title: Alarming consequences - autoinflammatory disease spectrum due to mutations in proline-serine-threonine phosphatase-interacting protein 1.
abstract: To give an overview about the expanding spectrum of autoinflammatory diseases due to mutations in proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) and new insights into their pathogenesis.
  
  
  
  In addition to classical pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome has been described as a distinct clinical phenotype of PSTPIP1-associated inflammatory diseases (PAID) and other entities are emerging. In addition to dysregulation of IL-1ß release from activated PAPA monocytes that requires NLR family, pyrin domain containing 3 (NLRP3), PSTPIP1 mutations have an general impact on cellular dynamics of cells of the innate immune system. In addition, overwhelming expression and release of the alarmins myeloid-related protein (MRP) 8 and 14 by activated phagocytes and keratinocytes, which promote innate immune mechanisms in a Toll like receptor (TLR) 4-dependent manner, are a characteristic feature of these diseases and form a positive feed-back mechanism with IL-1ß.
  
  
  
  Autoinflammatory diseases due to PSTPIP1 mutations are not restricted to the classical PAPA phenotype but might present with other distinct clinical features. MRP8/14 serum levels are a hallmark of PAPA and PAMI and can be used as screening tool to initiate targeted genetic testing in suspected cases. The feedback mechanism of IL-1ß and MRP-alarmin release may offer novel targets for future therapeutic approaches.
authors.affiliation: aDepartment of Paediatric Rheumatology and Immunology, University Children's Hospital bInstitute of Immunology, University Hospital Muenster, Muenster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000152:Acne Vulgaris / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000067531:Alarmins / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001170:Arthritis, Infectious / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D040502:Calgranulin B / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use; D003598:Cytoskeletal Proteins / Q000235:genetics; D005938:Glucocorticoids / Q000627:therapeutic use; D056660:Hereditary Autoinflammatory Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D009154:Mutation; D010641:Phenotype; D011239:Prednisolone / Q000627:therapeutic use; D017511:Pyoderma Gangrenosum / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D000067531:Alarmins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040502:Calgranulin B; D003598:Cytoskeletal Proteins; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; C486382:PSTPIP1 protein, human; D014409:Tumor Necrosis Factor-alpha; C541220:canakinumab; D016572:Cyclosporine; D011239:Prednisolone