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1
Autoinflammatory Diseases:A Primer
Dan Kastner, MD, PhD
Intramural Research Program
NHGRI/NIH/DHHS
April 27, 2018
Disclosures
Nothing to disclose
Learning Objectives
• Discuss the distinction between autoinflammatoryand autoimmune diseases
• Enumerate various autoinflammatory diseases and list their most common clinical manifestations
• Discuss the diagnosis and pathophysiology of selected autoinflammatory diseases
• Delineate treatment options for selected autoinflammatory diseases
2
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 overt infection
• Dramatic evidence of inflammation
• Disorders of innate immunity, providing new insights into human biology
p13.3 p13.2p13.13
Chromosome 16p
Telomere Centromere
PKD1, TSC2
D16S3373
NK4
OR1F2
v57c10
v9
ZNF213ZNF205(ZNF210)
OR1F1v57c7 v57c7x4
MEFVZNF200
D16S3082D16S468/
S3070 D16S3405 D16S2617 AFMef101 D16S3275
FPM315
CREBBP
Pyrin / Marenostrin
NH2 COOH
bZIP B-Box
Coiled-coil B30.2PYD
Cell 90:797, 1997
Positional Cloning of MEFV, the Gene Mutated in Familial Mediterranean Fever (FMF)
3
Curr Opin Immunol12:479, 2000
NEJM 343:338, 2000
Manthiram et al. Nat Immunol 18:832, 2017
4
The Inflammasomopathies
Manthiram et al. Nat Immunol 18:832, 2017
FMF: Clinical Features
Peritonitis (air-fluid levels)
Pleurisy (left pleural effusion)
Posterior pericardial effusion
Chronic arthritis of the hip
Erysipeloid erythema
PMNs, synovial fluid Renal amyloidosis
IL-1 Inhibition in FMF Amyloidosis
Chae et al PNAS 103:9982, 2006
5
Pyrin S242R in a Family with a Severe Dominantly Inherited Autoinflammatory
Disease: PAAND
Masters et al. Science Transl Med 8:332ra45, 2016
The Inflammasomopathies
Manthiram et al. Nat Immunol 18:832, 2017
Hyperimmunoglobulinemia D with Periodic Fever Syndrome (HIDS)
•3 – 7 day febrile episodes
•Abdominal pain
•Arthritis/arthralgia
•Diffuse maculopapular rash
•Prominent cervical adenopathy
•Aphthous ulcers
•Onset within first year of life
•Episodes sometimes induced by childhood immunizations
•Amyloidosis very rare
Rheumatology 5th edn, 1648, 2011
6
The Inflammasomopathies
Manthiram et al. Nat Immunol 18:832, 2017
781Pyrin
domain B-BOX CC1 B30.2
413SH3
261
FCH CC1
30A230T E250Q
**
PSTPIP1
pyrin Shoham et al., PNAS 100:13501, 2003
PAPA Syndrome (Pyogenic Arthritis with PyodermaGangrenosum and Acne)
The Inflammasomopathies
Manthiram et al. Nat Immunol 18:832, 2017
7
Familial Cold Autoinflammatory Syndrome (FCAS)
• Fever, hives-like skin rash upon generalized exposure to cold
• Rash occurs about 2 hr after cold exposure
• Not true urticaria: neutrophils, not mast cells
• Dominant inheritance
125 250 500 1000 2000 4000 8000–10
0102030405060708090
100110
He
ari
ng
Le
ve
l in
dH
BL
–100
102030405060708090
100110
125 250 500 1000 2000 4000 8000
Muckle-Wells Syndrome
•Inflammatory episodes
–Fever
–Limb pain
–Urticarial rash
•Sensorineural hearing loss
•Systemic amyloidosisRheumatology 5th edn, 1653, 2011
Neonatal-Onset Multisystem InflammatoryDisease (NOMID)/Chronic Infantile NeurologicCutaneous and Articular Syndrome (CINCA)
8
Treatment of 18 NOMID Patients with the IL-1 Receptor Antagonist Anakinra
Goldbach-Mansky R et al. N Engl J Med 2006;355:581-592
The Inflammasomopathies
Manthiram et al. Nat Immunol 18:832, 2017
NLRC4-Macrophage Activation Syndrome/Syndrome of Enterocolitis and Autoinflammation Associated with
Mutation in NLRC4 (SCAN4)
Canna et al. Nature Genet 46:1140, 2014 and Romberg et al. Nature Genet 46:1135, 2014
9
The Inflammasomopathies
Manthiram et al. Nat Immunol 18:832, 2017
Aksentijevich I et al. N Engl J Med 2009;360:2426‐2437
Deficiency of the IL-1 Receptor Antagonist (DIRA)
The TNF Receptor-Associated Periodic Syndrome (TRAPS)
Hull et al. Medicine (Baltimore) 81:349 (2002)
Rheumatology 5th edn. 1637-57, 2011
10
The Interferonopathies
Manthiram et al. Nat Immunol 18:832, 2017
STING‐Associated Vasculopathy with Onset in Infancy (SAVI)
Liu et al. NEJM 371:507, 2014
The Interferonopathies
Manthiram et al. Nat Immunol 18:832, 2017
11
Liu et al Arthritis Rheum 64:895-907, 2012
Huber et al Cell 148:727-738, 2012
NF-B-Mediated Autoinflammation
Manthiram et al. Nat Immunol 18:832, 2017
Zhou et al., Nat Genet 48:67, 2016
Zhou et al., PNAS 113:10127, 2016
Disorders of Deubiquitination
12
NF-B-Mediated Autoinflammation
Manthiram et al. Nat Immunol 18:832, 2017
Variants of CARD15/NOD2 Underly Both Crohn’s Disease and Granulomatous Arthritis (Blau Syndrome) /
Early-Onset Sarcoidosis (EOS)
Crohn’s Disease,
Nature 411, 599 (2001)
Blau Syndrome
Miceli-Richard et al., Nature Genet 29:19, 2001
Summary
• The systemic autoinflammatory diseases are disorders of innate immunity
• Several autoinflammatory diseases are disorders of IL-1 signaling, with significant therapeutic response to IL-1 inhibitors
• The interferonopathies are disorders of type I interferon signaling, and may respond to JAK inhibitors
• Disorders of NF-B signaling include otulipeniaand Blau syndrome, which may respond to TNF inhibitors
13
NIH Colleagues in the Laboratory
Raman SoodNHGRI
Manfred BoehmNHLBI
JaeJin ChaeNHGRI
Yong Hwan ParkNHGRI
Monique StoffelsNHGRI
Geryl WoodNHGRI
Geun-Shik LeeNHGRI
Yohei KirinoNHGRI
Masaki TakeuchiNHGRI
Elaine RemmersNHGRI
Mike OmbrelloNIAMS
Pravitt GourhNIAMS
Julie LeNHGRI Kalpana Manthiram
NHGRI
Hongying WangNHGRI
Ivona AksentijevichNHGRI
Qing ZhouNHGRI
Angeliki GiannelouNIAMS
Natalie DeuitchNHGRI
Hiro OdaNHGRI
Steve BoydenNHGRI
NIH Colleagues in the Clinic
Camilo ToroNHGRI
Hirsh KomarowNIAID
Dean MetcalfeNIAID
Bob LemboOD
Don GoldsmithDrexel
Amanda OmbrelloNHGRI
RaphaelaGoldbach-Mansky
NIAID
Debbie StoneNHGRI
Karyl BarronNIAID
Paola PintoNHGRI
Patrycja HoffmannNHGRI Bev Barham
NHGRIAnne Jones
NHGRITina Romeo
NHGRIDaniella Schwartz
NIAMS
Additional ContributorsNIH
Manfred Boehm
Hyejeong Bolan
Settara
Chandrasekharappa
Celeste Chen
David Chin
Ed Cowen
Glenn Cruse
Avanti Desai
Robin Eisch
Massimo Gadina
Eric Hanson
Sarfaraz Hasni
Chyia-Chia Lee
Daniel Long
Jonathan Lyons
Josh Milner
International
Ankara – Seza Ozen, Ezgi Batu,
Erkan Demirkaya
Beirut – André Mégarbané
Fanar – Myrna Medlej-Hashim
Genentech – Ingrid Wertz
Istanbul – Ahmet Gül, Burak Erer
Melbourne – Seth Masters
New Haven – Ken Kidd
Andrew Pakstis
Paris – Elaine Chouery
Portland – Cailin Sibley
UCSF – Tony Shum, Andy Gross
Toronto – Ron Laxer
Utrecht – Helen Leavis
Annet van Royen-Kerkof
Yokohama – Yoshi Ishigatsubo
Nobuhisa Mizuki
Yohei Kirino
Jim Mullikin
Ana Olivera
Claudia Ouyang
Sergio Rosenzweig
Colleen Satorius
Linda Scott
Richard Siegel
Masaki Takeuchi
Wanxia Tsai
Dan Yang
Michael Young
Xiaomin Yu
Zhen Yu
Kristien Zaal
Yuan Zhang
14
NIH Clinical Center
kastnerd@mail.nih.govajones@mail.nih.gov, Tina.Romeo@nih.gov, referrals
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