Pediatrics Grand Rounds 29 April University of Texas Health Science Center at San Antonio. Ancestral Mutations in FMF

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1 Horror Autoinflammaticus: The Expanding Spectrum of Systemic Autoinflammatory Disease The Systemic Autoinflammatory Diseases: What Are They and Why Should You Care? Recurring episodes of seemingly unprovoked localized and systemic inflammation, without high titer autoantibodies, antigen-specific T cells, or evidence of infection Dramatic evidence of inflammation Dan Kastner, MD, PhD NHGRI/NIH/DHHS UTHSCSA Pediatrics Grand Rounds April 29, 2011 Disorders of innate immunity, providing new insights into human biology Kastner et al., Cell 140: , Samuels et al., Medicine (Baltimore) 77:268, 1998 Positional Cloning of MEFV, the Gene Mutated in Familial Mediterranean Fever (FMF) p13.3 p13.2p13.13 Chromosome 16p v57c7 OR1F1 v57c7x4 NK4 ZNF213 FPM315 ZNF205 D16S468/ (ZNF210) v9 D16S3373 S3070 D16S3082 D16S3405 D16S2617 OR1F2 AFMef101 D16S3275 Telomere Centromere PKD1, TSC2 v57c10 ZNF200 MEFV CREBBP bzip B-Box NH 2 Coiled-coil B30.2 COOH Pyrin / Marenostrin Cell 90:797,

2 The PYRIN Domain: A Cognate Interaction Motif Human and Mouse NLR Family Members Pyrin Richards et al., J Biol Chem 276:39320, 2001 PYRIN ASC PYRIN Caspase-1 pro-il-1b IL-1b IL-1b Converting Enzyme (ICE) Schröder and Tschopp, Cell 140:821, 2010 Ancestral Mutations in FMF Smallpox: The Selective Pressure? Origins in the Nile valley? Requires high population density 25 30% mortality Kastner, Hospital Practice 33:131, 1998 Hopkins DR, The Greatest Killer: Smallpox in History, U Chicago Press, Masters et al. Annu Rev Immunol 27:621, 2009 FMF Knockin Mice: IL-Dependent Inflammation IL-1 Inhibition in FMF Amyloidosis WT V726A WT V726A Chae et al. Immunity, in press. Chae et al. PNAS 103:9982,

3 FMF Variant or New Disease? Periodic fever in the Irish: an allelic variant of FMF in descendants of ship-wrecked sailors from the Spanish Armada? TNFRSF1A Mutations Can Cause Dominantly Inherited Periodic Fever The TNF Receptor-Associated Periodic Syndrome (TRAPS) 13 TNFRSF1A CRD1 CRD2 CRD1 12 CRD CRD CRD2 14 Death domain Rheumatology 5 th edn, , 2011 Hull et al. Medicine (Baltimore) 81:349 (2002) Rheumatology 5 th edn , 2011 TRAPS: Shedding Defect or Constipated Monocytes? TNFR1-YFP GalT(Golgi)-CFP merge TNFR1-wt Confocal microscopy on live HT1080 TNFR1-YFP Srb (ER)-CFP merge transfected with full-length TNFR1-YFP TNFR1-T50M Lobito et al Blood 108:1320, 2006 TNFR1-H22Y Human PBMCs TRAPS Wt Wt H22Y H22Y C52F TNFR1(H5) Simon et al PNAS 107:9801, 2010 HSC70 Rheumatology 5 th edn ,

4 TRAPS-Etanercept Trial Protein-Misfolding Disorders Masters et al. Annu Rev Immunol 27:621, 2009 CAPS: Three Diseases Caused by Mutations in One Gene Common clinical features: fever and urticarial rash q Monocytes Granulocytes Mutations in a Gene in the Pyrin Family Cause Muckle-Wells Syndrome (MWS) and Familial Cold Autoinflammatory Syndrome (FCAS) T-cells FCAS (familial cold urticaria) cold-induced fever and urticarial rash Muckle-Wells fever, urticarial rash, arthritis, sensorineural deafness, amyloidosis NOMID/CINCA fever, urticarial rash, bony overgrowth, CNS disease LRR C NBS (NACHT) 1034 Cryopyrin/PYPAF1/NALP3/NLRP3 N 1 N ASC C NF-kB, IL-1b activation Rheumatology 3rd edn, 1730, 2003 NLRP3 Mutation in NOMID/CINCA D303N Ivona Aksentijevich Raphaela Goldbach-Mansky Aksentijevich et al, Arthritis Rheum 46:3340, 2002 SoJIA? Neonatal-Onset Multisystem Inflammatory Disease (NOMID) Aksentijevich et al Arthritis Rheum 56:1273,

5 Cryopyrin (NLRP3) inflammasome Treatment of 18 NOMID Patients with the IL-1 Receptor Antagonist Anakinra Cardinal pro-caspase-1 pro-il-1b p20 p10 p10 p10 p20 p10 ASC pro-caspase-1 caspase-1 complex IL-1b Fever Inflammation Goldbach-Mansky R et al. N Engl J Med 355: , 2006 Response to Canakinumab, as Compared with Placebo Could This be NOMID? Lachmann HJ et al. N Engl J Med 360: , 2009 Mutations in IL1RN, IL-1 Receptor Antagonist Gene Age 9 months, before therapy 3 days post treatment initiation 7 days post treatment initiation Aksentijevich I et al. N Engl J Med 360: , 2009 Deficiency of the IL-1 Receptor Antagonist (DIRA) 5

6 Frequency of the mutation in the founder population Caucasian Controls (NY) Population of origin p.n52kfs25 c delca Father Neg in 364 2:555 p. E77X c.229g>t Neg in 364 0:351 p.q54x c.160c>t Mother Neg in kB deletion Neg in 364 Not done 3:119 The Netherlands Newfoundland 0.4% Puerto Rico 2.6% Extending the Pyrin Pathway: Proline Serine Threonine Phosphatase Interacting Protein 1 (PSTPIP1/CD2BP1) 1 FCH 30 A230T E250 * * Q CC PSTPIP1 261 SH3 413 Pyrin 1 domain B-BOX CC B pyrin IL-1b Activation Disorders The NIH Autoinflammatory Cohort Masters et al. Annu Rev Immunol 27:621, 2009 Familial Shar-Pei Fever Genome-wide SNP genotype analysis identifies a region on chromosome 13 with evidence of recent selection and that is associated with FSF Selective sweeps (regions identified by reduced heterozygosity) FSF-disease association A-C: Meatmouth variety D: Traditional variety Hyaluronic acid synthase 2 Zinc fingers and Olsson homeoboxes et al. 2 PLoS Genetics,

7 Targeted next generation sequencing reveals increased frequency of reads in a region 5 of the HAS2 gene. An Inflammasome Signature in PFAPA Flares Olsson et al. PLoS Genetics, 2011 Stojanov et al. PNAS 108:7148, 2011 Anakinra in PFAPA Behçet s Disease: A Genetically Complex Disorder with an Autoinflammatory Component Stojanov et al. PNAS 108:7148, 2011 l s > 10 IL10 and IL23R Associations in Independent Collections of BD Cases and Controls Sample Collection # cases # controls Allele freq cases Allele freq ctrls Chi-squared ChiSq P- value Odds ratio (95% CI) rs (IL10) A/G Discovery - Turkish E ( ) Replication - Turkish (0.02) ( ) Replication - Middle Eastern ( ) Replication - Greek ( ) Replication - UK Caucasian ( ) Replication - Korean ( ) Replication - Japanese E ( ) CMH-Meta-analysis E * ( ) rs (IL23R/IL12RB2) A/G Discovery - Turkish E ( ) Replication - Turkish (0.05) ( ) Replication - Middle Eastern ( ) Replication - Greek ( ) Replication - UK Caucasian ( ) Replication - Japanese E ( ) Replication - Korean ( ) CMH-Meta-analysis E * ( ) *Breslow-Day Test for Homogeneity of the Odds Ratios: P =0.54 and 0.71, for rs and rs924080, respectively. Remmers et al. Nature Genet 42: ,

8 Homozygotes for the Behçet s Risk Allele Produce Reduced Amounts of IL-10 Gout as an Autoinflammatory Disease Remmers et al. Nature Genet 42: , 2010 Martinon and Glimcher JCI 116: , 2006 Type 2 Diabetes Mellitus as an Autoinflammatory Disease Atherosclerosis as an Autoinflammatory Disease Larsen CM et al. N Engl J Med 356: , 2007 Duewell et al. Nature 464: , 2010 Summary NIH Intramural Research Program The autoinflammatory diseases manifest constitutive or easily triggered innate immune activation Mendelian autoinflammatory diseases have provided important insights into the regulation of inflammation IL-1b activation and protein misfolding are two important mechanisms of Mendelian autoinflammatory disease Genome-wide association studies allow the identification of susceptibility loci for the more common but genetically complex autoinflammatory disorders Based on the demonstration of an important role for the inflammasome in their pathophysiology, a number of common disorders have been shown to have an autoinflammatory component Ivona Aksentijevich JaeJin Chae Elaine Remmers Silvia Stojanov Raphaela Goldbach-Mansky Karyl Barron 8

9 NHGRI Inflammatory Disease Section, 2010 It s a genome world... NIH Bev Barham Karyl Barron Andy Baxevanis George Bertsias Trevor Blake Jillian Brady Margaret Brown Jun Cheng Puja Chitkara Young-Hun Cho Francis Collins Mike Dean Lionel Feigenbaum Tom Fleisher Patrycja Hoffman Anne Jones Steve Katz Acknowledgments Peter Kim Yohei Kirino Sivia Lapidus Julie Le Geun-shik Lee Paul Liu Amanda Ombrello Mike Ombrello John O Shea Francesca Puppo Colleen Satorius Afzal Sheikh Deb Stone Hong-Wei Sun Marcia Vital Geryl Wood Qing Zhu International Athens Phedon Kaklamanis Birmingham Graham Wallace Cambridge Kerstin Linblad-Toh Genentech Vishva Dixit Hartford Hank Feder Hokkaido Shigeaki Ohno Istanbul Ahmet Gül Nashville Kathy Edwards Seoul Dongsik Bang Tel-Hashomer Mordechai Pras Elon Pras UCSD Hal Hoffman Uppsala Mia Olsson Wilmington Balu Athreya Wurstboro Linda Tintle Yokohama Yoshi Ishigatsubo Nobuhisa Mizuki NIH Clinical Center Suggested Reading kastnerd@mail.nih.gov ajones@mail.nih.gov, referrals Stojanov S, Lapidus S, Chitkara P, et al. (2011) Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL- 1 blockade. PNAS 108: Remmers EF, Cosan F, Kirino Y, et al. (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB regions associated with Behçet s disease. Nature Genet 42: Kastner DL, Aksentijevich I, Goldbach-Mansky R (2010) Autoinflammatory disease reloaded: a clinical perspective. Cell 140: Masters SL, Simon A, Aksentijevich I, Kastner DL (2009) Horror Autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 27: Aksentijevich I, Masters SL, Ferguson PJ et al. (2009) An autoinflammatory disease with deficiency of the IL-1-receptor antagonist. N Engl J Med 360: