Cryopyrin-associated periodic syndromes (CAPS)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Inflammasome

The inflammasome is a multiprotein complex consisting of:

- caspase 1, an enzyme that proteolytically cleaves other proteins
- PYCARD, PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase-recruitment domain (CARD), a death domain-fold superfamily that mediates assembly of large signaling complexes
- NALP, Nod-like receptor(NLR)

The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly.

The inflammasome is a multiprotein complex that is responsible for the activation of caspases 1 and 5, leading to the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18.

Two types of inflammasome have been identified to date:

- the NALP1 inflammasome, composed of NALP1, the adaptor protein ASC, caspase 1 and caspase 5
- the NALP2/3 inflammasomes that contain, in addition to NALP2 or NALP3, the caspase recruitment domain (CARD)-containing protein Cardinal, ASC and caspase 1

The NALPs are the central proteins and chief platforms in the inflammasome complex. NALPs belong to the NLR (NACHT-LRR) family of cytoplasmic proteins that also includes the NOD proteins. Fourteen NALP proteins have been identified in humans.

The amino-terminal sequence of NALPs is characterized by the presence of a pyrin domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD) and several leucine-rich repeats (LRRs).

NLRs (NACHT-LRRs) are cytoplasmic molecules that serve as intracellular sensors of bacterial infection. They initiate signaling cascades that activate inflammatory responses. NLRs are receptors for PAMPs similar to TLRs.

Subsets of the NLRs:
- Nods (Nucleotide-binding oligomerization domain)
- NALPs (NACHT-, LRR- and pyrin domain-containing proteins)

Three NLRs, including Nod1, Nod2, and NALP3, recognize peptidoglycan, a common component of bacterial cell wall.

Caspase activation and recruitment domain (CARD)-containing proteins

CARDs cytoplasmic receptors that bind viral RNA. CARDs include retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5).

CARDs activate the IRF-3 and NF-κB transcription factors, which stimulate the expression of antiviral type I interferons.

Homozygous mutations in the CARD9 gene are associated with chronic mucocutaneous candidiasis. Dysfunction of CARD9 impairs the innate signaling of dectin-1, an antifungal pattern-recognition receptor (NEJM, 10/2009).

Cryopyrin

Cryopyrin is a protein involved in innate immunity as part of the multiprotein inflammasome. It belongs to a family of NLR (nucleotide-binding domain and leucine-rich-repeat containing) proteins that respond to intracellular pathogens and other danger signals.

The pyrin domain was first noted in the familial Mediterranean fever protein from which it takes its name. It belongs to a structural superfamily that includes death domains, death effector domains and caspase activation and recruitment domains.

Cryopyrin-associated periodic syndromes (CAPS)

Cryopyrin-associated periodic syndromes (CAPS) or cryopyrinopathies include:

- familial cold autoinflammatory syndrome (FCAS)
- Muckle-Wells syndrome (MWS), also known as urticaria-deafness-amyloidosis (UDA)
- neonatal onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic cutaneous and articular syndrome, or (CINCA)

Mnemonic for CAPS - FUN:

FCAS
Urticaria-deafness-amyloidosis (UDA), Muckle-Wells syndrome (MWS)
NOMID/CINCA

Spectrum of CAPS

<-- Mild --------- Severe-->
FCAS, UDA/MWS, NOMID

All 3 CAPS are autosomal dominant.

All three cryopyrinopathies arise from mutations in a single gene, NLRP3 (also called CIAS1) at chromosome 1q44 (long arm of chromosome 1), encoding a protein called cryopyrin (also known as NALP3 and PYPAF1). The mode of inheritance is autosomal dominant with variable penetrance.

CIAS1 encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif.

CIAS1 stands for cold induced autoinflammatory syndrome 1. The gene product cryopyrin is also known under the names CATERPILLER-like receptor 1.1 (CLR1.1), NALP3, and NOD-like receptor family, pryin domain containing 3 (NLRP3).

Dysregulation of leukocyte apoptosis may be a common molecular pathway leading to inflammatory disease.

Hereditary periodic-fever syndromes or cryopyrin-associated periodic syndromes (CAPS) affect fewer than 500 patients worldwide.

Familial cold autoinflammatory syndrome (FCAS)

Familial cold urticaria (also known as "familial cold autoinflammatory syndrome") is an autosomal dominant condition characterized by rash, conjunctivitis, and arthralgias elicited by exposure to cold.

Muckle-Wells syndrome

Muckle-Wells syndrome (MWS), also known as urticaria-deafness-amyloidosis (UDA), is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis. MWS was first described in 1962 by Thomas James Muckle and Michael Vernon Well.

Individuals with MWS often have episodic fever, chills, and painful joints. As a result, MWS is considered a type of periodic fever syndrome. MWS is caused by a defect in the CIAS1 gene which creates the protein cryopyrin. MWS is closely related to two other syndromes, familial cold urticaria and neonatal onset multisystem inflammatory disease — in fact, all three are related to mutations in the same gene, CIAS1.

Neonatal onset multisystem inflammatory disease (NOMID)

Neonatal Onset Multisystem Inflammatory Disease (also known as NOMID, chronic infantile neurologic cutaneous and articular syndrome, or CINCA) is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Urticaria-like rash within the first 6 weeks of life. CNS manifestations include chronic aseptic meningitis, mental retardation, cerebral atrophy, and chronic papilledema.

NOMID can result from a mutation in the CIAS1 gene, which helps control inflammation. Mutations in this gene also cause familial cold urticaria and Muckle-Wells syndrome. NOMID has been successfully treated with an interleukin-1 (IL-1) receptor antagonist, anakinra.

The symptoms of NOMID begin before age 3 months, in almost all children that have NOMID.

Treatment of CAPS

Anakinra (IL-1RA) is an IL-1 receptor antagonist that inhibits IL-1. Recombinant IL-1Ra or Anakinra (Kineret) is available commercially to treat systemic juvenile rheumatoid arthritis (JRA). Live vaccines should not be given concurrently with Anakinra.

Canakinumab is a human anti–interleukin-1β monoclonal antibody. Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS.

Rilonacept (Arcalyst), is a dimeric fusion protein. IL-1 Trap or Rilonacept (Arcalyst) is used for management of cryopyrin-associated periodic syndromes (CAPS). Patients must me evaluated for latent TB before initiating therapy. Live vaccines should not be given concurrently. Taking rilonacept with TNF inhibitors is not recommended and may increase the risk of serious infections.

References

Autoinflammatory syndromes: Fever is not always a sign of infection - CCJM http://goo.gl/uTc2X
Primer: inflammasomes and interleukin 1 in inflammatory disorders. Leigh D Church, Graham P Cook and Michael F McDermott. Nature Clinical Practice Rheumatology (2008) 4, 34-42.
The Inflammasome — A Linebacker of Innate Defense. Joost P.H. Drenth, M.D., Ph.D., and Jos W.M. van der Meer, M.D., Ph.D. NEJM, Volume 355:730-732 August 17, 2006 Number 7.
The inflammasome. Virginie Petrillia, Stéphanie Papina and Jürg Tschopp. Current Biology, Volume 15, Issue 15, 9 August 2005, Page R581.
Use of Canakinumab in the Cryopyrin-Associated Periodic Syndrome. NEJM, 2009.
An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist. NEJM, 2009.
Cryopyrin-associated periodic syndromes. UpToDate, 2009.
A fever gene comes in from the cold. Daniel L. Kastner & John J. O'Shea. Nature Genetics 29, 241 - 242 (2001).

Related reading

Therapy of autoinflammatory syndromes. Hal M. Hoffman MD. Journal of Allergy and Clinical Immunology, Volume 124, Issue 6, December 2009, Pages 1129-1138.
Neonatal onset multisystem inflammatory disease. Wikipedia.
Muckle-Wells syndrome. Wikipedia.
Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) have a potential role in chronic rhinosinusitis/polyps http://goo.gl/QAS4r

Periodic Fever Syndromes - 25-min COLA video lecture http://bit.ly/URcsBy:



Published: 06/05/2009
Updated: 10/12/2012