INTRODUCTION
The discovery of the genetic causes of various periodic fever syndromes (PFS) has heralded an unprecedented expansion of research focusing on the role of inflammation in the pathogenesis of many common and chronic diseases. In particular a type of inflammation mediated by the innate immune system, termed autoinflammation, has captured the imagination and efforts of many researchers. This term was coined by Dan Kastner in 1999 after the discovery of the genetic basis of familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) [1], to highlight the differences between the pathogenesis of these uncommon conditions and that of well known autoimmune diseases, which are characterized by the presence of autoantibodies and autoantigen-specific T and B cells.
The final common pathway that defines many autoinflammatory conditions is caspase-1 activation and the release of IL-1β. In the case of the monogenic diseases this might occur because one of many molecular pathways that converge to activate caspase-1 is inappropriately activated or inadequately regulated by a mutated protein component (Table 1) [2▪▪,3–6,7▪▪,8▪▪,9▪,10,11,12▪–14▪,15–20]. In the case of polygenic autoinflammatory conditions, this may be due to the accumulation of various metabolites or tissue degradation products. This concept has been recently discussed in great detail by Charles Dinarello, who has pioneered much of IL-1 research [21▪▪]. There is now a greater recognition of the critical role that innate immune-mediated inflammation plays in the pathogenesis of not only PFS but also some common chronic systemic conditions, such as type 2 diabetes (T2D), as well as some diseases that were previously thought to be autoimmune in nature, such as Crohn's disease.
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Table 1: Monogenic autoinflammatory syndromes
Box 1: no caption available
Concerted efforts, made through the development of databases such as INFEVERS (http://www.fmf.igh.cnrs.fr/ISSAID/infevers/) and Eurofever Project (http://www.printo.it/eurofever/autoinflammatory_diseases.asp), to systematically collect clinical and genetic information on patients with PFS, have led to improved recognition of the spectrum of clinical problems associated with these conditions as well as development of targeted treatment strategies. Efforts have also been made to develop accurate disease activity scores, which is an essential requirement for the future success of any clinical trials comparing different treatment strategies and requiring participation of several different treatment centres.
The aim of this review is to provide an update on some of the significant advances in the past 12–18 months in the fields of PFS and autoinflammation.
FAMILIAL MEDITERRANEAN FEVER
Familial Mediterranean fever was the first PFS for which the genetic basis was identified in 1997 [22,23]. This is an autosomal recessive disorder caused by mutations in the MEFV gene coding for the protein pyrin. The clinical features are outlined in Table 2.
Table 2: Clinical features of periodic fever syndromes
Since FMF is an autosomal recessive condition, it was initially assumed that the mutations lead to loss of the protein function; however, experiments with mice expressing the truncated form of pyrin failed to recapitulate the clinical features of FMF [24]. Chae et al.[2▪▪] have recently re-examined the role of pyrin in FMF by generating both pyrin-deficient and ‘knock-in’ mice harbouring mutant human B30.2 domains. Pyrin-deficient animals and heterozygous knock-in mice had no clinical features of FMF, whilst the mice with two mutated copies of the gene (homozygous knock-in) showed a number of inflammatory features consistent with the human disease, including generalized neutophilia, dermatitis and arthritis. To determine if the disease phenotype is dependent on the amount of mutated protein expressed, hemizygous animals were created which showed no evidence of the disease. On the basis of these experiments it was concluded that disease-causing mutations result in a gain of function, but that disease expression is dependent on the amount of mutated protein produced. This might explain why the heterozygous state in FMF patients is sometimes associated with clinical disease.
In subsequent experiments Chae et al.[2▪▪] used RAG1-deficient animals to demonstrate that the inflammatory phenotype in murine FMF is solely dependent on cells of the innate immune system. Furthermore, they showed that this is due to inappropriate IL-1β release, which was exclusively dependent on ASC but not the NLRP3 inflammasome. Collectively these findings confirm the long-held view that FMF is an autoinflammatory disorder caused by abnormalities confined to the innate immune system. It also confirms the critical role of IL-1β in producing the disease phenotype.
There has been an increasing number of case reports in which IL-1 blockade has been used successfully in FMF; these included patients who had either incomplete disease control on colchicine alone, or high serum amyloid A levels despite colchicine, or were unable to use colchicine due to side-effects, or had FMF in association with vasculitis [25]. These clinical cases, together with various functional pyrin studies, suggest that IL-1 blockade is likely to be used more widely in the future for colchicine-resistant cases of FMF.
TUMOUR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME
Mutations in TNFRSF1A were first described as the cause of TRAPS in 1999 [1]. The link between mutations and the associated phenotype remains poorly understood with much heterogeneity between different mutations as well as patients with the same mutation.
Historically, the main mechanisms suggested for the pathogenesis of TRAPS include defective shedding of the receptor from the cell surface [26–27], defective apoptosis [28], increased nuclear factor-kappaB (NF-κB) activation and defective trafficking of the receptor leading to intracellular retention [29–31] (Fig. 1). More recently Simon et al.[7▪▪] described a potential new mechanism to explain hyper-inflammation in TRAPS patients. They reported that TRAPS patients demonstrated higher mitogen-activated protein kinase (MAPK) activation in response to lipopolysaccaride (LPS) than healthy controls and they also showed a hyper-responsiveness whereby TNFRSF1A mutant peripheral blood mononuclear cells (PBMC) could respond to low dose LPS (0.01 ng/ml) [7▪▪]. A follow-up study [8▪▪] investigated the role of reactive oxygen species (ROS) production in the pathogenesis of TRAPS. ROS are known to inactivate MAPK phosphatases by oxidation of the catalytic cysteine residue, thereby enhancing MAPK activation. Therefore, the group investigated whether increased ROS was the cause of the MAPK activation in TRAPS. Monocytes and neutrophils from TRAPS patients showed higher baseline levels of ROS than cells from healthy donors. Increased ROS was shown to mediate increased pro-inflammatory cytokine secretion and also caused an increase in MAPK activation, which is therefore thought to be mediating the cytokine release. Further studies demonstrated the source of the ROS production to be the mitochondria and not the NADPH oxidase system [8▪▪].
FIGURE 1: A summary of the proposed mechanism of TRAPS and the pro-inflammatory pathways they can activate. (a) Defective shedding of TNFR1 from the cell surface leading to constitutive signalling
[26,27]. (b) Hyper-responsiveness to low-dose LPS
[7▪▪]. (c) Defective apoptosis
[28]. (d) Intracellular retention of mutant TNFR1
[29–31]. (e) Higher ROS production originating from mitochondria
[8▪▪]. All of these mechanisms may be able to activate a range of pro-inflammatory pathways such as increased NF-κB activation, MAPK activation and ROS generation leading to pro-inflammatory cytokine release.LPS, lipopolysaccaride; NF-κB, nuclear factor-kappaB; ROS, reactive oxygen species; TRAPS, tumour necrosis factor receptor-associated periodic syndrome.
The complexity of TRAPS pathogenesis is also suggested by different types of treatments that have been used with varying degrees of success. These include corticosteroids and anti-tumour necrosis factor agents such as etanercept, a recombinant human TNFR2-Fc fusion protein [32] but not the monoclonal anti-tumour necrosis factor antibody infliximab, which may induce paradoxical inflammatory reactions and should be avoided [33–34]. More recently the recombinant IL-1 receptor antagonist anakinra has shown promising results [35–37], particularly in patients who do not respond to etanercept [38]. However, there has already been at least one study [39] of nonresponse to anakinra in T50M patients who had previously also failed etanercept. Tocilizumab, a humanized monoclonal antibody that targets the IL-6 receptor α-chain (IL-6Rα), has recently been trialled in TRAPS with promising results in a single patient [40▪].
HYPERIMMUNOGLOBULINAEMIA D WITH PERIODIC FEVER SYNDROME
This autosomal recessive condition is caused by mutations in mevalonate kinase gene [41] (MVK) resulting in deficiency of mevalonate kinase enzyme, which is part of the isoprenoid and cholesterol synthesis pathway. The clinical features and pathogenesis of this condition have recently been reviewed in this journal [42]. Despite its name, elevated IgD levels are not found in all patients and therefore measuring IgD levels is not a useful diagnostic test [3].
IL-1β has previously been shown to have a role in the disease pathogenesis [4,5]. Recently another explanation of how elevated levels of IL-1β may be generated in this condition has been suggested. NLRP3 expression was shown to increase in the PBMC when the mevalonate pathway was inhibited with alendronate. This was also associated with increased IL-1β secretion in response to LPS [6].
The clinical features of patients with hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS) have been previously well described [43]. Recently a cohort of 50 HIDS patients has been characterized from centres in France and Belgium [44]. Most patients had the usual features of HIDS, but interestingly 13 patients also had a history of recurrent or severe infections and three patients were found to have hypogammaglobulinaemia. This raised the possibility that HIDS might be paradoxically associated with an immunodeficiency state in some patients. Furthermore three patients died from HIDS-related causes and the disease remained highly active in more than 50% of surviving symptomatic patients, which suggests that HIDS might have a more severe phenotype than previously thought. IL-1 inhibition with anakinra or canakinumab was the most successful therapeutic approach with 9 out of 14 patients having a complete or partial response.
CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES
Three related systemic autoinflammatory syndromes comprise cryopyrin-associated periodic syndromes (CAPS): familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). Clinical features of these conditions are outlined in Table 2. Most of the clinical manifestations result from excessive release of IL-1β due to autosomal dominant mutations in the NLRP3/CIAS1 gene. The mutated form of NLRP3/CIAS1 is thought to have a tendency for spontaneous oligorimerization, leading to augmented activity of caspase-1 and therefore increased conversion of pro-IL-β into its active form.
Conventional genomic sequencing detects mutations in the NLRP3/CIAS1 gene in approximately 55–60% of CAPS patients. Somatic mosaicism of NLRP3/CIAS1 was first reported in a Japanese CAPS patient in 2005 [45] and the same group went on to report that NLRP3/CIAS1 mutations induced death in monocytes [46]. Somatic NLRP3/CIAS1 mosaicism has recently been reported as a major cause of CINCA/NOMID in an international case-control study [47▪▪] of 26 patients with clinical features of CINCA/NOMID but in whom no mutations were found during conventional sequencing. Subcloning and sequencing of NLRP3/CIAS1 were performed in these mutation-negative patients and their healthy relatives. Somatic NLRP3/CIAS1 mosaicism was identified in 18 of the 26 patients (69.2%) and the levels of mosaicism were estimated to range from 4.2 to 35.8%; mosaicism was not detected in any of the 19 healthy relatives.
The dysregulated production of IL-1β observed in CAPS patients may affect the IL-23/IL-17 axis that links innate and adaptive responses in host defense. Serum and blood samples from CAPS patients were used to study the role of IL-1β in the development of human Th17 cells [9▪]. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of Th17 cells compared with control individuals; serum levels of IL-17 and Th17 frequency were decreased in CAPS patients following in-vivo IL-1β blockade. Likewise, monocyte-derived dendritic cells (MoDCs) from CAPS patients exhibited enhanced secretion of IL-1β and IL-23 upon toll-like receptor stimulation, which was reduced after anti-IL-1 treatment. By contrast systemic-onset juvenile idiopathic arthritis (SoJIA) patients displayed a frequency of Th17 cells similar to normal donors, but had significantly increased serum levels of IL-6 when compared with CAPS patients or healthy donors.
Despite these findings and the fact that the NLRP3 inflammasome is also involved in IL-18 release, CAPS patients respond readily to anti-IL1 blockade using any of currently available agents. These and similar issues related to how best to monitor treatment response in CAPS have recently been reviewed [48▪].
NLRP12-ASSOCIATED PERIODIC SYNDROME
NLRP12-associated periodic syndrome (NAPS12) or NLRP12-associated disorder (NLRP12AD) is also known as FCAS2 since it clinically resembles this condition, but it has a different genetic cause. Similarly to FCAS, attacks of urticarial rash, arthralgia and myalgias are precipitated by exposure to cold and associated with elevated acute-phase response. However, this dominantly inherited condition is associated with mutations in NLRP12 gene.
The effects of the disease-causing mutations on NLRP12 function are currently being investigated. NLRP12 was previously shown to act as a negative regulator of inflammation by suppressing NF-κB activation with subsequent production of pro-inflammatory cytokines and chemokines [10]. In the original description of this PFS, a nonsense mutation, resulting in a premature stop codon, and a splice site mutation, associated with a truncated form of the protein, were described in two different families. Functional studies in these patients demonstrated that both mutations caused decreased inhibition of NF-κB activity compared with the wild type [11].
More recently, additional patients with mutations of NLRP12 have been identified [12▪,13▪]. These, unlike the original cases, had missense mutations, which in the case of the Italian NAPS12 family were thought to affect the highly conserved ATP binding site on the NOD domain. Two independent functional studies in these patients failed to demonstrate any deleterious effect on NF-κB regulation, but both suggested a role for IL-1β in the disease pathogenesis. Borghini et al.[13▪] showed that although IL-1β secretion was normal in these patients, the kinetics of secretion in response to pathogen-associated molecular patterns (PAMPs) was significantly altered, which was associated with increased ROS and a change in the antioxidant kinetics. Jeru et al.[14▪] found spontaneous IL-1β secretion from PBMC in two NAPS12 patients; IL-1Ra and IL-6 levels were also much higher, but tumour necrosis factor levels were similar to controls. Initially these patients responded well to treatment with anakinra; however, it was then discontinued after 14 months, as the bouts of fever and new-onset chronic severe disabling myalgia occurred despite the treatment. The initial response was associated with normalized levels of IL-1β but IL-6 and IL-1Ra levels remained elevated. The relapse was associated with reactivation of the spontaneous IL-1β secretion.
Although IL-1β seems to have a role in the pathogenesis of NAPS12, this does not appear to be as clear-cut as in the case of CAPS. Alternative inflammatory pathways, such as those mediated by IL-6, may turn out to have a more prominent role in this condition.
PERIODIC FEVER APHTHOUS STOMATITIS AND PHARYNGITIS
The acronym ‘PFAPA’ defines a syndrome in which periodic fever (usually recurring every 3–8 weeks, and lasting for 3–6 days) is associated with recurrent aphthous stomatitis, pharyngitis with negative throat cultures, and cervical adenitis, starting before the age of 5 in the majority of the patients [49]. Although these symptoms were included in the original set of diagnostic criteria, Gattorno et al.[50] have questioned their specificity, finding analogous manifestations in the classic monogenic periodic fevers.
The pathogenesis of periodic fever aphthous stomatitis and pharyngitis (PFAPA) remains unclear. An association with a mutant gene has yet to be demonstrated, despite the often positive family history and the possible modifier effects of MEFV mutations on the PFAPA phenotype [51,52]. Tonsillar histology shows no abnormalities other than nonspecific chronic inflammation [53].
The involvement of both the innate and adaptive immune responses in PFAPA has been suggested [54]. Stojanov et al.[55▪▪] have recently reported that gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals in the same patients. PFAPA flares were characterized by upregulation of complement, inflammasome and IFN-gamma-signalling-related transcripts from peripheral blood. In addition high serum levels of some Th-1-related chemokines and cytokines (namely IP-10/CXCL10, MIG/CXCL9 and G-CSF) and a reduction of circulating CD4+ T cells were observed. The authors hypothesize the recruitment of T cells to the periphery after activation of innate immunity by an infectious trigger [55▪▪].
Although up to 30% of PFAPA cases may spontaneously resolve after the age of 5, most patients will require medical or surgical treatment. One to three doses of corticosteroids (usually ∼ 1 mg/kg prednisolone per dose) are generally effective in aborting a flare, but may shorten the asymptomatic interval. Cimetidine has been used prophylactically in some patients [56]. Currently there is insufficient evidence to support the routine use of tonsillectomy or adenotonsillectomy over medical treatment in the management of PFAPA [57,58]. Demonstration of an inflammasome signature in PFAPA has recently prompted the use of anakinra in five patients, leading to a reduction of symptoms and a decrease in the overexpression of circulating chemokines [55▪▪].
THE ROLE OF AUTOINFLAMMATION IN COMMON DISEASES
The importance of IL-1β-mediated inflammation in the pathogenesis of a number of common diseases has been increasingly appreciated. In the pathogenesis of T2D, caspase-1-mediated IL-1β release has been found to cause a decrease in insulin sensitivity and lead to direct toxicity to insulin producing islet cells [21▪▪]. Randomized control trials of anti-IL-1 directed therapy showed this to be effective in improving glycaemic control and reducing insulin requirements [59]. Caspase-1 activation in T2D is thought to be dependent on NLRP3, which in turn is activated by protein aggregates, such as oligomers of islet amyloid polypeptides (IAPPs) [60▪▪]. Similar processes have been suggested to occur in the pathogenesis of unrelated diseases, such as Alzheimer's and amyotrophic lateral sclerosis, in which different types of protein aggregates also lead to NLRP3 activation [61].
IL-1β is also released in response to tissue damage, which may occur for example as a result of ischaemia. This is relevant for cardiac myocyte survival following an acute myocardial infarction, when IL-1β has been shown to be toxic to the cells [62]. Subsequent trials of anakinra in patients who suffered ST-elevation myocardial infarction showed significantly less myocardial remodelling in the patients receiving the treatment compared with controls [63].
CONCLUSION
The advances in basic biology of the PFS continue to provide fascinating insights into the nature of inflammation and the numerous pathways that control activation and resolution of the inflammatory responses. The success of IL-1 blockade in a range of these conditions as well as recent discoveries in the biology of TRAPS and T2D would suggest there is a tangible connection between disordered metabolism and pathological inflammation. This is arguably the most exciting recent development in this field and was predicted by the late Jürg Tschopp (in whose laboratory the inflammasomes were discovered) to have a significant impact on future research and therapy of autoinflammatory diseases.
Acknowledgements
Partial funding by the NIHR-Leeds Musculoskeletal Biomedical Research Unit, Arthritis Research UK (19269), FP7-HEALTH-2007-2.4.4-1 grant, and the Leeds Teaching Hospitals NHS Trust Charitable Foundation.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 124).
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