a here is an article from our files describing THE PFS's

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a

BELOW is an article from our file section.

It describes the PFS syndromes.

Hereditary Periodic Fever Syndromes

L. Kastner

Correspondence: Correspondence: Kastner, MD, PhD, National Institute

of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of

Health, Building 10, Room 9N214, Bethesda MD 20892; Phone: (301) 496-8364,

Fax: (301) 402-0012, kastnerd@...

Abstract

The hereditary periodic fevers are a group of Mendelian disorders

characterized by seemingly unprovoked fever and localized inflammation.

Recent data indicate that these illnesses represent inborn errors in the

regulation of innate immunity. Pyrin, the protein mutated in familial

Mediterranean fever, defines an N-terminal domain found in a large family of

proteins involved in inflammation and apoptosis. Through this domain pyrin

may play a role in the regulation of interleukin (IL)-1ß, nuclear factor

(NF)-{kappa}B, and leukocyte apoptosis. Cryopyrin/NALP3, another protein in

this family, is mutated in three other hereditary febrile syndromes and

participates in the inflammasome, a newly recognized macromolecular complex

crucial to IL-1ß activation. Somewhat unexpectedly, mutations in the 55 kDa

receptor for tumor necrosis factor also give rise to a dominantly inherited

periodic fever syndrome, rather than immunodeficiency, a finding that has

stimulated important investigations into both pathogenesis and treatment.

Finally, the discovery of the genetic basis of the hyperimmunoglobulinemia D

with periodic fever syndrome suggests an as yet incompletely understood

connection between the mevalonate pathway and the regulation of cytokine

production. These insights extend our understanding of the regulation of

innate immunity in man, while providing the conceptual basis for the

rational design of targeted therapies, both for the hereditary periodic

fevers themselves and other inflammatory disorders as well.

_____

The hereditary periodic fever syndromes are a group of disorders

characterized by recurrent episodes or, in some cases, fluctuating degrees

of fever and localized inflammation,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R1#R1> 1,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R2#R2> 2

initially described as affecting primarily the serosal and synovial surfaces

and the skin, but now recognized to include a somewhat broader distribution

of affected tissues. The prototypic and probably most common hereditary

periodic fever syndrome is familial Mediterranean fever (FMF). The

hereditary periodic fevers now also include the tumor necrosis factor (TNF)

receptor–associated periodic syndrome (TRAPS), the hyperimmunoglobulinemia D

with periodic fever syndrome (HIDS), and three different clinical disorders

all caused by mutations in CIAS1, which encodes a protein denoted cryopyrin

or NALP3.

The hereditary periodic fevers differ from autoimmune diseases such as

systemic lupus erythematosus and rheumatoid arthritis in that they lack

high-titer autoantibodies or antigen-specific T-cells; they are termed

autoinflammatory diseases (Table 1

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#T1#T1> ) to

highlight this distinction.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R2#R2> 2 A

number of other illnesses have subsequently been included under the

autoinflammatory rubric, including Mendelian disorders such as Blau

syndrome, as well as conditions with a more complex mode of inheritance,

such as Behçet’s disease. Recent advances in the genetics and molecular

biology of the hereditary periodic fever syndromes have defined important

new gene families and pathways in the regulation of innate immunity, thus

substantiating the distinction from autoimmune disorders, which more

directly affect the adaptive immune system. Insights into the pathogenesis

of the hereditary periodic fevers have also catalyzed dramatic advances in

targeted biologic therapies for some of these conditions.

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Table 1. The systemic autoinflammatory diseases, a partial listing.

Familial Mediterranean Fever

FMF is a recessively-inherited disorder typically presenting in childhood or

adolescence with 1- to 3-day episodes of fever often accompanied by severe

abdominal pain, pleurisy, monoarticular arthritis, or an erythematous rash

on the ankle or foot known as erysipeloid erythema (Table 2

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#T2#T2> ). During

attacks there is usually neutrophilia and a brisk acute-phase response, and

histologically there is a massive (sterile) influx of polymorphonuclear

leukocytes into the affected anatomic compartment(s). Between attacks,

patients feel well, although biochemical evidence for inflammation may

persist. Among some FMF patients, systemic amyloidosis develops due to the

deposition of a misfolded fragment of serum amyloid A (SAA), one of the

acute-phase proteins. FMF is most common among individuals of Jewish,

Armenian, Turkish, Arab, and Italian ancestry, but, with the availability of

genetic testing, cases have been documented worldwide. Treatment with daily

oral colchicine markedly reduces the frequency and severity of FMF attacks,

and usually prevents the development of amyloidosis,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R1#R1> 1 and

thus with early diagnosis the prognosis of FMF is good.

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Table 2. Clinical features of the hereditary periodic fever syndromes.

The gene for FMF, MEFV, is located on human chromosome 16p (Table 3

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#T3#T3> ) and was

independently identified by two positional cloning consortia in 1997.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R3#R3> 3,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R4#R4> 4 MEFV is

comprised of 10 exons, spanning approximately 15 kb of genomic DNA. All four

of the initial FMF-associated mutations in MEFV were in exon 10, and even

now, with over 55 mutations having been identified (available at

http://fmf.igh.cnrs.fr/infevers), exon 10 remains the major site of

mutations, with a smaller cluster in exon 2. Nearly all of the known

FMF-associated mutations encode conservative missense changes. This suggests

that the disease phenotype may require some level of residual protein

function and that the episodic nature of FMF may be due to as yet

uncharacterized environmental perturbations of the variant protein. r

frequencies for FMF mutations of 1:3 to 1:5 have been observed in several

Mediterranean and Middle Eastern populations,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R5#R5> 5–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R8#R8> 8 raising

the possibility of heterozygote selection. Intragenic convergence of single

nucleotide polymorphism haplotypes strongly suggests independent ancient

ancestral origins for ethnically diverse modern-day carriers of at least

four different common mutations.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R4#R4> 4,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R9#R9> 9

Although genetic testing may help confirm the diagnosis of FMF, particularly

in countries in which the disease is uncommon, there are substantial numbers

of patients with the clinical picture of FMF who have only one identifiable

mutation, and even some patients with no identifiable mutations in MEFV, and

thus clinical judgment remains important in establishing the diagnosis.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R1#R1> 1

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Table 3. Genetics and pathophysiology of the hereditary periodic fever

syndromes.

Consistent with the biology of FMF, MEFV is expressed predominantly in

granulocytes, monocytes, dendritic cells, and in fibroblasts derived from

skin, peritoneum, and synovium.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R10#R10> 10–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R12#R12> 12 It

encodes a full-length 781 aa protein denoted pyrin or marenostrin. In

transfection experiments full-length pyrin is exclusively cytoplasmic, while

endogenous pyrin is cytoplasmic in monocytes but is predominantly nuclear in

granulocytes, dendritic cells, and synovial fibroblasts.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R12#R12> 12,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R13#R13> 13

Although sui generis at the time pyrin was discovered, the domain encoded by

exon 1 is now recognized as the prototype for a 92 aa motif, the PYRIN

domain, that is found in 20 human proteins involved in the regulation of

inflammation and apoptosis.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R14#R14> 14–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R17#R17> 17 This

motif has a six alpha-helix structure similar to that of death domains,

death effector domains, and caspase-recruitment domains, a configuration

known to mediate homotypic interactions. Through cognate PYRIN-PYRIN

interactions with the bipartite adaptor protein ASC (apoptosis-associated

speck-like protein with a caspase recruitment domain, which is comprised of

an N-terminal PYRIN domain and a C-terminal caspase recruitment domain),

pyrin acts as an upstream regulator of interleukin (IL)-1ß activation.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R18#R18> 18,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R19#R19> 19

Pyrin appears to have both inhibitory and potentiating effects on IL-1ß

production depending on experimental conditions, and thus the role of

wildtype human pyrin in the IL-1 pathway remains controversial. There is

also evidence that pyrin plays a role in regulating nuclear factor

(NF)-{kappa}B activation and apoptosis, at least in part through its

interactions with ASC.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R18#R18> 18–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R22#R22> 22

Perhaps reflecting the relevance of these PYRIN domain–mediated interactions

to the development of autoinflammatory disease, mutations in exon 1 are

extremely rare in FMF.

In contrast, mutations in the C-terminal B30.2/rfp/SPRY domain of pyrin,

encoded by exon 10, predominate in FMF. This motif is found in proteins with

a variety of different functions, and is thought to mediate protein-protein

interactions. Some authors have suggested the possibility that the

B30.2/rfp/SPRY domain of pyrin might be an intracellular domain that binds

pathogens, similar to the leucine-rich repeat domain of cryopyrin/NALP3

(vide infra).

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R19#R19> 19,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R23#R23> 23 This

hypothesis is based on (1) the large number of FMF-associated mutations in

this domain; (2) the evidence for heterozygote selection for exon 10

mutations in Mediterranean populations; (3) data suggesting selection for

specific B30.2/rfp/SPRY sequences in primate evolution;

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R23#R23> 23 and

(4) evidence that the B30.2/rfp/SPRY domain of another protein, TRIM5a,

blocks infection with certain retroviruses, and has undergone positive

selection in primate evolution similar to pyrin.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R24#R24> 24,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R25#R25> 25

Nevertheless, at the time of this writing there is no direct experimental

evidence that the C-terminal domain of pyrin binds pathogen-derived

molecules.

TNF Receptor–Associated Periodic Syndrome

TRAPS is a dominantly-inherited disorder caused by mutations in the 55 kDa

TNF receptor (TNFRSF1A), which is encoded on human chromosome 12p.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R26#R26> 26

Several years before the discovery of these TNF receptor mutations, a

dominantly inherited periodic fever syndrome that later proved to be TRAPS

was described in a family of Irish and ish ancestry whose illness had

been termed familial Hibernian fever. Subsequent studies have demonstrated a

very broad population distribution of patients with periodic fever and TNF

receptor mutations, and hence the more ethnically neutral TRAPS terminology

is usually preferred. To be consistent with the original description of

TRAPS, mutations in the TNFRSF1A gene in the appropriate clinical setting

are required to make the diagnosis, although there remain a number of

patients with TRAPS-like illnesses who do not have identifiable mutations.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R1#R1> 1

As is the case for FMF, TRAPS presents in childhood or adolescence, but in

TRAPS the duration of attacks tends to be more variable, ranging from short

episodes of one to two days to flares lasting weeks at a time and, in some

cases, patients experience nearly continuous, fluctuating symptoms. In

addition to fever, common clinical features of TRAPS include abdominal pain

(due to sterile peritonitis), pleurisy, periorbital edema, a migratory

erythematous skin rash with underlying myalgia, arthralgia or frank

arthritis, and scrotal pain. Marked leukocytosis and elevation of

acute-phase reactants is usually seen during attacks, and often persists

into the intercritical period. Systemic amyloidosis may occur in up to 10%

of patients, with an increased risk observed in patients with mutations

involving cysteine residues.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R27#R27> 27

Although the attacks of TRAPS can often be debilitating, amyloidosis appears

to be the major factor limiting longevity.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R1#R1> 1

The p55 TNF receptor protein is 455 aa in length, including a 29 aa leader,

a 182 aa extracellular domain, a 21 aa transmembrane domain, and a 223 aa

intracellular region that includes a death domain. The extracellular domain

is, in turn, divided into four cysteine-rich subdomains, each of which

contains three disulfide-bonded pairs of cysteines that constrain the

three-dimensional folding of the protein. To date all of the over 45 known

TRAPS mutations (http://fmf.igh.cnrs.fr/infevers) reside in the

extracellular domain of the protein, and most are in the first two

cysteine-rich subdomains, with about half being missense substitutions at

cysteine residues that disrupt normal disulfide bonding. To date no patients

have been identified with mutations in the transmembrane or intracellular

domains, with null mutations, or with mutations in the p75 TNF receptor,

which is encoded on chromosome 1p.

The pathophysiology of TRAPS is complex. Initial studies of a family with

the C52F TNFRSF1A mutation indicated a defect in activation-induced

ectodomain shedding of p55 (but not p75) receptors.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R26#R26> 26

Since receptor shedding is thought to play a homeostatic role both by

limiting available cell surface TNF receptors and by creating a pool of

potentially antagonistic soluble receptors, it was attractive to hypothesize

that the " shedding defect " observed in TRAPS patients might explain their

autoinflammatory phenotype. Subsequent studies indicate that, while

plausible, this hypothesis cannot fully explain the TRAPS phenotype, since

the shedding defect is seen in patients with some, but not all, p55

mutations.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R26#R26> 26–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R29#R29> 29

Moreover, recent studies indicate a number of other functional abnormalities

in mutant p55 receptors, including altered intracellular trafficking,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R30#R30> 30

impaired TNF binding,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R30#R30> 30 and

a defect in TNF-induced leukocyte apoptosis.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R31#R31> 31

Patients with TRAPS generally do not respond to treatment with colchicine,

which is highly effective in FMF, and, although they are responsive to

high-dose corticosteroids, side effects are often limiting. The recognition

of the role of the TNF-pathway has led to the introduction of etanercept,

the soluble p75 TNFR:Fc fusion protein, in the treatment of TRAPS.

Etanercept is effective in reducing, although usually not totally

eliminating, clinical and laboratory evidence of inflammation in TRAPS,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R32#R32> 32–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R34#R34> 34 a

result that is consistent with a role for both TNF-dependent and

-independent pathways in the pathogenesis of TRAPS.

Hyperimmunoglobulinemia D with Periodic Fever Syndrome

HIDS is a recessively inherited periodic fever syndrome first described in

the Netherlands and still diagnosed most often in Northern Europeans.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R35#R35> 35

Attacks often begin during the first year of life, lasting 3–7 days, and are

sometimes triggered by childhood immunizations. Concomitant findings may

include headache, abdominal pain, prominent cervical lymphadenopathy,

polyarthralgia or polyarticular arthritis, diffuse maculopapular rash, and

aphthous ulcerations.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R36#R36> 36 As

in FMF and TRAPS, HIDS attacks are accompanied by leukocytosis and elevated

acute-phase reactants. Serum polyclonal IgD levels are also elevated in most

HIDS patients, regardless of whether they are experiencing an attack, but do

not correlate with disease severity, either over time for any given patient

or when comparing patients. Increased serum IgD levels have also been

observed in the minority of patients with FMF

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R37#R37> 37 and

TRAPS, <http://www.asheducationbook.org/cgi/content/full/2005/1/74#R38#R38>

38, <http://www.asheducationbook.org/cgi/content/full/2005/1/74#R39#R39> 39

but the magnitude is usually much less in these latter two conditions. In

contrast with FMF or TRAPS, systemic amyloidosis is extremely rare in HIDS,

although it has been reported.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R40#R40> 40

In 1999 two groups, using complementing positional and functional

approaches, identified HIDS-associated mutations in MVK, an eleven-exon gene

on chromosome 12q that encodes the mevalonate kinase (MK) enzyme.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R41#R41> 41,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R42#R42> 42 MK

catalyzes the conversion of mevalonic acid to 5-phospho-mevalonic acid in

the synthesis of a number of important molecules, including cholesterol,

vitamin D, bile acids, steroid hormones, and nonsterol isoprenoids.

HIDS-associated mutations leave some residual enzymatic activity, while more

profound mutations in MVK that totally ablate enzymatic activity cause

mevalonic aciduria, a rare condition manifesting not only periodic fevers

but also a number of other severe developmental abnormalities. Currently

over 35 HIDS-associated mutations have been described

(http://fmf.igh.cnrs.fr/infevers), and they are distributed throughout the

396 aa MK protein. The mutations associated with mevalonic aciduria cluster

around the active sites of the enzyme.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R43#R43> 43,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R44#R44> 44

Recognition of the molecular genetic basis of HIDS permits the use of

genetic testing and/or screening for urinary mevalonate (during attacks) to

help establish the diagnosis. This is especially helpful in the minority of

patients with borderline or normal serum IgD levels.

In vitro studies suggest that HIDS-mutant MK functions best at 30°C, with

progressive decreases in function at 37°C and 39°C.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R45#R45> 45 This

observation may account for the association of HIDS attacks with

immunizations and infections, and may also explain the increased urinary

mevalonate levels observed during HIDS attacks. It is unlikely that IgD

plays a primary role in the pathogenesis of HIDS, given the poor correlation

of IgD levels with disease severity, and the identification of occasional

patients with the HIDS phenotype and MVK mutations but persistently normal

IgD levels.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R42#R42> 42,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R46#R46> 46,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R47#R47> 47

Diminished cholesterol biosynthesis also appears an unlikely mechanism of

disease, since HIDS patients generally have low-normal serum cholesterol

levels, and more severe disorders of cholesterol synthesis do not exhibit a

HIDS-like phenotype. Instead, current thinking on the pathogenesis of HIDS

focuses either on the accumulation of mevalonic acid or the shortage of

isoprenoids. Favoring the latter hypothesis are in vitro data demonstrating

accentuated IL-1ß secretion by leukocytes from HIDS patients that can be

reversed by the addition of farnesol or geranyl-geraniol.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R48#R48> 48

Possibly, the small guanoside triphosphate-binding proteins, which undergo

farnesylation or geranylation, may be the link between the mevalonate

pathway and the innate immune system.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R47#R47> 47

There are currently no established therapies for HIDS, although TNF

inhibition and statins are investigational.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R1#R1> 1

The Cryopyrinopathies

The cryopryinopathies are a spectrum of clinical disorders caused by

mutations in CIAS1,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R49#R49> 49–

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R52#R52> 52 a

nine-exon gene on chromosome 1q encoding a protein that has variously been

denoted cryopyrin, NALP3, PYPAF1, or CATERPILLER 1.1. Although a number of

overlap syndromes have been described, three relatively distinct clinical

disorders are recognized: familial cold autoinflammatory syndrome (FCAS),

Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory

disease (NOMID, also known as chronic infantile neurologic cutaneous and

arthropathy [CINCA] syndrome). An urticaria-like rash is common to all of

the cryopyrinopathies and is characterized histologically by infiltrates of

lymphocytes and neutrophils rather than mast cells, indicating that it is

not true urticaria. FCAS is characterized by episodes of fever,

urticaria-like rash, and polyarthralgia, usually precipitated by generalized

exposure to the cold and lasting about 12 hours. In MWS, attacks are not

usually precipitated by cold exposure but include the same urticaria-like

rash as well as fever, malaise, limb pain, and, at times, abdominal pain,

conjunctivitis, and arthralgia. Sensorineural hearing loss and/or systemic

AA amyloidosis may also develop. Patients with NOMID/CINCA, the most severe

of the cryopyrinopathies, often exhibit nearly continuous disease activity

that fluctuates in severity. In addition to the fevers, arthralgia, hearing

loss, and amyloidosis seen in MWS, patients with NOMID/CINCA often develop a

deforming arthropathy and central nervous system involvement that can

include chronic aseptic meningitis, intellectual impairment, and loss of

vision. Eosinophilia or coagulopathy can also be seen in some patients with

NOMID/CINCA.

The full-length cryopyrin/NALP3 protein is 920 aa in length, and consists of

three major domains: an N-terminal PYRIN domain (aa 13–83) similar to the

N-terminal domain of pyrin, a central NACHT domain (aa 217–513) that appears

to be important both in intra- and inter-molecular interactions, and a

C-terminal tandem array of 7 leucine rich repeats (LRR, aa 697–920). Nearly

all of the more than 40 known mutations in cryopyrin

(http://fmf.igh.cnrs.fr/infevers) are missense substitutions in the NACHT

domain, encoded by exon 3 of CIAS1.

Cryopyrin/NALP3 has been shown to play an important role in the regulation

of IL-1ß activation through its participation in a macromolecular complex

denoted the NALP3 inflammasome (Figure 1

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#F1#F1> ).

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R53#R53> 53 In

addition to cryopyrin/NALP3, this complex includes ASC, caspase-1 (which

cleaves pro-IL-1ß to produce biologically active IL-1ß), and Cardinal, a

caspase-recruitment domain-containing protein. The NALP3 inflammasome is a

potent activator of IL-1ß, and macrophages from patients with MWS

spontaneously secrete active IL-1ß. Through its LRR, cryopyrin/NALP3 binds

muramyl dipeptide,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R54#R54> 54 a

component of the bacterial cell wall, an event that increases inflammasome

activity. Moreover, this process appears to be accentuated in the

macrophages of patients with MWS.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74/F1>

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<http://www.asheducationbook.org/cgi/content-nw/full/2005/1/74/F1>

Figure 1. Activation of interleukin (IL)-1ß through the cryopyrin/NALP3

inflammasome. On the lower left, the major domain structure of cryopyrin is

depicted. Interaction of cryopyrin with muramyl dipeptide (MDP) is thought

to activate cryopyrin and allow it to interact with the other components of

the inflammasome. In the upper left, activated cryopyrin binds ASC through

cognate PYRIN-PYRIN domain interactions. ASC, in turn, binds caspase-1

through homotypic interactions of their caspase recruitment (CARD) domains

(upper right). This complex then binds Cardinal, which has recruited a

second caspase-1 molecule. The full assembly of this macromolecular complex,

the inflammasome, induces proximity of the catalytic domains of the two

caspase-1 molecules, leading to autocatalysis. The released catalytic

domains are then available to activate pro-IL-1ß to its biologically active

form, which mediates fever and inflammation. Abbreviations: PYD, PYRIN

domain; NACHT, the nucleotide-binding domain of cryopyrin; LRR, leucine-rich

repeat; FIIND, a domain of Cardinal that interacts with cryopyrin; CARD,

caspase-recruitment domain.

The newly recognized role of cryopyrin/NALP3 in IL-1ß activation has

provided the conceptual basis for a series of studies establishing an

important role for IL-1ß inhibition in the cryopryinopathies. In one

protocol, pretreatment with the IL-1ß receptor antagonist anakinra

effectively prevented clinical symptoms or acute-phase elevations in

patients with FCAS exposed to cold temperatures.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R55#R55> 55

Anakinra also induced a complete remission of clinical symptoms and

biochemical changes in MWS.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R56#R56> 56,

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R57#R57> 57 Most

recently, in a series of 18 patients with NOMID/CINCA, anakinra doses of 1–2

mg/kg/d resulted in a resolution of uveitis, rash, and fever and a

significant decline in cerebrospinal fluid pressure.

<http://www.asheducationbook.org/cgi/content/full/2005/1/74#R58#R58> 58

These results will not only dramatically improve the quality of life and

prognosis of patients with a potentially devastating disease, but will

provide powerful support for a model that places cryopyrin/NALP3 at a

critical juncture in the regulation of IL-1ß activation.

Footnotes

From the Genetics and Genomics Branch, National Institute of Arthritis and

Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda,

MD