Alteration in the Gene Encoding Protein Tyrosine Phosphatase Nonreceptor Type 6 (PTPN6/SHP1) May Contribute to Neutrophilic Dermatoses

Nesterovitch, Andrew B.; Gyorfy, Zsuzsa; Hoffman, Mark D.; Moore, Ellen; Elbuluk, Nada; Tryniszewska, Beáta; Rauch, Tibor A.; Simon, Melinda; Kang, Sewon; Fisher, Gary J.; Mikecz, Katalin; Tharp, Michael D.; Glant, Tibor T.

doi:10.1016/j.ajpath.2010.12.035

Cited by 68 publications

(61 citation statements)

References 49 publications

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“…The neutrophilic dermatoses have been recently included in the group of autoinflammatory diseases, 52,53 which are clinically characterized by recurrent episodes of sterile inflammation in the affected organs, in absence of high titers of circulating autoantibodies, and autoreactive T cells. [53][54][55][56] These conditions are associated with a number of genetically determined alterations of the innate immune response inducing an overproduction of active IL-1b possibly leading, through the release of several proinflammatory cytokines and chemokines, to a neutrophil-mediated inflammation.…”

Section: Reactive Skin Manifestations Of Ibdmentioning

confidence: 99%

Cutaneous Manifestations in Patients With Inflammatory Bowel Diseases

Marzano

Borghi

Stadnicki

et al. 2014

Inflammatory Bowel Diseases

114

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The skin is one of the most common extraintestinal organ system affected in patients with inflammatory bowel disease (IBD), including both Crohn's disease and ulcerative colitis. The skin manifestations associated with IBD are polymorphic and can be classified into 4 categories according to their pathophysiology: (1) specific, (2) reactive, (3) associated, and (4) induced by IBD treatment. Cutaneous manifestations are regarded as specific if they share with IBD the same granulomatous histopathological pattern: perianal or metastatic Crohn's disease (commonly presenting with abscesses, fistulas or hidradenitis suppurativa-like features) is the prototype of this setting. Reactive cutaneous manifestations are different from IBD in the histopathology but have close physiopathological links: pyoderma gangrenosum, a neutrophil-mediated autoinflammatory skin disease typically manifesting as painful ulcers, is the paradigm of this group. Among the cutaneous diseases associated with IBD, the most commonly seen are erythema nodosum, a form of panniculitis most commonly involving bilateral pretibial areas, and psoriasis, a T helper 1/T helper 17-mediated erythematous squamous inflammatory disease. Finally, the number of cutaneous adverse reactions because of IBD therapies is progressively increasing. The most frequent drug-induced cutaneous manifestations are psoriasis-like, eczema-like, and lichenoid eruptions, as well as cutaneous lupus erythematosus for biologics, and nonmelanoma skin cancer, mainly basal cell and squamous cell carcinomas for thiopurines.

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Section: Reactive Skin Manifestations Of Ibdmentioning

confidence: 99%

Cutaneous Manifestations in Patients With Inflammatory Bowel Diseases

Marzano

Borghi

Stadnicki

et al. 2014

Inflammatory Bowel Diseases

114

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“…The only major sequela of this dysregulated neutrophil function is the development of chronic skin inflammation, which is prevented by neutrophil-specific genetic blockade of integrin signaling. Alterations in the gene encoding the SHP-1 phosphatase ( PTPN6 ) have been reported in cases of human neutrophilic dermatoses [138]. Clearly, further work in this area is warranted.…”

Section: Roles For Neutrophils In Non-classical Autoinflammatory-lmentioning

confidence: 99%

Neutrophils in animal models of autoimmune disease

Németh

Mócsai

Lowell

2016

Seminars in Immunology

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Neutrophils have traditionally been thought to play only a peripheral role in the genesis of many autoimmune and inflammatory diseases. However, recent studies in a variety of animal models suggest that these cells are central to the initiation and propagation of autoimmunity. The use of mouse models, which allow either deletion of neutrophils or the targeting of specific neutrophil functions, has revealed the many complex ways these cells contribute to autoimmune/inflammatory processes. This includes generation of self antigens through the process of NETosis, regulation of T-cell and dendritic cell activation, production of cytokines such as BAFF that stimulate self-reactive B-cells, as well as indirect effects on epithelial cell stability. In comparing the many different autoimmune models in which neutrophils have been examined, a number of common underlying themes emerge – such as a role for neutrophils in stimulating vascular permeability in arthritis, encephalitis and colitis. The use of animal models has also stimulated the development of new therapeutics that target neutrophil functions, such as NETosis, that may prove beneficial in human disease. This review will summarize neutrophil contributions in a number of murine autoimmune/inflammatory disease models.

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“…These include neutrophilia, the formation of intraepidermal pustules and cutaneous tissue damage that is associated with marked infiltration of neutrophils. Interestingly, splice variants and coding mutations in Ptpn6 are closely associated with multiple neutrophilic dermatoses including Sweet syndrome and pyoderma gangrenosum in humans 21 . This association between mutations in Ptpn6 and clinic cases of neutrophilic dermatoses highlights the value of Ptpn6 mutant mice in the study of physiological autoinflammatory skin disorders.…”

Section: Introductionmentioning

confidence: 99%

SHP-1 and IL-1α conspire to provoke neutrophilic dermatoses

Lukens¹,

Kanneganti²

2014

Rare Diseases

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Neutrophilic dermatoses are a spectrum of autoinflammatory skin disorders that are characterized by extensive infiltration of neutrophils into the epidermis and dermis. The underlining biological pathways that are responsible for this heterogeneous group of cutaneous diseases have remained elusive. However, recent work from our laboratory and other groups has shown that missense mutations in Ptpn6, which encodes for the non-receptor protein tyrosine phosphatase Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1), results in a skin disease with many of the major histopathological and clinical features that encompass neutrophilic dermatoses in humans. In particular, we found that loss-of-function mutation in Ptpn6 results in unremitting footpad swelling, suppurative inflammation, and neutrophilia. Dysregulated wound healing responses were discovered to contribute to chronic inflammatory skin disease in SHP-1 defective mice and genetic abrogation of interleukin-1 receptor (IL-1R) protected mice from cutaneous inflammation, suggesting that IL-1-mediated events potentiate disease. Surprisingly, inflammasome activation and IL-1β-mediated events were dispensable for Ptpn6spin-mediated footpad disease. Instead, RIP1-mediated regulation of IL-1α was identified to be the major driver of inflammation and tissue damage.

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Alteration in the Gene Encoding Protein Tyrosine Phosphatase Nonreceptor Type 6 (PTPN6/SHP1) May Contribute to Neutrophilic Dermatoses

Cited by 68 publications

References 49 publications

Cutaneous Manifestations in Patients With Inflammatory Bowel Diseases

Cutaneous Manifestations in Patients With Inflammatory Bowel Diseases

Neutrophils in animal models of autoimmune disease

SHP-1 and IL-1α conspire to provoke neutrophilic dermatoses

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