Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation.
Pyoderma gangrenosum is a rare inflammatory neutrophilic dermatosis manifesting as painful ulcers with violaceous, undermined borders on the lower extremities. It may occur in the context of classic syndromes like PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis), as well as in a recently described entity named PASH (pyoderma gangrenosum, acne and suppurative hidradenitis). Pyoderma gangrenosum has recently been included within the spectrum of autoinflammatory diseases, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T cells. In PAPA syndrome, different mutations involving the PSTPIP1 gene, via an increased binding affinity to pyrin, induce the assembly of inflammasomes. These are molecular platforms involved in the activation of caspase 1, a protease that cleaves inactive prointerleukin (pro-IL)-1β to its active isoform IL-1β. The overproduction of IL-1β triggers the release of a number of proinflammatory cytokines and chemokines, which are responsible for the recruitment and activation of neutrophils, leading to neutrophil-mediated inflammation. In SAPHO syndrome, the activation of the PSTPIP2 inflammasome has been suggested to play a role in inducing the dysfunction of the innate immune system. Patients with PASH have recently been reported to present alterations of genes involved in well-known autoinflammatory diseases, such as PSTPIP1, MEFV, NOD2 and NLRP3. Pyoderma gangrenosum and its syndromic forms can be regarded as a single clinicopathological spectrum in the context of autoinflammation.
Unità Operativa di Dermatologia, IRCCS Fondazione Cá Granda, Ospedale Maggiore Policlinico, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy. angelovalerio.marzano@policlinico.mi.it.
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http://orcid.org/0000-0002-8160-4169
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Marzano
Dipartimento di Scienze Mediche, Sezione di Dermatologia e Malattie Infettive, Università degli Studi di Ferrara, Ferrara, Italy.
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Borghi
Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Cattedra di Reumatologia, Istituto G. Pini, IRCCS Istituto Auxologico Italiano, Milan, Italy.
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Meroni
Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Sezione di Medicina Interna, Università degli Studi di Milano, IRCCS Fondazione Cá Granda, Ospedale Maggiore Policlinico, Milan, Italy.
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D020083:Acquired Hyperostosis Syndrome / Q000209:etiology / Q000276:immunology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics; D003872:Dermatitis / Q000276:immunology; D017497:Hidradenitis Suppurativa / Q000209:etiology / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D058847:Inflammasomes / Q000096:biosynthesis / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D017511:Pyoderma Gangrenosum / Q000209:etiology* / Q000276:immunology / Q000628:therapy; D013577:Syndrome
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C486382:PSTPIP1 protein, human