Dataset Information

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

ABSTRACT: Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

SUBMITTER: Haskamp S

PROVIDER: S-EPMC7477008 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Haskamp Stefan S Bruns Heiko H Hahn Madelaine M Hoffmann Markus M Gregor Anne A Löhr Sabine S Hahn Jonas J Schauer Christine C Ringer Mark M Flamann Cindy C Frey Benjamin B Lesner Adam A Thiel Christian T CT Ekici Arif B AB von Hörsten Stephan S Aßmann Gunter G Riepe Claudia C Euler Maximilien M Schäkel Knut K Philipp Sandra S Prinz Jörg C JC Mößner Rotraut R Kersting Florina F Sticherling Michael M Sefiani Abdelaziz A Lyahyai Jaber J Sondermann Wiebke W Oji Vinzenz V Schulz Peter P Wilsmann-Theis Dagmar D Sticht Heinrich H Schett Georg G Reis André A Reis André A Uebe Steffen S Frey Silke S Hüffmeier Ulrike U

American journal of human genetics 20200805 3

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encod ...[more]

PMID: 32758447

Similar Datasets

Project description:Introduction and importance: Generalized pustular psoriasis of pregnancy (GPPP) is a rare dermatosis that causes maternal and fetal morbidity and mortality. Pustular psoriasis of pregnancy (PPP) is a challenging dermatological Condition, which can have impact on the life pregnant woman's and her unborn child's life. Case presentation Here we report a 26-year-old woman with a history of persistent plaque psoriasis presented with generalized pustular lesions. Ultrasonography revealed normal fetal development despite high serum ESR and CRP levels. Pustular psoriasis was confirmed by histopathology. The patients were given systemic prednisolone 32 mg once daily, which was raised to 60 mg once daily on the tenth day of treatment to manage fresh outbreaks, and the patient's rash continued to gradually improve. When the lesions faded after 4 weeks of treatment, the dose was reduced to 16 mg/day. At 31 weeks' gestation, the patient was discharged and she was kept on prednisolone at a low dose of 4 mg once daily for the duration of the pregnancy. Clinical discussion Generalized pustular psoriasis of pregnancy (GPPP), herpetiformis, is a less common form dermatosis that can be fatal for both mother and the fetus. Response to treatment is good when initiated early in the course of the disease. This present case shows young pregnant mother with GPPP successfully treated with systemic corticosteroid. Conclusion Contrary to the majority of other common pregnant dermatosis, pustular psoriasis is an uncommon condition that can have harmful effects on the fetus. Our patient's PPP symptoms included systemic ones as well as body and palm involvement. Close monitoring and administration of systemic corticosteroids ensured secure outcomes. Highlights • Generalized pustular psoriasis (GPPP) is a rare dermatosis that causes maternal and fetal morbidity and mortality.• This case illustrates a woman that had history of psoriasis vulgaris two years before pregnancy and developed pustular psoriasis type.• Systemic corticosteroids are regarded as the gold standard in the treatment of GPPP.• In this paper, we will present the case report of 26 year old pregnant woman who developed widespread pustular lesions in the 27th week of her fifth pregnancy.

Project description:BackgroundGeneralized Pustular Psoriasis (GPP) is an autoinflammatory, multisystemic disease, characterized by widespread eruption of neutrophilic pustules on erythematous base, accompanied by systemic symptoms such as fever, leukocytosis, arthralgia, and general malaise. Globally, the disease is rare, particularly in children. If not adequately diagnosed and treated, systemic inflammation and multiorgan involvement can be life-threatening. The pathogenesis of GPP mainly involves the innate immune system, with inflammatory processes and neutrophil activation driven primarily by IL-36, but also by IL-1, TNF-alpha, IL-17 A. In particular, IL-17 A acts as a potent inducer of neutrophil recruitment. We report the case of a 7-years-old girl with GPP successfully treated with Ixekizumab, an IL-17 A antagonist.Case presentationA 7-years-old girl with an history of plaque psoriasis came to our attention for the sudden appearance of erythematous patches surmounted by pustules on the trunk and lower limbs, following repeated episodes of purulent tonsillitis. We started therapy with cyclosporine at a dosage of 3,5 mg/kg/day, with no clinical benefit and progression of manifestations to a sub-erythrodermic state after 2 weeks. Blood tests showed neutrophilic leukocytosis, and the patient experienced hyperpyrexia and malaise. Since ixekizumab was recently approved for pediatric use in patients with moderate to severe plaque psoriasis, we started therapy with 80 mg Ixekizumab, combined with prednisone at a dosage of 12.5 mg/day, gradually tapered until discontinuation after 15 days. A second dose of Ixekizumab 40 mg was administered at week-4, according to the indication of ixekizumab in pediatric plaque psoriasis. At week-8 the patient achieved complete remission of skin manifestations and normalization of blood count. After achieving a stable remission, at week 36 we decided to increase the administration interval to 6 weeks. The patient is still on therapy with ixekizumab 40 mg every 6 weeks, maintaining complete remission during a 52-week follow-up, without safety concerns.ConclusionsThis report supports the use of ixekizumab as a safe and effective option, both in the short and long-term, in the treatment of GPP, even at pediatric age. Larger studies are needed to confirm this positive, real-life experience.

Dataset Information

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Publications

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets