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Hereditary Periodic Fever Syndromes A group of inherited disorders characterized by recurrent, self-limited episodes of fever and synovial, serosal, and/or oculocutaneous inflammation. 169 Claudius Galen 1790 Heberden 1895 Osler 1908 Janeway & Mosenthal 1940 Kile & Rusk 1945 Siegal 1949 Reimann 1958 Heller 1962 Muckle & Wells 1981 Prieur, Griscelli 1982 Williamson et al 1984 van der Meer et al
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Differential Diagnosis of Periodic Fevers
FMF HIDS TRAPS (FHF) MWS/FCU/CINCAGenetics MEFV MVK TNFRSF1A CIAS1/NALP3 (16p13) (12q24) (12p13) (1q44) Protein Pyrin/Mnstrn Mevalonate TNF receptor 1 NALP3/
kinase cryoppyrin Onset < 20 Childhood May remit/ 95% <5 years
relapse
Fever Abrupt Fast on, Variable, 24 hours on + off slow off less in adults
Duration 1- 4 days 3 - 7 days Up to weeks 1- 2 days
Nodes Rare Cervical Common No nodes ++
Rash Rare; legs 90%(pleiomorphic) All over (erysipelas) Maculo-papular
Oedema Very rare No Peri-orbital No
Amyloid Common None 25% 25%
Therapy Colchicine Etanercept? Etanercept Anakinra
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CARD
CARDPyrin
Pyrin
ASC can act as a Link between Pyrin and Apoptotic pathways
PYRIN
ASC
NALP1
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Amyloidosis of the kidney
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A heterogenous group of inherited disorders characterised by spontaneous attacks of systemic inflammation without apparent autoimmune basis
• No demonstrable source of infection as precipitating cause
• Absence of high-titre autoantibodies and antigen specific autoreactive T cells
• No evidence of auto-antigenic exposure
Autoinflammatory Syndromes
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Autoinflammatory Syndromes and related disorders
Hereditary periodic fevers
Gene/chromosome Protein FMF MEFV (16p13) Pyrin/marenostrin HIDS MVK (12q24) Mevalonate kinase TRAPS (FHF) TNFRSF1A (12p13) TNF Receptor 1 FCU/FCAS NALP3/CIAS1/PYPAF1 (1q44) NALP3/Cryopyrin/PYPAF1 MWS/FCAS NALP3/CIAS1/PYPAF1 (1q44) NALP3/Cryopyrin/PYPAF1 CINCA/NOMID NALP3/CIAS1/PYPAF1 (1q44) NALP3/Cryopyrin/PYPAF1 PAPA PSTPIP1/CD2BP1 (15q24) CD2-binding protein 1
Granulomatous disorders
Crohn’s (IBD) NOD2 (16q12) Nucleotide binding oligomerization domain
Blau Snydrome NOD2 (16q12) Nucleotide binding oligomerization domain
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sTNF/sTNFR
mTNFRSF1A(mTNFR1)
Disulphide bondsDisulphide bonds
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TNFRSF1A
DD
trimerise
DD
DD
DD
DD
DD
DD
RIP
1
TRADD
DD
TR
AF
2
DD
RIP
1
TRADD
DD
TR
AF
2Complex I
NF-Bactivation
DD
DD
DDModification/
dissociation
DD
RIP
1
TRADD
DD
TR
AF
2
DD
RIP
1
TRADD
DD
TR
AF
2
Recruitment of FADD and caspase-8/10
Complex II
Apoptosis
DISC
FADD
DD
TR
AD
D
DD
DD
TR
AD
D
DDTRAF2
TRAF2
RIP1
RIP1DDDED
DDDEDCASP-8/10
TNF
c-FLIP
Micheau et al. Cell 114, 1810190, 2003Micheau et al. Cell 114, 1810190, 2003
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Two views of the six helical Death Domain-FoldMotifs
Death domains
Caspase activation and recruitment domains (CARDs)
Pyrin domains
Adaptor domain architecture important in homotypic protein- protein interactions
Protein Science 10:1911, 2001
Death effector domains
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The conserved pyrin domain defines a family of apoptotic/inflammatory proteins
CARDCARD
B SPRY
ASC/CARD5
NACHTNACHT
NACHTNACHT LRRLRR
NACHTNACHTPYD??????
B30.2B30.2
NALP3/CIAS1/PYPAF1
LRRLRR
NOD2/CARD15
PYD
NALP1/ CARD7
PYD
PYD
PYRIN/MARENOSTRIN
LRRLRR
CARDCARD
CARDCARD CARDCARD
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PYD is a flexibly disordered loop instead of 3 (NALP1)
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MRI showing fronto-parietal subcortical lesions in TRAPS patientMRI showing fronto-parietal subcortical lesions in TRAPS patient
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FAMILY A
I
1
1
1 2
2
2
3
3
3
4
4
4 65
5 7
7
8
8
9
9
10
10
11 12 13
A BC
D
FAMILY B
IV
I
possibly affected.
FAMILY C
affected.
III
II
I
II
III
IV
I
III
II
IV
Familial Hibernian Fever families
6
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Location and genomic structure of TNFRSF1A gene- chromosome 12p13
Exons 1 2 3 4 5 6 7 8 9 10
Signal Peptide Extracellular Transmembrane Intracellular
3’UTR
ptercen
C1 S/R TNFRSF1ACD4 CD9 VWFDRPLA
0.09 0.02 0.002 0.12
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DNA Sequence Electropherograms Showing Disease-Associated TNFRSF1A MutationsDNA Sequence Electropherograms Showing Disease-Associated TNFRSF1A Mutations
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Missense Mutations in the TNFRSF1A Extracellular Domains
Mutation Exon Amino Acid Ethnic Background
175 TC 2 Cys30Arg Irish
185 GA 2 Cys33Tyr Irish/Scottish
236 CT 3 Thr50Met Irish
French-Canadian
242 GT 3 Cys52Phe Irish/English/German
349 TC 4 Cys88Arg Scottish (Australian)
350 GA 4 Cys88Tyr Finnish
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2) constitutive activation, formation of intermolecular disulfide bonds between unpaired cysteines in mutant receptors (Santoro, 1995) -Il-6 induction - crude test - normal
3) resistance of mutant TNFRSF1A to the normal homeostatic effects of activation-induced cleavage
.
- FACS analysis - reduced/delayed TNFRSF1A shedding in affected members of family with C52F mutation
1) increased affinity of mutant TNFRSF1A for ligand (i.e TNF) -binding and affinity studies - normal
.
Possible Disease Mechanisms in TRAPS
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Periodic fever family with amyloidosis of kidney
affected
unaffected
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TNF Receptors on Leukocytes from Patients with the C52F MutationTNF Receptors on Leukocytes from Patients with the C52F Mutation
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Leukocytes Bearing the C52F Mutation Have Defective Clearance of TNFRSF1A (CD120a)Leukocytes Bearing the C52F Mutation Have Defective Clearance of TNFRSF1A (CD120a)
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“TRAPS”
TNF Receptor-Associated Periodic Syndrome
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IL-1
Haem A Ubiquinone
Endothelial cellICAM1, ELAM
Lymph node organogenesis
TNF
Acute phase response (Il-6, SAA, CRP)
Overproduction Septic shock
Hepatic failure Vasculitis Encephalitis Cardiac cachexia
Dolichol
HypothalmusFever/Sleep
T cell activation Il-6
B cell activation
Ig production
Cellular activation
(Cardiac, hepatic, bone, etc)matrix metalloproteinase (stromelysin), plasmin and collagenase production
Breaches anti-protease barrier
TISSUE DESTRUCTION
Virus/endothelium
Macrophage activation
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IK K
IK K
NE MO
S ignal osome
m TNF TACE
SODD
MAP kinase
NF B tr anscri ption
Su rvi val - Anti -apo ptot ic
pr otein s
FADD
TRADD
CASPASE-8 RA IDD
RIP
FLIP
sTNF /
sTNF R
?Shedd ase
NFkB
TRAF2RIP
TRADD
S ign al pr eventi on
sTNF /
sTNF R
TNF RSF 1A
(TN FR 1)
BID/BI M
Bax Bak
BA X
Bcl2 Bclx
Cytochrome c release, Apaf1 activation of downstream caspases e.g 3, 6 and 7
***Death - apoptosis
Extrinsic death receptors
Intrinsic Plasma membraneEndoplasmic reticulum
CytosolNucleus
Anti-apoptotic Bcl2, Bclxl, Bclw, Mcl1
Pro-apoptotic (multi-domain) Bax, Bakl, Bok/Mtd
Pro-apoptotic (BH3 domain only)Bid, Bad, Blk, Bim/Bod, Nix, Noxa
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SCREENING METHODS for TRAPSSCREENING METHODS for TRAPS Genotyping: microsatellites within (TNFRp55)
and flanking (D12S99 and D12S77)TNFRSF1A locus used to genotype family members.
DHPLC: we screened 20 ADRF families and 184 sporadic cases forTNFRSF1A mutations using the Transgenomic WAVE® System.
Sequencing: ABI 373A sequencer.
ELISA assays: used to determine serum levels of TNFRSF1A and TNFRSF1B (sTNFRSF1A and sTNFRSF1B).
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DHPLC elution profileDHPLC elution profile
0.0
1.5
3.0
. 1. 2. 3. 4. 5. 6. 7. 8. 9.
Time (min)
0.0
2.5
. 1. 2. 3. 4. 5. 6. 7. 8. 9.
Time (min)
Wt C70R
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a b05 0903 0708 13
MARKERSD12S99TNFRp55D12S77
a d05 0403 0708 12
a d05 0403 0708 12
c d04 0407 0708 12
a c05 0403 0708 08
21
3
831
875 326
Israeli Arab family A
612
1114
Periodic fever
C70R M 1 2 3 4 5 C
500
800
Not genotyped
4 5
De-novo C70R mutation (Israeli Arab family)
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II
IV
III
I
c d04 04A A06 0606 11
e f04 08G G02 0211 12
a e04 04G G02 0205 11
a e/f04 04G G02 0205 12*
d g04 06-- --06 0111 10
d b04 04A A06 0711 11
c j04 01A A06 0706 11
c j04 01A A06 0706 11
826 731
g h 04 04 G A 06 01 06 03
a c04 04G A02 0605 06
Order of markers D12S99 +36 A/G TNFRp55 D12S77
Irish Family
727
781 11401450
1450
650
650
Soluble TNFRSF1A levels n= 746-1966pg/ml
Periodic fever in an Irish Family - unlinked to all known HPF loci
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7 8 9 10 11 12 13 14 S2
sTN
FR
SF
1A
(p
g/m
l)
s TNFRSF1A levels in affected family members of
(A) TRAPS (B) families without mutation s TNFRSF1A levels in affected family members of
(A) TRAPS (B) families without mutation
(A)
(B)
746
1966
746
1966
unaffected
Periodic fever
Probably affected
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A total of 8 novel TNFRSF1A mutations (T37I, D42, G46E, T50K, F60L,C70R, C70S and R92P), and 5 known (c.193-14 G>A, P46L, T50M, C88R,
and R92Q) mutations in a study of 20 families. The C70S mutation found in a Japanese patient
Affected members in 4 of the 7 families without TNFRSF1A mutations have low sTNFRSF1A
These findings indicate the presence of genetic heterogeneity in ADRFs.
Summary of TRAPS and ADRF families
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Etanercept (a recombinant p75 TNFR:Fc fusion protein), in TRAPS: the Promise of Molecular MedicineEtanercept (a recombinant p75 TNFR:Fc fusion protein), in TRAPS: the Promise of Molecular Medicine
Patient 3 (14yo, M, H22Y)
0
10
20
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 3 (14yo, M, H22Y)
0
10
20
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 4 (32yo, M, T50M)
0
20
40
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 4 (32yo, M, T50M)
0
20
40
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 2 (15yo, F, T50M)
0
30
60
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 2 (15yo, F, T50M)
0
30
60
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 1 (50yo, M, T50M)
0
25
50
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
Patient 1 (50yo, M, T50M)
0
25
50
Q1 Q2 Q3 Q4
Study Phase
Att
ack
Sco
re
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Apoptosis -
A type of programmed cell death in which the cell dies (commits suicide) through a series of cellular events including enzymatic fragmentation of DNA.
# necrosis - cells bursts and discharges contents. e.g. infarction
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Pyrin/marenostin is mainly expressed in leucocytesPyrin/marenostin is mainly expressed in leucocytes
Cell 90; 797, 1997
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Pyrin Interaction with ASC proteinPyrin Interaction with ASC protein
Apoptosis-Associated speck-like protein with a caspase recruitment domain(CARD)
Interacts with pyrintwo-hybrid, IP, andfluorescence microscopy
Aggregates during Apoptosis in HL-60 cells
Proapoptotic
Interacts with pyrin by yeasttwo-hybrid, IP, andfluorescence microscopy
Proapoptotic
N-terminal pyrin domain, C- terminal CARD
GFP-pyrin + ASC-myc(Cy3 label) merged
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Monocytes from Pyrin Truncation MiceManifest a Defect in ApoptosisMonocytes from Pyrin Truncation MiceManifest a Defect in Apoptosis
24 hr 48 hr 72 hr
+/+ -/- +/+ -/- +/+ -/-
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Connecting Pathways with Patients: Mutations in a Pyrin-Binding Protein Cause PAPA Syndrome
*
E250Q
Pyrin
B CC B30.2Pyrin domain
1 781
CC SH31 415
PSTPIP1/CD2P1
*A230T
PAPA Syndrome: Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne
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Autosomal dominant disorders of unknown cause, variably associated with arthralgias, rashes and conjunctivitis
FCAS (also Familial cold urticaria (FCU)
cold induced fever (24-hour) and rash
Muckle-Wells syndrome (MWS)
sensorineural deafness, amyloidosis
Familial cold autoinflammatory Syndrome (FCAS)/Muckle Wells
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North-Indian familyNorth-Indian family
periodic fever with amyloidosis periodic fever without amyloidosis
a c01 0804 0103 0101 0101 0402 0403 04
d b01 0801 0211 0602 0801 0104 0102 02
e f 01 0802 0100 0001 0501 0403 0504 02
I
II
III
d b01 0101 0211 0602 0801 0104 0102 02
a d01 0104 0103 1101 0201 01-- --03 02
d b01 0104 0211 0602 0801 0104 0102 02
c b01 0801 0401 0601 0804 0104 0104 02
b n01 0901 0406 0308 0201 0101 0302 03
b m01 0901 0106 0408 0201 0101 0202 03
d l01 0804 0211 1102 0201 0104 0502 02
a k01 0104 0203 0201 0501 0102 0103 04
b i-- --02 0106 1108 0501 0401 0502 02
b j01 0102 0206 1108 0701 0101 0602 02
c f08 0804 0101 0601 0504 0104 0304 04
d h01 0101 0111 0202 0201 0104 0202 02
c g 01 01 01 04 01 01 01 02 04 04 04 04 04 02
a c08 0104 0403 0101 0101 0402 0403 04
a d01 0104 0403 1101 0201 0102 0403 02
c p 01 01 04 02 01 03 01 07 04 04 04 06 04 02
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The conserved pyrin domain defines a family of apoptotic/inflammatory proteins
CARDCARD
B SPRY
ASC/CARD5
NACHTNACHT
NACHTNACHT LRRLRR
NACHTNACHTPYD??????
B30.2B30.2
NALP3/CIAS1
LRRLRR
NOD2/CARD15
PYD
NALP1/ CARD7
PYD
PYD
PYRIN/MARENOSTRIN
LRRLRR
CARDCARD
CARDCARD CARDCARD
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periodic fever with amyloidosis
periodic fever without amyloidosis
I
II
III
M 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
2 6
11
1083 4 5
2019181715141312 16
97
1
4 51
7
3 6
8
2
M 1 2 3 4 5 6 7 8
I
I I
III
IV
A
B
Cold sensitivity/periodic fever without amyloidosis
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NACHT
V198MV198M
Q306LQ306L
D303ND303N
A352VA352V
A439TA439T
E627GE627G
R260WR260W
A439VA439V
G569RG569R
F573SF573S
FCU/FCAS mutations Mutations found in more than one disease
CINCA mutationsMWS mutations
L305PL305P
F309SF309S
H358RH358R
T436NT436N
M662TM662T
LRRPYRIN
T348MT348M V351MV351M
A374NA374N
F523LF523L
Y570CY570C
Motif III, Motif III, MgMg++
L264HL264H
L353PL353P
R488KR488K
NALP3/CIAS1/PYPAF1 mutations MWS,FCU/FCAS, CINCA/NOMIDNALP3/CIAS1/PYPAF1 mutations MWS,FCU/FCAS, CINCA/NOMID
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CARD
CARD P20 P10
ASC
IL-1-processing
NF-kB modulationInflammation with Fever
Caspase-1
Pyrin
Cryopyrin/NALP3Pyrin/marenostrin
PYDB box
CCB30.2
Apoptosis
LRR
PYD
NACHT
PYD
The assembly of cryopyrin/NALP3/PYPAF1 and pyrin/marenostrin with ASCThe assembly of cryopyrin/NALP3/PYPAF1 and pyrin/marenostrin with ASC
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IL-1 receptor antagonist (Kineret) therapy in FCU patient (100 mg daily subcutaneously)IL-1 receptor antagonist (Kineret) therapy in FCU patient (100 mg daily subcutaneously)
North Indian Patient
Mar01 Jan02 Dec02
1
10
100
1000
Seru
m S
AA
mg
/l
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Mechanisms - related to NFkB activation and ?defective apoptosis in FMF, TRAPS and MWS. HIDS?.
Proinflammatory polymorphisms TNFRSF1A - P46L, R92Q. NALP3 - V198M (V200M)
MEFV - E148Q (amyloidosis)
Modifier Genes e.g MICA in FMF susceptibility Behçets increases penetrance MEFV mutations.
SAA1a/a in FMF patients with amyloidosis.
Polygenic nature of all “Mendelian diseases”?
Genetic heterogeneity and reduced penetrance.
Developing Concepts
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Acetyl CoA
Acetyl CoA + Acetoacetyl CoA
HMG CoA
Mevalonate
Mevalonate-P
Mevalonate-PP
Isopentenyl-PP Isopentenyl-Adenine
Geranyl-PP
Farnesyl-PP
Squalene
Cholesterol
Plasma LDL
Dolichol
Haem A Ubiquinone
Farnesylated Proteins (Ras, lamin B, etc
Vitamin D
Bile Acids
Steroid Hormones
Lipoproteins LDL receptor
kinase Defect in HIDS
reductase
synthase Cholesterol Metabolism and Isoprenoid Biosynthesis
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Exon: 1 2 3 4 5 6 7 8 9 10 11
Organisation of the MVK gene and location of mutations leading to the HIDS/MA phenotype
= 2bp deletion
= Nonsense mutation
= Mevalonic Aciduria
= HIDS
= Mevalonic Aciduria
= Missense mutation