The role of the inflammasome in patients with autoinflammatory diseases

Autoinflammatory diseases are disorders of the innate immune system, characterized by systemic inflammation often driven by inflammasomes, and independent of infection and autoreactive antibodies or antigen-specific T cells. These diseases are increasingly recognized as disorders of immune dysregulation, presenting with a constellation of fevers, rashes, and mucosal symptoms in many cases, which suggests that the allergist/immunologist is the appropriate specialist for these patients. However, many practicing physicians are unaware of these disorders in their pediatric and adult patient populations, leading to substantial delays in diagnosis. Recognizing autoinflammatory disease symptom patterns, performing appropriate diagnostic tests, and instituting early effective therapy are essential to reduce morbidity and mortality in these patients. This review will focus on understanding the molecular basis of inflammasomes, recognizing the distinguishing features of the classic autoinflammatory disorders, and appreciating the treatment modalities available. Autoinflammatory diseases are disorders of the innate immune system, characterized by systemic inflammation often driven by inflammasomes, and independent of infection and autoreactive antibodies or antigen-specific T cells. These diseases are increasingly recognized as disorders of immune dysregulation, presenting with a constellation of fevers, rashes, and mucosal symptoms in many cases, which suggests that the allergist/immunologist is the appropriate specialist for these patients. However, many practicing physicians are unaware of these disorders in their pediatric and adult patient populations, leading to substantial delays in diagnosis. Recognizing autoinflammatory disease symptom patterns, performing appropriate diagnostic tests, and instituting early effective therapy are essential to reduce morbidity and mortality in these patients. This review will focus on understanding the molecular basis of inflammasomes, recognizing the distinguishing features of the classic autoinflammatory disorders, and appreciating the treatment modalities available. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: July 2016. Credit may be obtained for these courses until June 30, 2017.Copyright Statement: Copyright © 2016-2017. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Hal M. Hoffman, MD, and Lori Broderick, MD, PhDDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: H. M. Hoffman has received research support from Burroughs Wellcome; has received consultancy fees from SOBI and Novartis; has received travel support from SOBI, Novartis, and Regeneron; and has received lecture fees from Novartis. L. Broderick has received research support from the National Institutes of Health and the Arthritis National Research Foundation; has received consultancy fees from SOBI and Novartis; and has received travel support from Regeneron.Activity Objectives:1.To recognize the distinguishing features of autoinflammatory disorders.2.To be able to address available therapies that target the inflammasome pathway.3.To become familiar with the components and function of the inflammasome.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Katherine Clarridge, MD, MSc, Dimana Dimitrova, MD, Akilah Jefferson, MD, MSc, Rachel Sparks, MD, MPH, Martin Gaudinski, MD, Rekha Jhamnani, MD, Michael Weinreich, MD, PhD, and Kelly D. Stone, MD, PhD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.The traditional classification of immunologic diseases cleanly divides immunodeficiency and allergy or autoimmunity. However, this classification scheme has blurred edges because there is evidence of autoimmunity and allergy in patients with classic immunodeficiency disorders, such as common variable immune deficiency and Wiskott-Aldrich syndrome. Elucidation of the disease mechanisms has introduced the term immune dysregulation in diseases such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and, more recently, phospholipase C–associated antibody deficiency immune dysregulation syndromes.1Lehman H.K. Autoimmunity and immune dysregulation in primary immune deficiency disorders.Curr Allergy Asthma Rep. 2015; 15: 53Google Scholar The concept of unclassified immune dysregulation is not novel in that there are common inflammatory diseases that do not fit into any of the traditional classifications, including disorders of host-microbiome symbiosis, such as inflammatory bowel disease,2Ayres J.S. Inflammasome-microbiota interplay in host physiologies.Cell Host Microbe. 2013; 14: 491-497Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar or crystal-induced diseases, such as gout or pseudogout. However, it was the rare hereditary recurrent fever disorders that prompted the development of a completely new and continually expanding immune disease classification now known as autoinflammatory disorders.3McGonagle D. McDermott M.F. A proposed classification of the immunological diseases.PLoS Med. 2006; 3: e297Crossref PubMed Scopus (563) Google Scholar Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: July 2016. Credit may be obtained for these courses until June 30, 2017. Copyright Statement: Copyright © 2016-2017. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Hal M. Hoffman, MD, and Lori Broderick, MD, PhD Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: H. M. Hoffman has received research support from Burroughs Wellcome; has received consultancy fees from SOBI and Novartis; has received travel support from SOBI, Novartis, and Regeneron; and has received lecture fees from Novartis. L. Broderick has received research support from the National Institutes of Health and the Arthritis National Research Foundation; has received consultancy fees from SOBI and Novartis; and has received travel support from Regeneron. Activity Objectives:1.To recognize the distinguishing features of autoinflammatory disorders.2.To be able to address available therapies that target the inflammasome pathway.3.To become familiar with the components and function of the inflammasome. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Katherine Clarridge, MD, MSc, Dimana Dimitrova, MD, Akilah Jefferson, MD, MSc, Rachel Sparks, MD, MPH, Martin Gaudinski, MD, Rekha Jhamnani, MD, Michael Weinreich, MD, PhD, and Kelly D. Stone, MD, PhD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. The term autoinflammatory disease was first coined by Galon et al4Galon J. Aksentijevich I. McDermott M.F. O'Shea J.J. Kastner D.L. TNFRSF1A mutations and autoinflammatory syndromes.Curr Opin Immunol. 2000; 12: 479-486Crossref PubMed Scopus (233) Google Scholar after discovery of the gene for TNF receptor–associated periodic syndrome (TRAPS)5McDermott M.F. Aksentijevich I. Galon J. McDermott E.M. Ogunkolade B.W. Centola M. et al.Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.Cell. 1999; 97: 133-144Abstract Full Text Full Text PDF PubMed Scopus (1106) Google Scholar to differentiate the hereditary recurrent fever disorders from other diseases with similar clinical features but somewhat distinct immune pathobiology. Patients with autoinflammatory diseases can display clinical and laboratory features observed in infectious and autoimmune diseases, including fever, rash, joint pain, neutrophilia, and increased inflammatory markers, as well as typical features of allergic diseases, such as responses to external stimuli (cold exposure). In contrast, patients with autoinflammatory disorders demonstrate no evidence of pathogenic infection and no indication of self-directed autoantibody or antigen-specific T-cell or IgE-mediated inflammation. Although each of these immune disorders relies at least in part on the adaptive immune response, autoinflammatory diseases are primarily innate immune-driven diseases with predominance of neutrophil-, macrophage-, or monocyte-mediated inflammation and the presence of inappropriate cytokine-mediated pathology. Autoinflammatory disorders are characterized by systemic inflammation with specific tissue involvement, including the skin, joints, conjunctiva, and serosal tissues (abdomen and pleura). The rarity of these disorders, combined with the recurrent intermittent nature of symptoms, presents a challenge for medical professionals and frustration for patients and families. To encourage physicians and patients to think about autoinflammatory diseases, we have proposed a list of 5 characteristic signs of autoinflammation so that physicians and patients will consider these disorders in the search for a possible diagnosis (Table I).Table IFive signs of autoinflammation∗Two or more signs might suggest an autoinflammatory disease.•Recurrent unexplained noninfectious episodes (>3) of fever (>101°F)•Each episode has a predictable pattern or characteristic course•Episodes characterized by specific symptoms, including nonitchy rash, extremity/joint pain, severe abdominal pain, and/or conjunctivitis and absence of upper respiratory tract symptoms•Episodes that can be triggered by specific stimuli (cold exposure or vaccines)•Family history of autoinflammatory disease or amyloidosis∗ Two or more signs might suggest an autoinflammatory disease. Open table in a new tab The hereditary fever disorders are some of the best examples of translational research made possible by the timely combination of motivated large families with clear heritable phenotypes and the rapid advances in human genetics and molecular genetics technology at the end of the last century. This led to recognition of the genetic basis of these classically Mendelian-inherited diseases beginning in 1997 with the discovery of MEFV as the gene for familial Mediterranean fever (FMF)6French FMF ConsortiumA candidate gene for familial Mediterranean fever.Nat Genet. 1997; 17: 25-31Crossref PubMed Scopus (1278) Google Scholar, 7International FMF ConsortiumAncient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever.Cell. 1997; 90: 797-807Abstract Full Text Full Text PDF PubMed Scopus (1332) Google Scholar and followed by the identification of nucleotide binding domain, leucine rich repeat, pyrin 3 (NLRP3) as the gene for a continuum of disorders now known as cryopyrin-associated periodic syndromes (CAPS).8Aksentijevich I. Nowak M. Mallah M. Chae J.J. Watford W.T. Hofmann S.R. et al.De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.Arthritis Rheum. 2002; 46: 3340-3348Crossref PubMed Scopus (597) Google Scholar, 9Hoffman H.M. Wanderer A.A. Broide D.H. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever.J Allergy Clin Immunol. 2001; 108: 615-620Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar Investigations of the immune pathways underlying these unique inflammatory disorders have not only revealed novel innate immune mechanisms, namely inflammasomes, but also had a practical and significant effect on the treatment of patients with these diseases in the form of targeted biologic therapies. Although it was the “simple” Mendelian inheritance that led to identification of the first genes responsible for autoinflammatory disorders, further analysis has revealed numerous complexities to disease expression. FMF is inherited in a classic autosomal recessive fashion, but there are patients with a complete or mild FMF phenotype who possess only 1 detectable MEFV mutation, challenging the loss-of-function model and introducing the possibility of complex genetic mechanisms. Recently, evidence in FMF knock-in mice suggested a gain-of-function model that could explain the findings in these patients.10Chae J.J. Cho Y.H. Lee G.S. Cheng J. Liu P.P. Feigenbaum L. et al.Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice.Immunity. 2011; 34: 755-768Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar CAPS-associated NLPR3 mutations appear to be gain-of-function mutations consistent with autosomal dominant inheritance.11Rosengren S. Mueller J.L. Anderson J.P. Niehaus B.L. Misaghi A. Anderson S. et al.Monocytes from familial cold autoinflammatory syndrome patients are activated by mild hypothermia.J Allergy Clin Immunol. 2007; 119: 991-996Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar The search for the underlying disease etiology of patients with a classic clinical presentation of CAPS without detectable NLRP3 mutations by means of traditional Sanger sequencing has resulted in identification of patients with somatic mosaicism. In some cases mutant allele frequency is as low as 4% in whole blood, indicating that a small fraction of affected cells were sufficient to cause systemic symptoms.12Nakagawa K. Gonzalez-Roca E. Souto A. Kawai T. Umebayashi H. Campistol J.M. et al.Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes.Ann Rheum Dis. 2015; 74: 603-610Crossref PubMed Scopus (79) Google Scholar, 13Tanaka N. Izawa K. Saito M.K. Sakuma M. Oshima K. Ohara O. et al.High incidence of NLRP3 somatic mosaicism in chronic infantile neurological cutaneous and articular syndrome patients: the results of an international multicenter collaborative study.Arthritis Rheum. 2011; 63: 3625-3632Crossref PubMed Scopus (211) Google Scholar There are also cases of myeloid-restricted somatic mosaicism with disease onset in adulthood.14Zhou Q. Aksentijevich I. Wood G.M. Walts A.D. Hoffmann P. Remmers E.F. et al.Brief report: cryopyrin-associated periodic syndrome caused by a myeloid-restricted somatic NLRP3 mutation.Arthritis Rheumatol. 2015; 67: 2482-2486Crossref PubMed Scopus (67) Google Scholar In both patients with FMF and those with CAPS, there are well-documented examples of low-penetrance mutations associated with a range of phenotypes from typical clinical presentation, mild or atypical disease, to complete absence of signs or symptoms.15Federici S. Calcagno G. Finetti M. Gallizzi R. Meini A. Vitale A. et al.Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population.Ann Rheum Dis. 2012; 71: 1961-1965Crossref PubMed Scopus (49) Google Scholar, 16Rieber N. Gavrilov A. Hofer L. Singh A. Oz H. Endres T. et al.A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants.Clin Immunol. 2015; 157: 56-64Crossref PubMed Scopus (29) Google Scholar Although these new genetic findings are intriguing for understanding disease pathophysiology, they similarly introduce new diagnostic dilemmas for the treating physician and further underscore the idea that autoinflammatory diseases continue to challenge our traditional clinical paradigms. The term inflammasome was first used by Martinon et al17Martinon F. Burns K. Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.Mol Cell. 2002; 10: 417-426Abstract Full Text Full Text PDF PubMed Scopus (4208) Google Scholar and Srinivasula et al18Srinivasula S.M. Poyet J.L. Razmara M. Datta P. Zhang Z. Alnemri E.S. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.J Biol Chem. 2002; 277: 21119-21122Crossref PubMed Scopus (439) Google Scholar in 2002 to describe a large intracellular multiprotein multimeric complex, including adaptor proteins and caspases similar to the apoptosome. This concept followed the positional cloning of human disease genes, such as MEFV and NLRP3, and genome mining of novel genes that code for proteins with shared structural domains related to genes with known functional roles in apoptosis and inflammation.19Bertin J. DiStefano P.S. The PYRIN domain: a novel motif found in apoptosis and inflammation proteins.Cell Death Differ. 2000; 7: 1273-1274Crossref PubMed Scopus (159) Google Scholar, 20Martinon F. Hofmann K. Tschopp J. The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation.Curr Biol. 2001; 11: R118-R120Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 21Harton J.A. Linhoff M.W. Zhang J. Ting J.P. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains.J Immunol. 2002; 169: 4088-4093Crossref PubMed Scopus (236) Google Scholar This cooperative discovery of the inflammasome cemented its pathophysiologic role in the classic autoinflammatory disorders but also solved a large part of the longstanding mystery behind the mechanisms of IL-1β release and increased our understanding of basic innate immune mechanisms. Although medical dogma labeled the innate immune system as nonspecific, to contrast with the antigen specificity of the adaptive immune system, it is now well accepted that the innate immune system recognizes and rapidly responds to pathogens and metabolic danger signals by sensing nearly 1000 conserved protein and nucleic acid patterns.22Netea M.G. van de Veerdonk F.L. van Deuren M. van der Meer J.W. Defects of pattern recognition: primary immunodeficiencies of the innate immune system.Curr Opin Pharmacol. 2011; 11: 412-422Crossref PubMed Scopus (7) Google Scholar Pathogen-associated molecular patterns (PAMPs), such as LPS and peptidoglycan, are biochemically distinct from host proteins and are identified by germline-encoded pattern recognition receptors, such as the Toll-like receptors. The role of these innate immune sensors has extended to also detect and immediately respond to danger signals or damage-associated molecular patterns (DAMPs) that are upregulated with cell activation and cell death, including ATP or uric acid. Many of these danger signals are detected by intracellular pattern recognition sensors, known as the NLRs (eg, NLRP3), that nucleate multimeric protein scaffolds called inflammasomes. The innate immune response is highly programmed for immediate action involving a series of events, often resulting in overwhelming and self-perpetuating inflammation that can be detrimental to the host. Consequently, there are multiple checkpoints in the cascade that allow for downregulation and/or termination of this potent inflammatory process. These regulatory mechanisms take several forms, including modulation of gene expression, protein-protein interactions, posttranslational modifications, extracellular release, receptor antagonism, and positive feedback loops. The mechanisms involved in the termination of these inflammatory processes are still unclear but often involve various forms of programmed cell death, phagocytosis, autophagy (described in an accompanying review by Saitoh and Akira, page 28), and potentially a process known as netosis.23Schett G. Schauer C. Hoffmann M. Herrmann M. Why does the gout attack stop? A roadmap for the immune pathogenesis of gout.RMD Open. 2015; 1: e000046Crossref PubMed Scopus (54) Google Scholar The mechanisms of inflammasome regulation involve each of these types of checkpoints, allowing for tight modulation at several levels. Inflammasomes are made up of defined component proteins that interact with each other through specific protein domains known as death domains (pyrin and caspase activation and recruitment domains [CARD]) that form characteristic disc-like complexes consisting of homotypic and heterotypic oligomers, often involving 7 or more of the same protein molecules (Fig 1). At least 5 inflammasomes have been described to date, although there are likely several others. All inflammasomes are made up of a sensor protein including the NLRs—NLRP1, NLRP3, and NLRC (CARD) 4, or the nonNLRs—absent in melanoma 2 (AIM2) and pyrin, and an effector protein or inflammatory caspase, such as caspase-1 (also known as the IL-1–converting enzyme). Several inflammasome models include chaperone proteins, such as heat shock proteins, that appear to be important in stabilizing protein interactions. Most inflammasomes also contain the adaptor protein known as apoptosis associated Speck like protein containing a CARD (ASC), leading to rapid formation of helical and filamentous structures. These structures can be observed microscopically as specks within the cytoplasm but have also been shown to be released into the extracellular space, suggesting an ability to influence and activate neighboring cells.24Franklin B.S. Bossaller L. De Nardo D. Ratter J.M. Stutz A. Engels G. et al.The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation.Nat Immunol. 2014; 15: 727-737Crossref PubMed Scopus (515) Google Scholar Initiation of effector function begins when ASC recruits pro–caspase-1, allowing for autoproteolytic cleavage to form active caspase-1. Active caspase-1 can cleave the proforms of IL-1β and IL-18 and can induce an inflammatory cell death known as pyroptosis. Currently, there is controversy whether these active cytokines can be released in the absence of pyroptosis. The release of mature active cytokines allows for binding to specific receptors, leading to signal transduction, expression of downstream cytokines, chemokines, and adhesion molecules and resulting in an inflammatory cascade and recruitment of additional inflammatory cells (Fig 2).25Broderick L. De Nardo D. Franklin B.S. Hoffman H.M. Latz E. The inflammasomes and autoinflammatory syndromes.Annu Rev Pathol. 2015; 10: 395-424Crossref PubMed Scopus (206) Google Scholar Regulation of inflammasome activation occurs at multiple steps. Expression of sensor proteins is regulated at the RNA level but also at the protein level by proteolysis. Activation of the inflammasome is dependent on the intraprotein domain oligomerization and the formation of filamentous structures. Activation of caspase-1 and release of IL-1β and IL-18 are dependent on proteolytic cleavage to form mature active forms. Cytokine activity is dependent on receptor binding, leading to an autopositive feedback loop of increased transcription of the inflammasome component proteins and procytokines. Receptor binding is further regulated by competitive inhibition by IL-1 receptor antagonist (IL-1RA) and IL-18 binding protein. Similar to the Toll-like receptors, there is some degree of specificity of the NLRs for unique PAMPs or DAMPs, accounting for their likely important roles in the host response to pathogen or cell death (Fig 2). AIM2 senses double-stranded DNA of microbial or host origin,26Fernandes-Alnemri T. Yu J.W. Datta P. Wu J. Alnemri E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA.Nature. 2009; 458: 509-513Crossref PubMed Scopus (1339) Google Scholar, 27Hornung V. Ablasser A. Charrel-Dennis M. Bauernfeind F. Horvath G. Caffrey D.R. et al.AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.Nature. 2009; 458: 514-518Crossref PubMed Scopus (1780) Google Scholar pyrin detects Rho GTPase targeting bacterial toxins (eg, Clostridium difficile),28Xu H. Yang J. Gao W. Li L. Li P. Zhang L. et al.Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome.Nature. 2014; 513: 237-241Crossref PubMed Scopus (536) Google Scholar NLRC4 is triggered by flagellin and bacterial secretion systems,29Sutterwala F.S. Mijares L.A. Li L. Ogura Y. Kazmierczak B.I. Flavell R.A. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome.J Exp Med. 2007; 204: 3235-3245Crossref PubMed Scopus (408) Google Scholar and NLRP1 is activated by lethal anthrax toxin. However, NLRP3 is activated by numerous PAMPs and DAMPS, including several pathogens or toxins, crystals or aggregates, and nucleotides, through a number of potential shared mechanisms. including ion flux (K+ and Ca++), oxidative stress, mitochondrial translocation or damage, and cytosolic release of lysosomal contents. Although these triggers are important for immune responses in the normal host, mutations in genes that code for inflammasome components or related proteins result in hyperactivation or constitutive activation of inflammasomes in the absence of these triggers. The study of rare inborn errors of the immune system leading to human disease has been instrumental in revealing basic immune pathways involved in the normal response to pathogens. The earliest examples of these advances are the discovery of disease genes and then the molecular mechanisms involved in primary immune deficiencies, such as Bruton agammaglobulinemia and severe combined immune deficiency. Similarly, our understanding of the function of inflammasomes began with initial studies of patients with inflammasomopathies that have mutations in genes that code for inflammasome component proteins and proteins that interact with the inflammasome. CAPS is a continuum of autosomal dominant inherited diseases (from least to most severe): familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID).30Aksentijevich I. D Putnam C. Remmers E.F. Mueller J.L. Le J. Kolodner R.D. et al.The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model.Arthritis Rheum. 2007; 56: 1273-1285Crossref PubMed Scopus (310) Google Scholar Prevalence is estimated at approximately 1 to 3 per 1 million. Patients usually present early in life and have some daily symptoms, as well as flares lasting hours to days. Shared symptoms of all of the subphenotypes include fever/chills, painful generalized urticaria-like rash, extremity pain and swelling, headaches, and conjunctivitis. Unique features of the subphenotypes include generalized cold exposure–induced flares for FCAS, frequent progressive neurosensory hearing loss in patients with MWS and NOMID, and bony overgrowth of knees and symptoms indicative of central nervous system (CNS) inflammation, such as increased intracranial pressure, uveitis, developmental delay, and seizures in patients with NOMID. Physical findings include papilledema for NOMID (Table II). Laboratory findings include neutrophilic leukocytosis and chronically increased inflammatory markers. Patients with MWS are at risk for amyloidosis, often leading to end-stage renal disease if untreated. Recently, some patients with Schnitzler syndrome have been found to have somatic NLRP3 mutations, suggesting that this disease might be part of the CAPS continuum.31de Koning H.D. van Gijn M.E. Stoffels M. Jongekrijg J. Zeeuwen P.L. Elferink M.G. et al.Myeloid lineage-restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome.J Allergy Clin Immunol. 2015; 135: 561-564Abstract Full Text Full Text PDF PubMed Scopus (87) Google ScholarTable IIClinical features, genetics, and pathophysiology of autoinf