Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies

BackgroundPyoderma gangrenosum (PG) is a debilitating ulcerative skin disease that is one of the most common associated diseases seen in patients with inflammatory bowel disease and rheumatoid arthritis. Although PG is classified as a neutrophilic dermatosis, its pathophysiology is poorly understood...

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Main Authors: Elizabeth A. Wang, Andrea Steel, Guillaume Luxardi, Anupam Mitra, Forum Patel, Michelle Y. Cheng, Reason Wilken, Jason Kao, Kristopher de Ga, Hawa Sultani, Alexander A. Merleev, Alina I. Marusina, Alain Brassard, Maxwell A. Fung, Thomas Konia, Michiko Shimoda, Emanual Maverakis
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-01-01
Series:Frontiers in Immunology
Subjects:
CD4
Online Access:http://journal.frontiersin.org/article/10.3389/fimmu.2017.01980/full
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author Elizabeth A. Wang
Andrea Steel
Guillaume Luxardi
Anupam Mitra
Forum Patel
Michelle Y. Cheng
Reason Wilken
Jason Kao
Kristopher de Ga
Hawa Sultani
Alexander A. Merleev
Alina I. Marusina
Alain Brassard
Maxwell A. Fung
Maxwell A. Fung
Thomas Konia
Thomas Konia
Michiko Shimoda
Emanual Maverakis
spellingShingle Elizabeth A. Wang
Andrea Steel
Guillaume Luxardi
Anupam Mitra
Forum Patel
Michelle Y. Cheng
Reason Wilken
Jason Kao
Kristopher de Ga
Hawa Sultani
Alexander A. Merleev
Alina I. Marusina
Alain Brassard
Maxwell A. Fung
Maxwell A. Fung
Thomas Konia
Thomas Konia
Michiko Shimoda
Emanual Maverakis
Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies
Frontiers in Immunology
pyoderma gangrenosum
CD4
T cell
autoimmune
cytokine
pilosebaceous unit
author_facet Elizabeth A. Wang
Andrea Steel
Guillaume Luxardi
Anupam Mitra
Forum Patel
Michelle Y. Cheng
Reason Wilken
Jason Kao
Kristopher de Ga
Hawa Sultani
Alexander A. Merleev
Alina I. Marusina
Alain Brassard
Maxwell A. Fung
Maxwell A. Fung
Thomas Konia
Thomas Konia
Michiko Shimoda
Emanual Maverakis
author_sort Elizabeth A. Wang
title Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies
title_short Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies
title_full Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies
title_fullStr Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies
title_full_unstemmed Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies
title_sort classic ulcerative pyoderma gangrenosum is a t cell-mediated disease targeting follicular adnexal structures: a hypothesis based on molecular and clinicopathologic studies
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2018-01-01
description BackgroundPyoderma gangrenosum (PG) is a debilitating ulcerative skin disease that is one of the most common associated diseases seen in patients with inflammatory bowel disease and rheumatoid arthritis. Although PG is classified as a neutrophilic dermatosis, its pathophysiology is poorly understood.ObjectiveUse data obtained from patient-reported histories, immunohistochemistry, and gene expression analysis to formulate a hypothesis on PG pathophysiology.MethodsTen PG patients participated and answered questions about new ulcer formation. Skin biopsies of healed prior ulcers and adjacent normal skin were obtained from four patients for immunohistochemistry. Scars from healthy patients and patients with discoid lupus were used as additional controls. New onset PG papules were analyzed using immunohistochemistry and gene expression analysis via quantitative real-time PCR.ResultsAll PG patients reported that healed sites of previous ulceration are refractory to re-ulceration. Simultaneous biopsies of healed and uninvolved skin triggered ulceration only in the latter. On immunohistochemistry, healed PG scars showed complete loss of pilosebaceous units, which were present in normal skin, and to a lesser extent in control scars, and discoid scars. Early PG papules showed perivascular and peripilosebaceous T cell infiltrates, rather than neutrophils. These early inflammatory events were dominated by increased gene expression of CXCL9, CXCL10, CXCL11, IL-8, IL-17, IFNG, and IL-36G and transcription factors consistent with Th1 phenotype.LimitationsSmall sample size was the main limitation.ConclusionWe put forth the hypothesis that PG is a T cell response resulting in the destruction of pilosebaceous units.
topic pyoderma gangrenosum
CD4
T cell
autoimmune
cytokine
pilosebaceous unit
url http://journal.frontiersin.org/article/10.3389/fimmu.2017.01980/full
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spelling doaj-fe3ea2b9197646ba9e0c3fd94e1b89c62020-11-24T22:56:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-01-01810.3389/fimmu.2017.01980316327Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic StudiesElizabeth A. Wang0Andrea Steel1Guillaume Luxardi2Anupam Mitra3Forum Patel4Michelle Y. Cheng5Reason Wilken6Jason Kao7Kristopher de Ga8Hawa Sultani9Alexander A. Merleev10Alina I. Marusina11Alain Brassard12Maxwell A. Fung13Maxwell A. Fung14Thomas Konia15Thomas Konia16Michiko Shimoda17Emanual Maverakis18Department of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Pathology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Pathology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesDepartment of Dermatology, University of California, Davis, Sacramento, CA, United StatesBackgroundPyoderma gangrenosum (PG) is a debilitating ulcerative skin disease that is one of the most common associated diseases seen in patients with inflammatory bowel disease and rheumatoid arthritis. Although PG is classified as a neutrophilic dermatosis, its pathophysiology is poorly understood.ObjectiveUse data obtained from patient-reported histories, immunohistochemistry, and gene expression analysis to formulate a hypothesis on PG pathophysiology.MethodsTen PG patients participated and answered questions about new ulcer formation. Skin biopsies of healed prior ulcers and adjacent normal skin were obtained from four patients for immunohistochemistry. Scars from healthy patients and patients with discoid lupus were used as additional controls. New onset PG papules were analyzed using immunohistochemistry and gene expression analysis via quantitative real-time PCR.ResultsAll PG patients reported that healed sites of previous ulceration are refractory to re-ulceration. Simultaneous biopsies of healed and uninvolved skin triggered ulceration only in the latter. On immunohistochemistry, healed PG scars showed complete loss of pilosebaceous units, which were present in normal skin, and to a lesser extent in control scars, and discoid scars. Early PG papules showed perivascular and peripilosebaceous T cell infiltrates, rather than neutrophils. These early inflammatory events were dominated by increased gene expression of CXCL9, CXCL10, CXCL11, IL-8, IL-17, IFNG, and IL-36G and transcription factors consistent with Th1 phenotype.LimitationsSmall sample size was the main limitation.ConclusionWe put forth the hypothesis that PG is a T cell response resulting in the destruction of pilosebaceous units.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01980/fullpyoderma gangrenosumCD4T cellautoimmunecytokinepilosebaceous unit