogenic processes.

Results

Ocular surface clinical and functional markers worsened in patients with OcMMP with fibrotic disease progression. In more advanced disease stages, both impression cytologies and conjunctival biopsies revealed increased tissue remodeling and profibrotic markers (α-SMA and TGF-β), and decreased levels of inflammatory markers (I-CAM1, IL-10, and IL-17). Increased epithelial expression of profibrotic markers and histological changes were detected.

Conclusions

Chronic OcMMP is characterized by a progressive, aberrant self-sustaining fibrotic process that worsens clinical signs and symptoms. Conjunctival epithelial cells may transdifferentiate into myofibroblast-like phenotypes when chronically exposed to high levels of inflammation, as in the case of OcMMP. Tissue remodeling markers in OcMMP could be used as early diagnostic, prognostic, and therapeutic biomarkers, harvested in a non-invasive and painless procedure such as impression cytologies.

SUBMITTER: Di Zazzo A

PROVIDER: S-EPMC10723221 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Tissue Remodeling in Ocular Mucous Membrane Pemphigoid.

Di Zazzo Antonio A Cutrupi Francesco F De Antoniis Maria Grazia MG Ricci Milena M Esposito Graziana G Antonini Marco M Coassin Marco M Micera Alessandra A Perrella Eleonora E Bonini Stefano S

Investigative ophthalmology & visual science 20231201 15

<h4>Purpose</h4>Ocular mucous membrane pemphigoid (OcMMP) is a rare eye disease characterized by relapsing-remitting or persisting long-lasting inflammatory events associated with progressive scarring. Despite long-term immunomodulating therapy, abnormal fibrosis keeps worsening in patients with OcMMP. This study investigates the fibrotic process in patients with OcMMP, as well as the critical role of the epithelium in modulating the local fibrosis.<h4>Methods</h4>In this prospective, observatio ...[more]

PMID: 38095906

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Project description:Mucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. Loss of tolerance to epithelial basement membrane proteins and generation of autoreactive T cell and/or autoantibodies are central to the disease process. The gut microbiome plays a critical role in the development of the immune system. Alteration in the gut microbiome (gut dysbiosis) affects the generation of autoreactive T cells and B cell autoantibody repertoire in several autoimmune conditions. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP by comparing OcMMP gut microbiome profiles with healthy controls. DNA was extracted from faecal samples (49 OcMMP patients, 40 healthy controls), amplified for the V4 region of the 16S rRNA gene and sequenced using Illumina Miseq platform. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. After adjusting for participant factors in the multivariable model (age, gender, BMI, diet, proton pump inhibitor use), OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. Within the OcMMP cohort, the number of OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). The linear discriminant analysis effect size scores indicated that Streptococcus and Lachnoclostridium were enriched in OcMMP patients whilst Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group were enriched in healthy controls (Log10 LDA score < 2, FDR-adjusted p <0.05). In conclusion, OcMMP patients have gut dysbiosis correlating with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP.

Project description:ImportanceAn accurate diagnosis of mucous membrane pemphigoid (MMP) is essential to reduce diagnostic and therapeutic delay.ObjectiveTo assess the diagnostic accuracy of direct immunofluorescence microscopy on mucosal biopsy specimens and immunoserology in a large cohort of patients with suspected MMP.Design, setting, and participantsThis retrospective cohort study was carried out in a single tertiary care center for blistering diseases between January 2002 and March 2019. Eligible participants were patients with suspected MMP and paired data on at least a mucosal biopsy specimen for direct immunofluorescence microscopy (DIF) and indirect immunofluorescence microscopy (IIF) on a human salt-split skin substrate (SSS). In addition, an optional DIF test on a skin biopsy specimen and one or more performed routine immunoserologic tests were analyzed. Data analysis was conducted from April 2019, to June 2020.Main outcomes and measuresDiagnostic accuracy of DIF, IIF SSS, and immunoblot for BP180 and BP230.ResultsOf the 787 participants, 121 (15.4%) received the diagnosis of MMP (50 men [41.3%], 71 women [58.7%]; mean [SD] age at diagnosis, 60.1 [17.7] years). Sixty-seven of the patients with MMP (55.4%) had monosite involvement, of which oral site was the most frequently affected (51 [42.1%]). No significant difference was found between the sensitivity of DIF on a perilesional buccal biopsy and a normal buccal biopsy (89.3% vs 76.7%). Three patients with solitary ocular involvement showed a positive DIF of only the oral mucosa. In 6 patients with a negative mucosal DIF, a skin biopsy confirmed diagnosis of MMP. Overall, IIF SSS was less sensitive (44.6%), but highly specific (98.9%). The sensitivity of immunoblot (66.1%) was higher compared to SSS, but with lower specificity (91.3%).Conclusions and relevanceThis comparative diagnostic accuracy study of a cohort of 787 patients found a high sensitivity of a mucosal DIF biopsy for diagnosis of MMP, and lower sensitivity of serologic analysis. A biopsy can be taken from either perilesional or normal buccal mucosa. An additional DIF biopsy of another mucosal site or of affected or unaffected skin may increase the diagnostic yield and is recommended in patients with negative DIF results and high clinical suspicion.

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Project description:ImportanceMucous membrane pemphigoid (MMP) is a rare, heterogeneous subepithelial autoimmune bullous disease. The association between its clinical and immunological features is yet to be fully evaluated.ObjectivesTo characterize the clinical, immunoserological, and immunopathological characteristics of patients with MMP and to identify site- and autoantigen-specific characteristics.Design, setting, and participantsA retrospective cohort study encompassing all consecutive patients diagnosed with MMP from January 2007 through February 2020 in 2 tertiary referral centers in Germany.Main outcomes and measuresThe clinical, immunoserological, and immunopathological features of eligible patients were evaluated. Associations of different anatomical sites and autoantigens were assessed using a multivariable logistic regression model.ResultsThe study encompassed 154 patients (96 [62.3%] women and 58 [37.7%] men; mean [SD] age at diagnosis, 66.2 [13.8] years) with MMP, of whom 125 (81.2%), 61 (39.6%), 34 (22.1%), and 16 (10.4%) presented with lesions involving the oral, ocular, nasal, and genital mucosae, respectively, and 35 (22.7%) presented with cutaneous involvement. Among the 154 patients, the most frequently targeted antigen was BP180 (90 patients [58.4%]), followed by laminin 332 (13 patients [8.4%]) and BP230 (3 patients [1.9%]). Ocular disease was inversely associated with oral (adjusted odds ratio [aOR], 0.02; 95% CI, 0.01-0.13) and nasal (aOR, 0.20; 95% CI, 0.04-0.91) involvement and was associated with a 13-fold increased risk of malignant neoplasm (aOR, 13.07; 95% CI, 1.56-109.36). Anti-laminin 332 reactivity was associated with malignant neoplasm (aOR, 23.27; 95% CI, 1.83-296.68), whereas anti-BP180 NC16A immunoglobulin G seropositivity was associated with absence of ocular lesions (aOR, 0.09; 95% CI, 0.01-0.99).Conclusions and relevanceIn this cohort study of patients with MMP, malignant neoplasms were associated with ocular disease and anti-laminin 332 reactivity, suggesting potential benefit of malignant neoplasm screening in these patients.

Project description:BackgroundBullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare autoimmune blistering disorders characterized by autoantibodies (autoAbs) targeting dermo-epidermal junction components such as BP180 and BP230. The differential diagnosis, based on both the time of appearance and the extension of cutaneous and/or mucosal lesions, is crucial to distinguish these diseases for improving therapy outcomes and delineating the correct prognosis; however, in some cases, it can be challenging. In addition, negative results obtained by commercially available enzyme-linked immunosorbent assays (ELISAs) with BP and MMP sera, especially from patients with ocular involvement, often delay diagnosis and treatment, leading to a greater risk of poor outcomes.ObjectivesOur aim was to find potentially different reactivity profiles in BP and MMP and improve available approaches for diagnosis with focus on ocular MMP.MethodsTwo cohorts of 90 BP and 90 MMP, recruited from different Italian clinical centers, were characterized also employing a novel ELISA based on the BP180 extracellular domain (ECD-BP180).ResultsImmunoglobulin G (IgG) reactivity to BP180 and BP230 in MMP sera was significantly reduced in comparison with BP, mostly affecting BP230 and E-1080 (53% and 36% in BP vs. 11% and 3% in MMP, respectively, p < 0.0001). The combined sensitivity of BP180-NC16A and ECD-BP180 ELISAs was greater compared to BP180-NC16A and BP230 ELISAs both in BP (97% and 92%, respectively) and in MMP (42% and 31%, respectively). The present study shows that MMP patients with ocular involvement rarely reacted to BP180 by IgG in contrast with patients with oral and/or cutaneous involvement (p = 0.0245 and p = 0.0377, respectively), suggesting that an oral and/or cutaneous MMP positive to BP180 hardly evolves to ocular MMP. Of note, one-third of ocular MMP showed immunoglobulin A (IgA) reactivity to ECD-BP180 by immunoblotting.ConclusionsThe present study provides several hints to perform a correct and timely diagnosis in BP and MMP, which is crucial for improving therapy outcomes and delineating the correct prognosis.

Dataset Information

Tissue Remodeling in Ocular Mucous Membrane Pemphigoid.

Purpose

Methods

Results

Conclusions

Publications

Tissue Remodeling in Ocular Mucous Membrane Pemphigoid.

Similar Datasets

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