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Autoinflammation is defined by aberrant, antigen-independent activation of the innate immune signaling pathways. This leads to increased, pro-inflammatory cytokine expression and subsequent inflammation. In contrast, autoimmune and allergic diseases are antigen-directed immune responses from activation of the adaptive immune system. The innate and adaptive immune signaling pathways are closely interconnected. The group of ‘complex multigenic diseases’ are a result of mutual dysregulation of both the autoinflammatory and autoimmune physiologic components. In contrast, monogenic autoinflammatory syndromes (MAIS) result from single mutations and are exclusively autoinflammatory in their pathogenesis. Studying the clinical and histopathological findings for the various MAIS explains the phenotypical correlates of their specific mutations. This review aims to group the histopathologic clues for autoinflammation into three recognizable patterns. The presence of these histologic patterns in a pediatric patient with recurrent fevers and systemic inflammation should raise suspicion of an autoinflammatory component in MAIS, or, more frequently, in a complex multigenic disease. The three major histopathological patterns seen in autoinflammation are as follows: (i) the ‘neutrophilic’ pattern, seen in urticarial neutrophilic dermatosis, pustular psoriasis, aseptic neutrophilic folliculitis, and Sweet’s syndrome; (ii) the ‘vasculitic’ pattern seen in small vessel-vasculitis (including hypersensitivity/leukocytoclastic vasculitis, thrombosing microangiopathy and lymphocytic vasculitis), and intermediate-sized vessel vasculitis, mimicking polyarteritis nodosa; and (iii) the ‘granulomatous’ pattern. Beyond these three patterns, there are additional histopathologic clues, which are detailed below. It is important for a dermatopathologist to recognize the patterns of autoinflammation, so that a diagnosis of MAIS or complex multigenic diseases may be obtained. Finally, careful histopathologic analyses could contribute to a better understanding of the various clinical manifestations of autoinflammation.

The structure of inflammasomes, history of their discovery, and their potential use as therapeutic targets were discussed. Inflammasomes represent cytosolic polyprotein complexes that are formed in response to various external and internal stimuli, including viral and bacterial infections. The main products of inflammasomes are pro-inflammatory cytokines: interleukin-1-beta (IL-1β) and interleukin-18 (IL-18). Both cytokines are formed through proteolytic cleavage by active caspase-1. Caspase-1 activation leads to a special form of cell death called pyroptosis. Depending on external stimuli (bacterial, viral infections, cell damage, changes in ion concentration), various types of inflammasomes are activated. The possibilities of using caspase-1 inhibitors and other drugs in medicine were described.

Aim:Cryopyrin-associated Periodic Syndromes (CAPS) are a subgroup of the Periodic fever syndromes, caused by mutations in the NLRP3 gene. NLRP3 gene mutations can cause three clinically different phenotypes. It is known that even the same mutations in the NLRP3 gene can cause different phenotypes. To investigate this situation, we have constructed a hypothesis that if an individual with the Interleukin-1 Beta (IL-1β)-511 T/T genotype which is associated with overexpressed IL-1β levels, he/she might have a more severe CAPS phenotype.Materials and Methods:Thirty-six NLRP3 Exon three variant-positive patients with detailed clinical data and 30 healthy controls were selected for the IL-1β genotype investigation. For the analysis of IL-1β-511 allele, the SNP rs1143634 was genotyped using the TaqMan 5’-exonuclease allelic discrimination assay.Results:Neither the Muckle Wells Syndrome patients (severe phenotype) with a p.Val198Met mutation nor symptomatic patients with the p.Gln703Lys variant showed an increased IL-1β-511T/T genotype frequency.Conclusion:We suggest that IL-1β-511 T/T polymorphism is not a modifying factor regarding the clinical severity of CAPS patients. However, to expand this theory and in order to find other modifying genetic factors, other polymorphisms of IL-1β or other genes in the inflammasome pathway such as caspase-1 or ASC should be analyzed.

Autoinflammation is defined by aberrant, antigen-independent activation of the innate immune signaling pathways. This leads to increased, pro-inflammatory cytokine expression and subsequent inflammation. In contrast, autoimmune and allergic diseases are antigen-directed immune responses from activation of the adaptive immune system. The innate and adaptive immune signaling pathways are closely interconnected. The group of 'complex multigenic diseases' are a result of mutual dysregulation of both the autoinflammatory and autoimmune physiologic components. In contrast, monogenic autoinflammatory syndromes (MAIS) result from single mutations and are exclusively autoinflammatory in their pathogenesis. Studying the clinical and histopathological findings for the various MAIS explains the phenotypical correlates of their specific mutations. This review aims to group the histopathologic clues for autoinflammation into three recognizable patterns. The presence of these histologic patterns in a pediatric patient with recurrent fevers and systemic inflammation should raise suspicion of an autoinflammatory component in MAIS, or, more frequently, in a complex multigenic disease. The three major histopathological patterns seen in autoinflammation are as follows: (i) the 'neutrophilic' pattern, seen in urticarial neutrophilic dermatosis, pustular psoriasis, aseptic neutrophilic folliculitis, and Sweet's syndrome; (ii) the 'vasculitic' pattern seen in small vessel-vasculitis (including hypersensitivity/leukocytoclastic vasculitis, thrombosing microangiopathy and lymphocytic vasculitis), and intermediate-sized vessel vasculitis, mimicking polyarteritis nodosa; and (iii) the 'granulomatous' pattern. Beyond these three patterns, there are additional histopathologic clues, which are detailed below. It is important for a dermatopathologist to recognize the patterns of autoinflammation, so that a diagnosis of MAIS or complex multigenic diseases may be obtained. Finally, careful histopathologic analyses could contribute to a better understanding of the various clinical manifestations of autoinflammation. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome is an intracellular complex that regulates the release of proinflammatory cytokines such as interleukin-1β in response to exogenous pathogens and endogenous danger signals. Evidence from studies involving human genetics, human ex vivo mononuclear cell responses, and in vivo and in vitro murine models confirms the importance of the inflammasome and interleukin-1β in the pathogenesis of several inherited and complex diseases. The availability of several effective interleukin-1β targeted therapies has allowed for successful proof-of-concept studies in several of these disorders. However, many other diseases are likely to be mediated by the inflammasome and interleukin-1β, providing additional targets in the future.

An otherwise healthy male child of 9 years presented with paroxysmal fever and diffuse abdominal pain along with loss of appetite and nausea lasting for 3-4days every 4-6 weeks for last 2 years. He also has stretchable skin and hypermobile joint which he inherited from his mother who never suffered any paroxysmal attack of the kind. Work up for acute intermittent porphyria, lead poisoning and familial mediterranean fever was negative. A novel harmful sequence change in NLRP12 gene was detected and a diagnosis of NLRP12 associated autoinflammatory syndrome was made. This sequence change with disease has not yet been reported in the literature and is the first such case of NLRP12 related autoinflammatory syndrome from India.

Aim: Cryopyrin-associated Periodic Syndromes (CAPS) are a subgroup of the Periodic fever syndromes, caused by mutations in the NLRP3 gene. NLRP3 gene mutations can cause three clinically different phenotypes. It is known that even the same mutations in the NLRP3 gene can cause different phenotypes. To investigate this situation, we have constructed a hypothesis that if an individual with the Interleukin-1 Beta (IL-1β)-511 T/T genotype which is associated with overexpressed IL-1β levels, he/she might have a more severe CAPS phenotype. Materials and Methods: Thirty-six NLRP3 Exon three variant-positive patients with detailed clinical data and 30 healthy controls were selected for the IL-1β genotype investigation. For the analysis of IL-1β-511 allele, the SNP rs1143634 was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. Results: Neither the Muckle Wells Syndrome patients (severe phenotype) with a p.Val198Met mutation nor symptomatic patients with the p.Gln703Lys variant showed an increased IL-1β-511T/T genotype frequency. Conclusion: We suggest that IL-1β-511 T/T polymorphism is not a modifying factor regarding the clinical severity of CAPS patients. However, to expand this theory and in order to find other modifying genetic factors, other polymorphisms of IL-1β or other genes in the inflammasome pathway such as caspase-1 or ASC should be analyzed. [ABSTRACT FROM AUTHOR]

Autoinflammatorische Erkrankungen, wie z. B. das familiäre Mittelmeerfieber oder das Cryopyrin-assoziierte periodische Syndrom, können durch eine gestörte Aktivierung des angeborenen Immunsystems zu einer überschießenden Entzündungsreaktion führen. Mutationen im Erbgut führen zu veränderten Genprodukten, und diese wiederum zur Produktion pro-inflammatorischer Zytokine. Durch Fortschritte in der Genetik konnten neue hocheffektive Therapien für bisher kaum behandelbare Erkrankungen gefunden werden. [ABSTRACT FROM AUTHOR]

Neuroinflammation contributes to the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Cytotoxic events following SAH, such as extracellular accumulation of adenosine triphosphate (ATP), may activate the P2X purinoceptor 7 (P2X7R)/cryopyrin inflammasome axis, thus inducing the proinflammatory cytokine IL-1β/IL-18 secretion. We therefore hypothesized that inhibition of P2X7R/cryopyrin inflammasome axis would ameliorate neuroinflammation after SAH. In the present study, SAH was induced by the endovascular perforation in rats. Small interfering RNAs (siRNAs) of P2X7R or cryopyrin were administered intracerebroventricularly 24 h before SAH. Brilliant blue G (BBG), a non-competitive antagonist of P2X7R, was administered intraperitoneally 30 min following SAH. Post-assessments including SAH severity score, neurobehavioral test, brain water content, Western blot and immunofluorescence, were performed. Administration of P2X7R and cryopyrin siRNA as well as pharmacologic blockade of P2X7R by BBG ameliorated neurological deficits and brain edema at 24 h following SAH. Inhibition of P2X7R/cryopyrin inflammasome axis suppressed caspase-1 activation, which subsequently decreased maturation of IL-1β/IL-18. To investigate the link between P2X7R and cryopyrin inflammasome in vivo, Benzoylbenzoyl-ATP (BzATP), a P2X7R agonist, was given to lipopolysaccharide (LPS) primed naive rats with scramble or cryopyrin siRNAs. In LPS-primed naive rats, BzATP induced caspase-1 activation and mature IL-1β release were neutralized by cryopyrin siRNA. Thus, the P2X7R/cryopyrin inflammasome axis may contribute to neuroinflammation via activation of caspase-1 and thereafter mature IL-1β/IL-18 production following SAH. Therapeutic interventions targeting P2X7R/cryopyrin pathway may be a novel approach to ameliorate EBI following SAH.

The cryopyrin-associated periodic syndromes (CAPS) comprise a group of rare autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. NLRP3 contains a leucine-rich repeats (LRR) domain with a highly conserved exonic organization that is subjected to extensive alternative splicing. Aberrant NLRP3 inflammasome assembly in CAPS causes chronic inflammation; however, the mechanisms regulating inflammasome function remain unclear. We aimed to elucidate the mechanisms regulating NLRP3-mediated autoinflammation in human disease, characterizing the role of LRR in inflammasome activation. We analyzed sequence read archive data to characterize the pattern of NLRP3 splicing in human monocytes and investigated the role of each LRR-coding exon in inflammasome regulation in genetically modified U937 cells representing CAPS and healthy conditions. We detected a range of NLRP3 splice variants in human primary cells and monocytic cell lines, including 2 yet-undescribed splice variants. We observe that lipopolysaccharides affect the abundance of certain splice variants, suggesting that they may regulate NLRP3 activation by affecting alternative splicing. We showed that exons 4, 5, 7, and 9 are essential for inflammasome function, both in the context of wild-type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 inflammasome assembly. Moreover, the SGT1-NLRP3 interaction is decreased in nonfunctional variants, suggesting that alternative splicing may regulate the recruitment of proteins that facilitate inflammasome assembly. These findings demonstrate the contribution of the LRR domain in inflammasome function and suggest that navigating LRR exon usage within NLRP3 is sufficient to dampen inflammasome assembly in CAPS. [ABSTRACT FROM AUTHOR]

Aim: Cryopyrin-associated periodic syndromes (CAPS) encapsulate three auto-inflammatory conditions, ranging in severity from mild (familial cold auto-inflammatory syndrome: FCAS), moderate (Muckle-Wells syndrome: MWS) and severe (neonatal onset multi-inflammatory disorder: NOMID). We aimed to describe the epidemiology, clinical features and outcomes of Australian children and adults with CAPS.Methods: Patients were identified and clinical data collected through a questionnaire sent during 2012-2013 to clinicians reporting to the Australian Paediatric Surveillance Unit and subscribing to the Australasian Societies for Allergy/Immunology, Rheumatology and Dermatology.Results: Eighteen cases of CAPS were identified (8 NOMID; 8 MWS, 2 FCAS); 12 in children <18 years of age. The estimated population prevalence of CAPS was 1 per million persons. Diagnostic delay was frequent, particularly in those with milder phenotypes (median diagnostic delay in MWS/FCAS 20.6 years compared with NOMID 2.1 years; P = 0.04). Common presenting features included urticaria (100%), periodic fever (78%), arthralgia (72%) and sensorineural hearing loss (61%). Almost all (90%) MWS patients had a family member similarly affected compared with none in the NOMID group (P = 0.004). A significant proportion of patients on anti-interleukin (IL)-1 therapy (n = 13) no longer had systemic inflammation. Only 50% with sensorineural hearing loss had hearing restored on anti-IL-1 therapy.Conclusions: Although CAPS are rare, patients often endured prolonged periods of systemic inflammation. This is despite almost all MWS patients having family members with similar symptoms and children with NOMID presenting with chronic infantile urticaria associated with multi-system inflammation. Hearing loss in NOMID/MWS was frequent, and reversible in only 50% of cases. [ABSTRACT FROM AUTHOR]

Cryopyrin-associated periodic syndrome are rare autosomal dominantly inherited diseases. They include three overlapping phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem autoinflammatory syndrome (NOMID/CINCA). Recurrent fevers, joint pain, and urticarial skin rash are the main clinical features of these conditions. Renal amyloidosis and sensorineural complications may occur. Gain-of-function mutations in NLRP3 gene are responsible for the overactivation of the NLRP3 inflammasome, a multimolecular complex involved in the inflammatory process. Missense mutations are almost always encountered, particularly in exon 3, which encodes the nucleotide-binding domain. Mosaicism is not rare, especially in CINCA/NOMID. Next-generation sequencing will grant access to new insights about NLRP3 implication in oligogenic and multifactorial diseases. [ABSTRACT FROM AUTHOR]

Abstract: Neuroinflammation contributes to the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Cytotoxic events following SAH, such as extracellular accumulation of adenosine triphosphate (ATP), may activate the P2X purinoceptor 7 (P2X7R)/cryopyrin inflammasome axis, thus inducing the proinflammatory cytokine IL-1β/IL-18 secretion. We therefore hypothesized that inhibition of P2X7R/cryopyrin inflammasome axis would ameliorate neuroinflammation after SAH. In the present study, SAH was induced by the endovascular perforation in rats. Small interfering RNAs (siRNAs) of P2X7R or cryopyrin were administered intracerebroventricularly 24h before SAH. Brilliant blue G (BBG), a non-competitive antagonist of P2X7R, was administered intraperitoneally 30min following SAH. Post-assessments including SAH severity score, neurobehavioral test, brain water content, Western blot and immunofluorescence, were performed. Administration of P2X7R and cryopyrin siRNA as well as pharmacologic blockade of P2X7R by BBG ameliorated neurological deficits and brain edema at 24h following SAH. Inhibition of P2X7R/cryopyrin inflammasome axis suppressed caspase-1 activation, which subsequently decreased maturation of IL-1β/IL-18. To investigate the link between P2X7R and cryopyrin inflammasome in vivo, Benzoylbenzoyl-ATP (BzATP), a P2X7R agonist, was given to lipopolysaccharide (LPS) primed naive rats with scramble or cryopyrin siRNAs. In LPS-primed naive rats, BzATP induced caspase-1 activation and mature IL-1β release were neutralized by cryopyrin siRNA. Thus, the P2X7R/cryopyrin inflammasome axis may contribute to neuroinflammation via activation of caspase-1 and thereafter mature IL-1β/IL-18 production following SAH. Therapeutic interventions targeting P2X7R/cryopyrin pathway may be a novel approach to ameliorate EBI following SAH. [Copyright &y& Elsevier]

Cryopyrin-associated periodic syndrome (CAPS) is due to gain-of-function mutations in the cryopyrin gene, which determines an overactive inflammatory response. AA amyloidosis is a complication of this syndrome. A 53-year-old man was referred to us because of lower limb edema. Past history: at the age of 20, he complained of arthralgia/arthritis and bilateral hypoacusis. At the age of 35, he presented posterior uveitis, several episodes of conjunctivitis, and progressive loss of visual acuity. Laboratory tests disclosed nephrotic syndrome, and renal biopsy showed AA amyloidosis. He was given anakinra with improvement of arthritis. A genetic study revealed the p.D303N mutation in the cryopyrin gene, and he was diagnosed as having AA amyloidosis due to CAPS. Twenty-one months after starting anakinra, the arthritis has disappeared, although nephrotic-range proteinuria persisted. It is important to be aware of cryopyrin-associated periodic syndrome because it can cause irreversible complications, and there is effective therapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. Methods: The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes ( NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. Results: Clinical diagnoses of the 102 patients were: CAPS ( n = 28), TRAPS ( n = 31), FMF ( n = 17), MKD ( n = 17) and PGA ( n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. Conclusion: We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis. [ABSTRACT FROM AUTHOR]

Cryopyrinopathies are a subgroup of autoinflammatory syndromes. Most cases have mutations in the CIAS1/NLRL3 gene, encoding the cryopyrin/NLRP3 protein. Cryopyrin, together with other proteins, is involved in the assembly of the cryopyrin/NLRP3 inflammasome. Mutations in CIAS1/NLRP3 result in increased IL-1β cleavage from biologically inactive pro-IL-1β. This results in systemic inflammation and three associated disorders of different severity, forming a clinical continuum with overlapping features. The mildest from, familial cold autoinflammatory syndrome (FCAS), is characterized by remitting fevers, urticaria-like rash, polyarthralgia/arthritis, and usually caused by cold exposure. More severe forms are Muckle-Wells syndrome (MWS) and CINCA/NOMID. We report an 8-year-old boy with FCAS, who presented with overlapping features with MWS. He showed good response to seasonal anakinra treatment. Mutation analysis in CIAS1/NLRP3, PYCARD, and CASP1 was performed. Serum cytokine profiles, and cytokine expression from resting monocytes, and in response to mild hypothermia, and LPS stimulation were determined. Mutations in CIAS1/NLRP3, PYCARD, and CASP1 were not found. In response to mild hypothermia, an enhanced IL-1β expression by patient monocytes resulted in increased IL-6 and TNF-α secretion, as compared to control cells. The addition of the IL-1β receptor antagonist (anakinra) reversed these effects. In response to LPS stimulation, patient monocytes produced high level of IL-1β, IL-6 and TNF-α. This was markedly less pronounced in control monocytes. FCAS results in cold-induced cytokine dysregulation and systemic inflammation. Symptoms can be treated, using IL-1β antagonists. Further research is warranted, particularly in order to investigate pathophysiological mechanisms in 'mutation negative' individuals. [ABSTRACT FROM AUTHOR]

We describe a 14-month-old girl who initially presented with 8 days of fever, conjunctival injection, rash, and irritability, admitted with a presumptive diagnosis of Kawasaki disease. Further history revealed intermittent urticarial-like rash since 3 months of age and pathological evaluation showed a perivascular infiltrate of neutrophils and lymphocytes. Here, we discuss the key points surrounding her diagnostic workup and our therapeutic approach. [ABSTRACT FROM AUTHOR]

The etiology of cryopyrin-associated periodic syndrome (CAPS) is caused by germline gene mutations in NOD-like receptor family, pryin domain containing 3 ( NLRP3)/cold-induced autoinflammatory syndrome 1 ( CIAS1). CAPS includes diseases with various severities. The aim of this study was to characterize patients according to the disease severity of CAPS. Five Japanese patients with four kinds of gene variations in NLRP3 were found and diagnosed as CAPS or juvenile idiopathic arthritis. Two mutations in NLRP3, Y563N and E688K, found in CAPS patients exhibit significant positive activities in the nuclear factor-κB reporter gene assay. Increased serum interleukin (IL)-18 levels were only observed in severe cases of CAPS. In mild cases of CAPS, the serum IL-18 levels were not increased, although lipopolysaccharide- or hypothermia-enhanced IL-1β and IL-18 production levels by their peripheral blood mononuclear cells were detectable. This series of case reports suggests that a combination of in vitro assays could be a useful tool for the diagnosis and characterization of the disease severity of CAPS. [ABSTRACT FROM AUTHOR]

Background: This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer's disease (AD). Methods: In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus. Results: Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II. Conclusions: Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife. [ABSTRACT FROM AUTHOR]

Hereditary periodic fever syndromes, comprise a group of hereditary disorders with similar clinical features of recurrent short episodes of fever associated with inflammatory manifestations. These are usually self-limited in nature and occur in the absence of infection or autoimmune reaction. Between attacks, patients feel well and regain their normal daily functions until the next episode occurs. The episodes are usually associated with elevated serum levels of acute-phase reactants (e.g., fibrinogen, serum amyloid A [SAA]), an elevated erythrocyte sedimentation rate (ESR), and leukocytosis. These illnesses represent inborn errors in the regulation of innate immunity thus sub-stantiating the distinction from autoimmune disorders, which more directly affect the adaptive immune system. Each of these disorders has a distinct genetic defect. Most of these proteins are members of the Death Domain Superfamily and are involved in inflammation and apoptosis. These proteins mediate the regulation of nuclear factor-kB (NF-kB), cell apoptosis, and interleukin 1β (IL-1β) secretion through cross-regulated and common signaling pathways. Six periodic fever syndromes have been characterized. Genetic defects, pathogenesis, epidemiology and management of these fevers will be discussed. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Cholesterol crystals have been shown to cause inflammation, and ultimately atherosclerotic lesions through the activation of the NLRP3 inflammasome. As cholesterol crystals have also been found in the walls of patients with abdominal aortic aneurysms (AAA), it is possible that the NLRP3 inflammasome is involved in AAA and genetic variability within this protein complex could alter disease risk. The primary objective of this study was to assess whether there is genetic evidence for a role of the NLRP3 inflammasome in AAA by testing for association of AAA with functional single nucleotide polymorphisms (SNPs) in the CARD8 and NLRP3 genes. Methods: AAA patients (n =1151) and controls (n =727) were genotyped for CARD8 SNP rs2043211 and NLRP3 SNP rs35829419 using TaqMan SNP assays. IL1-β, C-reactive protein (CRP), and lipoprotein (a) [Lp(a)] were measured in the plasma of a subset of study participants. The Kruskal–Wallis Rank test was conducted to test for differences in mean concentration of IL1-β, CRP and Lp(a). Logistic regression was used to test for interaction between CARD8 and NLRP3. Results: Significantly higher mean concentration of plasma IL1-β was observed in study participants who were homozygous for the common C allele of NLRP3 rs35829419 (p =0.010). Interaction between rs2043211 and rs35829419 was observed in this dataset (χ 2 =6.22; p =0.044), which strengthened when adjusted for age, gender, smoking, diabetes, hypertension, and dyslipidemia (χ 2 =14.75; p =0.012); and separately for NOD2 genotype (χ 2 =14.06; p =0.015). Conclusion: Our finding suggests genetic variability within the NLRP3 inflammasome may be important in the pathophysiology of AAA. [Copyright &y& Elsevier]

The autoinflammatory syndromes are a group of multisystem disorders characterized by recurrent episodes of fever and systemic inflammation affecting the eyes, joints, skin, and serosal surfaces in the absence of an immune reaction. Recent advances have revealed the importance of interleukin-1β, not only in the pathogenesis of many of these rare inherited diseases, but also in acquired diseases. The development and availability of anti-interleukin-1β therapeutics have introduced the possibility of proof-of-concept studies, which are likely to further widen this field. [ABSTRACT FROM AUTHOR]

The periodic syndromes represent a heterogeneous group of disorders that can be very difficult for practicing physicians to diagnosis and treat. This article presents an orderly approach to hyperimmunoglobulin D syndrome; tumor necrosis factor receptor-1 periodic syndrome; familial Mediterranean fever; periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome; and cryopyrin-associated periodic syndromes by highlighting the disease presentation, diagnosis, pathogenesis, and treatment. Recent advances are also discussed. [ABSTRACT FROM AUTHOR]

Objective Pre-eclampsia involves a maternal inflammatory response that differs from both normal pregnancy and normotensive intrauterine growth restriction (IUGR). Our objective was to examine neutrophil Toll-like receptor (TLR), cryopyrin, nuclear factor-κB (NF-κB) subunit and interleukin-1β (IL-1β), and inflammatory cytokine profiles in women with pre-eclampsia or normotensive IUGR, as well as in normal pregnancy and non-pregnancy controls. Design and method A case–control study was performed. We examined the messenger RNA (mRNA) and protein expressions of TLR4 and TLR2, mRNA levels of cryopyrin, IL-1β, NF-κB subunits p50 and p65, as well as maternal serum inflammatory cytokine profiles (IL-2, IL-6, tumour necrosis factor-α [TNF-α], interferon-γ [IFN-γ] and IL-10) in women with and without pre-eclampsia using real-time reverse transcription polymerase chain reactions, flow cytometry and multiplex immunoassays. Setting A single tertiary maternity hospital in Vancouver, Canada. Population Women with early-onset pre-eclampsia (<34 weeks of gestation, n = 25), women with late-onset pre-eclampsia (≥34+0 weeks of gestation, n = 25), women with normotensive IUGR ( n = 25), women with normal pregnancy ( n = 75) and non-pregnancy ( n = 25) controls. Results Women with pre-eclampsia (as a single combined group of early- and late-onset, and particularly in women with early-onset pre-eclampsia) had increased TLR2 and TLR4 mRNA and protein expressions elevated cryopyrin, NF-κB subunit, and IL-1β mRNA expression, and TNF-α:IL-10 and IL-6:IL-10 ratios compared with other groups. Conclusions These data suggest that TLRs and cryopyrin may modulate the innate immune response of the maternal syndrome of pre-eclampsia, and might also trigger the differential inflammatory response existing between early onset pre-eclampsia and normotensive IUGR. [ABSTRACT FROM AUTHOR]

Abstract: The host response against diverse bacterial pathogens involves activation of specialized immune cells and elaboration of pro-inflammatory cytokines that help to coordinate appropriate host defense. Members of the interleukin-1 (IL-1) cytokine family, IL-1β and IL-18, are central players in this process. Extracellular release of the mature, active form of these cytokines requires their processing by the cysteine protease caspase-1, which therefore serves as a key regulator of the inflammatory response. In addition to its role in secretion of pro-inflammatory cytokines, caspase-1 is also required for a form of cell death, recently termed pyroptosis, that occurs in macrophages infected by certain bacterial pathogens. Caspase-1 itself is synthesized as a pro-enzyme, which must first be activated by autocatalytic cleavage. This activation requires recruitment of caspase-1 into multiprotein complexes known as inflammasomes. The Nod-like receptor (NLR) family of cytosolic proteins play an important role in detecting inflammatory stimuli and subsequently mediate inflammasome assembly. A common feature of NLR proteins that trigger inflammasome assembly in response to bacterial infection is that they appear to sense membrane perturbation or delivery of bacterial components into the cytosol through bacterial pore-forming toxins or bacterial secretion systems. This review will discuss the recent developments regarding caspase-1 activation in response to bacterial infection, cross-talk between caspase-1 and other pathways involved in regulating cell death, and recent findings that a number of bacterial pathogens possess mechanisms to inhibit caspase-1 activation. [Copyright &y& Elsevier]

The innate immune system is critical in recognizing bacterial and viral infections to evoke a proper immune response. Certain members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family detect microbial components in the cytosol and trigger the assembly of large caspase-1-activating complexes termed inflammasomes. Autoproteolytic maturation of caspase-1 zymogens within these inflammasomes leads to maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. The NLR proteins ICE protease-activating factor (IPAF), NALP1b (NACHT domain-, leucine-rich repeat-, and PYD-containing protein 1b), and cryopyrin/NALP3 assemble caspase-1-activating inflammasomes in a stimulus-dependent manner. Bacterial flagellin is sensed by IPAF, whereas mouse NALP1b detects anthrax lethal toxin. Cryopyrin/NALP3 mediates caspase-1 activation in response to a wide variety of microbial components and in response to crystalline substances such as the endogenous danger signal uric acid. Genetic variations in Nalp1 and cryopyrin/Nalp3 are associated with autoinflammatory disorders and increased susceptibility to microbial infection. Further understanding of inflammasomes and their role in innate immunity should provide new insights into the mechanisms of host defense and the pathogenesis of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The concept of auto-inflammation was initially coined to define the group of mendelian disorders characterized by recurrent inflammatory symptoms. The core of this group mainly consists of hereditary recurrent fevers, which has been lately enlarged to other inflammatory mendelian disorders as well as to some sporadic diseases with a genetic component relevant to innate immunity. Current knowledge and key points: Cryopyrin, the product of the CIAS1/PYPPAF1/NALP3/NLRP gene, whose mutations underline some mendelian syndromes (Mückle-Wells and chronic infantile neurological cutaneous and articular (CINCA), familial cold urticaria) can now be considered as a major factor of the regulation of interleukin-1 production within the multiprotein complex called inflammasome. This discovery has lit up our view of innate immunity. Future prospects and projects: The contribution of the innate immunity mechanisms in inflammatory disorders have led to a new look to the current nosology of this vast group of diseases and to suggest a classification with two poles. The first would be defined by the predominance of auto-inflammation, whereas in the second one auto-immunity predominates. [Copyright &y& Elsevier]

Mutations in NLRP3 (CIAS1) are identified in a continuum of related inflammatory disorders, known as cryopyrinopathies since NLRP3 codes for the protein cryopyrin. Approximately 40% of patients with classic presentation lack mutations in the coding region of NLRP3 suggesting heterogeneity or epigenetic factors. Cryopyrin is a key regulator of proinflammatory cytokine release. Therefore, variations in the NLRP3 promoter sequence may have effects on disease state in patients with cryopyrinopathies and other inflammatory diseases. In this report, we confirmed three 5′-untranslated region splice forms with two separate transcriptional start sites, and identified potential promoter regions and six new DNA promoter variants. One variant is unique to a mutation negative cryopyrinopathy patient and increases in vitro gene expression. Additional studies can now be performed to further characterize the NLRP3 promoter and sequence variants, which will lead to better understanding of the regulation of NLRP3 expression and its role in disease.Genes and Immunity (2008) 9, 721–726; doi:10.1038/gene.2008.66; published online 21 August 2008 [ABSTRACT FROM AUTHOR]

Background: Cold-induced urticaria is a form of physical urticaria which is characterized by rapid onset of pruritus, erythema, and swelling after exposure to a cold stimulus. Familial cold autoinflammatory syndrome (FCAS) is a rare autosomal-dominant condition characterized by unremitting attacks of cold-induced urticaria, often accompanied by other systemic manifestations. The disorder was previously shown to be caused by mutations in CIAS1, encoding a pyrin-like protein also involved in the pathogenesis of Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular syndrome (CINCA). Methods: In the present study, using direct sequencing, we assessed a two-generation family of Jewish Ethiopian origin, including 3 members affected with FCAS. Results: We identified a novel CIAS1 mutation, F525C. The mutation was shown to affect a highly conserved residue of the protein and to segregate with the disease throughout the extended family. Conclusions: Our results add to the expanding spectrum of mutations in CIAS1 and provide evidence for striking phenotypic heterogeneity in inherited autoinflammatory syndromes. This is the first report of inherited cold urticaria in a family of Ethiopian origin. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The adapter molecules ASC, Ipaf and Cryopyrin/Nalp3 have each been proposed to regulate caspase-1 within a multi-protein complex called the “inflammasome”. Activation of caspase-1 leads to the cleavage and activation of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18. The analysis of mice deficient in ASC, Ipaf and Cryopyrin/Nalp3 has revealed that the inflammasome is a dynamic entity that is assembled from different adapters in a stimulus-dependent manner. [Copyright &y& Elsevier]

Background: Familial cold autoinflammatory syndrome (FCAS) is characterized by rash, fever, and arthralgia in response to cold exposure. CIAS1, the gene that codes for cryopyrin, is mutated in FCAS. Treatment with anakinra (IL-1 receptor antagonist) prevents symptoms, indicating a crucial role for IL-1 in this disease. Objective: To study cytokine responses to cold exposure in monocytes from subjects with FCAS. Methods: Adherence-enriched monocytes were incubated at 32°C or 37°C. Transcription and release of IL-1β, IL-6, and TNF-α were monitored by quantitative PCR and ELISA. Results: The FCAS monocytes but not control cells responded to 4 h incubation at 32°C with significant secretion of IL-1β. At 16 h, IL-1β, IL-6, and TNF-α were all significantly elevated in FCAS monocytes at 32°C. Increased cytokine transcription was observed in all monocytes at 4 hours, but at 16 hours it was only seen in FCAS monocytes incubated at 32°C. Incubation at 32°C for as little as 1 hour sufficed to induce measurable IL-1β release. Caspase-1 inhibitors prevented the cold-induced IL-1β release, whereas a purinergic antagonist did not. Anakinra had no effect on the early IL-1β release but significantly reduced the late-phase transcription and release of all cytokines. Conclusion: FCAS monocytes respond to mild hypothermia with IL-1β release, which in turn induces autocrine transcription and secretion of IL-6 and TNF-α as well as stimulation of further IL-1β production. Clinical implications: These results confirm the central role of IL-1β in FCAS and support the use of IL-1 targeted therapy in these patients. [Copyright &y& Elsevier]

Mutations in cryopyrin and pyrin proteins are responsible for several autoinflammatory disorders in humans, suggesting that these proteins play important roles in regulating inflammation. Using a HEK293 cell-based reconstitution system that stably expresses ASC and procaspase-1 we demonstrated that neither cryopyrin nor pyrin or their corresponding disease-associated mutants could significantly activate NF-κB in this system. However, both cryopyrin and two disease-associated cryopyrin mutants induced ASC oligomerization and ASC-dependent caspase-1 activation, with the disease-associated mutants being more potent than the wild-type (WT) cryopyrin, because of increased self-oligomerization. Contrary to the proposed anti-inflammatory activity of WT pyrin, our results demonstrated that pyrin, like cryopyrin, can also assemble an inflammasome complex with ASC and procaspase-1 leading to ASC oligomerization, caspase-1 activation and interleukin-1β processing. Thus, we propose that pyrin could function as a proinflammatory molecule.Cell Death and Differentiation (2006) 13, 236–249. doi:10.1038/sj.cdd.4401734; published online 22 July 2005 [ABSTRACT FROM AUTHOR]

Mutations in the human CIAS1 (hCIAS1) gene have been identified in a continuum of inflammatory disorders including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). CIAS1 codes for the protein Cryopyrin, which appears to play a role in innate immune function by regulating the production of proinflammatory cytokines. Human and mouse Cryopyrin are highly conserved and consist of three functional domains including a pyrin domain, an NACHT domain, and a leucine-rich repeat (LRR) domain that are characteristics of the NALP family of proteins. The pyrin and NACHT domains of Cryopyrin and other NALP proteins are highly conserved among primate and nonprimate mammals, suggesting purifying selection throughout mammalian evolution. Cryopyrin expression is also very similar in human and mouse with mouse CIAS1 mRNA expression found primarily in peripheral blood leukocytes consistent with the postulated inflammatory function. We also detected significant expression in mouse eye and skin tissue, which is consistent with symptoms observed in human Cryopyrin-associated diseases. [Copyright &y& Elsevier]

Pörksen G, Lohse P, Rösen-Wolff A, Heyden S, Förster T, Wendisch J, Heubner G, von Bernuth H, Sallmann S, Gahr M, Roesler J. Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the CIAS1 gene in three German patients – expanding phenotype of CIAS1 related autoinflammatory syndrome. Eur J Haematol 2004: 73: 123–127. © Blackwell Munksgaard 2004. Dominant mutations in the CIAS1 gene cause a spectrum of autoinflammatory diseases such as familial cold autoinflammatory syndrome, FCAS, which is characterized by episodes of urticaria, arthralgia, fever and conjunctivitis after generalized exposure to cold. We here describe patients of two German families with the 592G→A, V198M mutation, which has been described to induce FCAS before. However, in our patients the clinical phenotype was very different from this disease. They never had urticaria, cold induced fever or conjunctivitis; instead the following symptoms occurred: Very regular periodic fever, irregular severe febrile episodes, relatively mild arthralgia, dry cough, cardiomyopathy, nephropathy and euthyroid thyroiditis all being reversible. We conclude that the clinical phenotype associated with mutations in the CIAS1 gene is much broader than assumed before. [ABSTRACT FROM AUTHOR]