OP0260 The pathophysiology of S100A8/A9 in familial mediterranean fever (FMF)
Authors: J. Austermann, S. Fassl, D. Holzinger, J.J. Chae, K. Tilmann, R. Keitzer, J. Roth, D. Foell, H. Wittkowski
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Familial Mediterranean Fever (FMF) is an auto-inflammatory syndrome caused by mutations within the <i>MEFV</i> gene encoding pyrin protein. The FMF syndromeis associated with activation of phagocytic cells and secretion of IL-1β. The production and secretion of IL-1β is regulated by interactions of pyrin and the NALP3-inflammasome, but exact pathogenic mechanisms are still elusive. Like IL-1β, the pro-inflammatory Damage Associated Molecular Pattern (DAMP) molecules S100A8/A9 are released by a Golgi-independent but tubulin-dependent, so called alternative secretory pathway (1, 2). S100A8/A9 have been recently identified as endogenous activators of TLR4 and several studies on inflammatory disorders demonstrated their potential as biomarkers of inflammation (3). <h3>Objectives</h3> Our goal was i) to correlate S100A8/A9 serum concentrations in FMF-patients to disease activity and to evaluate the potential of S100A8/A9 as biomarker, ii) to study S100A8/A9 -pyrin interaction, iii) to analyze S100A8/A9 serum-concentrations in FMF-mice. <h3>Methods</h3> 52 genetically proven FMF-patients were studied longitudinally over 18 months. Serum-levels of S100A8/A9 (ELISA), ESR, CRP and SAA were analysed before and during colchicine treatment and compared to other autoinflammatory syndromes. S100A8/A9 serum-levels of homozygous Pyrin V726A knock-in mice ("FMF-mice") were determined for secretion analysis. Interaction and co-localization of S100A8/A9 and pyrin was analysed by immunofluorescence-, co-immunoprecipitation- and affinity-chromatography experiments. <h3>Results</h3> The mean serum-levels of S100A8/A9 during inflammatory episodes of FMF (Mean ± SEM 343,210±202,210 ng/ml) were significantly higher compared to chronic infantile neurological, cutaneous and articular (CINCA) syndrome (2,830±580 ng/ml; p&lt;0.001) or Muckle-Wells syndrome (MWS) (3,205±585 ng/ml; p&lt;0.001), and correlated to disease activity. Similar, sera of homozygous FMF-mice showed increased S100A8/A9 -levels (1,260±540 ng/ml) compared to WT- (150±40 ng/ml), or heterozygous FMF-mice (340±180 ng/ml). Immunofluorescence stainings of human monocytes showed a colocalisation of pyrin, S100A8/A9 and tubulin. Moreover a direct molecular interaction of pyrin with S100A8/A9 could be demonstrated in immunoprecipitation and affinity-chromatographyexperiments. <h3>Conclusions</h3> S100A8/A9 are strongly secreted in FMF-patients compared to other IL-1 driven diseases. Measurement of S100A8/A9 -levels in FMF might be a valuable tool to reflect disease activity and response to anti-inflammatory therapy. Pyrin interacts directly with S100A8/A9 pointing towards an important role in the alternative secretion of those proteins in FMF. <h3>References</h3> Vogl et al. (2007) Nat. Med. 13, 1042-1049. Rammes et al. (1997) J. Biol. Chem. 272, 9496-9502. Frosch et al. (2000) Arthritis Rheum. 43, 628-637. <h3>Disclosure of Interest</h3> None Declared