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OP0193 Pyrin and PSTPIP1, Mutated in FMF, PAPA-, and PAMI Syndrome, are Involved in the Hypersecretion of Alarmins MRP8/14
  1. S.K. Fassl1,
  2. D. Holzinger1,2,
  3. T. Vogl1,
  4. M. Gattorno3,
  5. A. Omenetti3,
  6. J.J. Chae4,
  7. I. Aksentijevich4,
  8. J. Austermann1,
  9. J. Roth1
  1. 1University Hospital Muenster, Institute of Immunology
  2. 2University Hospital Muenster, Department of Paediatric Rheumatology and Immunology, Münster, Germany
  3. 32nd Division of Pediatrics “G. Gaslini” Scientific Institute, Genova, Italy
  4. 4National Human Genome Research Institute, Bethesda, United States


Background Familial Mediterranean fever (FMF) and pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome are inherited autoinflammatory diseases. FMF patients have mutations in pyrin, a protein that has been suggested to play a role in the regulation of the inflammasome, PAPA patients have mutations in PSTPIP1, which interacts with pyrin. In both diseases, extraordinarily elevated serum levels of MRP8/14 were detected. Recently, we have identified two novel autosomal dominant mutations in the PSTPIP1 gene, p.E250K or p.E257K substitution, as genetic cause for a novel, more severe autoinflammatory entity: PAMI syndrome (PSTPIP1-associated myeloid-related-proteinaemia inflammatory syndrome). PAMI patients present with even higher levels of MRP8/14. MRP8 and MRP14 belong to the family of proinflammatory Damage Associated Molecular Pattern (DAMP) proteins, are mostly expressed in phagocytes and activate innate immune cells via TLR4 (Fassl et al. J. Immunol. 2015) after released via a so-called alternative pathway. However, the mechanism of secretion of MRP8/14 is still unknown.

Objectives We investigated if pyrin and PSTPIP1 play a role in the secretion of MRP8/14.

Methods MRP8/14 serum concentrations of patients were determined by ELISA. PSTPIP1 gene sequencing was performed in 14 patients with PAMI syndrome. Monocytes from patients were isolated and MRP8/14 levels were measured in culture supernatants prior and after activation. PSTPIP1-Pyrin-MRP8/14 interactions were investigated by immunoprecipitations and structural analysis.

Results Monocytes from patients with PSTPIP1 mutations release significantly higher amounts of MRP8/14 than control cells. Immunoprecipitation studies demonstrated that p.E250K-PSTPIP1 is hyperphsphorylated and binds stronger to pyrin compared to wildtype protein. Furthermore, we could prove a direct interaction of both PSTPIP1 and pyrin with MRP8/14. By using deletion constructs of PSTPIP1 we could demonstrate that the MRP8/14 binding motif is mutated in PAMI syndrome.

Conclusions Phagocytes seem to be the responsible cell type for the high serum concentration of MRP8/14 in PAMI syndrome. The DAMP proteins MRP8 and MRP14 interact directly with PSTPIP1 and mutations found in all patients are apparently located inside the PSTPIP1-MRP8/14 binding region. Moreover, the PSTPIP1 mutations influence the interaction with pyrin. Overall, our data indicate that hypersecretion of MRP8/14 is a relevant pathomechanism in PSTPIP1- and pyrin-associated diseases.

Disclosure of Interest None declared

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