From studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, ex vivo studies of human cells and murine cells, and in vivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

Cold urticaria is a chronic condition causing episodic symptoms of cold-induced wheals or angioedema in response to direct or indirect exposure to cold temperatures. Whereas symptoms of cold urticaria are typically benign and self-limiting, severe systemic anaphylactic reactions are possible. Acquired, atypical, and hereditary forms have been described, each with variable triggers, symptoms, and responses to therapy. Clinical testing, including response to cold stimulation, helps define disease subtypes. More recently, monogenic disorders characterized by atypical forms of cold urticaria have been described. Here, we review the different forms of cold-induced urticaria and related syndromes and propose a diagnostic algorithm to aid clinicians in making a timely diagnosis for the appropriate management of these patients.

NLRP3 is a cytoplasmic receptor protein, which initiates caspase-1 mediated inflammatory immune response upon detection of invading pathogen or a wide array of internal distress signals. Several gain-of function mutations of NLRP3 cause hereditary disorder of cold-induced hyper-inflammation known as familial cold autoinflammatory syndrome-1 (FCAS1). Although, caspase-1 activation and downstream interleukin-1β/interleukin-18 maturation are common effectors in pathophysiology of this disorder, molecular mechanisms of how exposure to subnormal temperature triggers mutant NLRP3-inflammsome activity is not understood. Here, we show that endogenous NLRP3 is in complex with HSC70 (HSPA8), and this interaction is reduced upon exposure to cold. FCAS-causing NLRP3-L353P and NLRP3-R260W mutants show enhanced interaction with HSC70. Upon exposure to subnormal temperature, NLRP3-L353P and NLRP3-R260W show enhanced inflammasome formation, increased caspase-1 activation and reduced interaction with HSC70. Knockdown of HSC70 results in increased inflammasome formation by L353P and R260W mutants of NLRP3. Our results suggest that interaction with HSC70 suppresses inflammasome formation by FCAS-causing NLRP3 mutants at physiological temperature, and loss of this inhibitory association at subnormal temperature causes aggravated inflammasome formation and caspase-1 activation leading to interleukin-1β maturation. These results provide evidence for HSC70 being a cold-sensor and a temperature-dependent regulator of inflammatory signaling by FCAS-causing NLRP3 mutants.

Familial cold autoinflammatory syndrome (FCAS) is a rare phenotype of cryopyrin-associated periodic syndrome (CAPS) and is characterized by repetitive systemic inflammation triggered by cold stimulation. Recently, we treated a 13-year-old female with FCAS/CAPS scheduled to undergo removal of an impacted tooth. To minimize perioperative heat loss, a forced-air warming system was utilized to prewarm the patient for 10 minutes before induction of general anesthesia. The patient\'s core and peripheral temperatures were monitored with axillary, superficial temporal artery, and rectal thermometers. The difference in temperatures at these 3 locations decreased to 0.4° C within 60 minutes as a result of the forced-air warming system before induction. Perioperative use of the warming system successfully prevented the occurrence any significant redistribution hypothermia and any symptoms of FCAS/CAPS.

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Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

Familial cold autoinflammatory syndrome (FCAS) is a cryopyrin-associated periodic syndrome that presents with episodic fever, skin rash, and joint pain after exposure to cold temperatures. Although the diagnosis is often singular, there are several instances of concurrent underlying autoimmune pathologies with either rheumatoid arthritis (RA) or amyloidosis. Because symptoms of the two entities overlap, it can be difficult to address a potential dual diagnosis of FCAS and an autoimmune disorder. We found seven previously reported cases of FCAS and amyloidosis and five cases of FCAS and RA and present another case of an FCAS-RA dual diagnosis.

Cyropyrin-associated periodic syndromes (CAPS) are clinically distinct syndromes that encompass a phenotypic spectrum yet are caused by alterations in the same gene, NLRP3. Many CAPS cases and other NLRP3-autoinflammatory diseases (NLRP3-AIDs) are directly attributed to protein-coding alterations in NLRP3 and the subsequent dysregulation of the NLRP3 inflammasome leading to IL-1β-mediated inflammatory states. Here, we used bioinformatics tools, computational modeling, and computational assessments to explore the proteomic consequences of NLRP3 mutations, which potentially drive NLRP3 inflammasome dysregulation. We analyzed 177 mutations derived from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome (MWS), and the non-hereditary chronic infantile neurologic cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease (CINCA/NOMID), as well as other NLRP3-AIDs. We found an inverse relationship between clinical severity and the severity of predicted structure changes resulting from mutations in NLRP3. Bioinformatics tools and computational modeling revealed that NLRP3 mutations that are predicted to be structurally severely-disruptive localize around the ATP binding pocket and that specific proteo-structural changes to the ATP binding pocket lead to enhanced ATP binding affinity by altering hydrogen-bond and charge interactions. Furthermore, we demonstrated that NLRP3 mutations that are predicted to be structurally mildly- or moderately-disruptive affect protein-protein interactions, such as NLRP3-ASC binding and NLRP3-NLRP3 multimerization, enhancing inflammasome formation and complex stability. Taken together, we provide evidence that proteo-structural mechanisms can explain multiple mechanisms of inflammasome activation in NLRP3-AID.

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterized by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold-induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold-induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient\'s history and cold stimulation testing. Additional diagnostic work-up, including a search for underlying infections, should only be done if indicated by the patient\'s history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines and the off-label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU.

Cryopyrin-associated periodic fever syndrome (CAPS) represents an increasingly recognized disease group entity, with varied presentations. CAPS includes 3 clinical entities, namely, familial cold-induced autoinflammatory syndrome (FCAS; MIM #120100), Muckle-Wells syndrome (MWS; MIM #191900) and chronic inflammatory neurologic cutaneous and articular syndrome (CINCA; MIM #607115); which share several overlapping clinical features. These patients often present with early-onset episodes of fever and rash, and variable systemic signs and symptoms, making it a great mimicker of other systemic autoimmune diseases. The episodes are transient and related to exposure to cold temperature and worsen in the winter season. We hereby present a case presenting with recurrent seasonal fever and rash, diagnosed as FCAS/ MWS overlap based on clinical signs and symptoms and positive testing for NLRP3 gene mutation. We also discuss the clinical presentation and complications of CAPS, chiefly FCAS and MWS, along with the previously described pediatric cases of CAPS. We tried to review the complexities of management of such patients, including the genetic diagnosis and the role of biological therapy. Based on the review of the literature, given the evident broad spectrum of symptoms and signs, use of next-generation sequencing can help in prompt diagnosis and early initiation of biological agents, which may play a great role in reducing the complications that these patients may experience in the long run.