7Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives
Introduction
The term ‘periodic disease’ was first employed by Hobart Reimann in 1948 to describe a clinical syndrome which manifested as benign paroxysmal peritonitis, periodic fevers, cyclical neutropenia and intermittent arthralgia [1]. In 1958, Heller et al. introduced the designation ‘familial Mediterranean fever’ (FMF) for the syndrome described by Reimann, based on its increased prevalence in people of Mediterranean descent and characteristic clinical features [2]. However, FMF, which usually has an autosomal recessive inheritance, is not restricted to these ethnic groups. Over subsequent years came recognition of the clinical aspects of other genetically determined recurrent fevers, both autosomal dominant and recessive, which were all collectively termed ‘hereditary periodic fevers (HPFs)’ (Table 1).
The autosomal dominant conditions include tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) (this condition was previously termed ‘familial Hibernian fever’ in 1982 [3]), familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria (FCU), first described in 1940 [4], Muckle–Wells syndrome (MWS), characterised by urticaria, deafness and amyloidosis, described in 1962 [5] and chronic infantile neurological cutaneous articular syndrome (CINCA; also known as neonatal-onset multisystemic inflammatory disease, abbreviated to NOMID) first described in 1981 [6]. The three syndromes, MWS, FCAS and CINCA/NOMID, are all closely related as they share a number of clinical features and a common genetic basis. In 2001, a heterozygous mutation in the CIAS1/NLRP3 gene was found to be responsible for FCAS and MWS [7]. A year later, a mutation in the same CIAS1/NLRP3 gene was reported to also cause CINCA/NOMID [8]. Subsequently, the umbrella term ‘cryopyrin-associated periodic fever syndromes (CAPS)’ was introduced to highlight the common genetic basis of these conditions.
Hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS) is an autosomal recessive HPF characterised by recurrent episodes of fever associated with lymphadenopathy, abdominal pain and skin rash, first reported in 1984 [9]. The association of HIDS with homozygous mutations in the mevalonate kinase (MVK) gene was first described in 1999 [10], [11].
With the identification of some of the genes underlying the HPFs, the term ‘autoinflammatory disease’ was first proposed in 1999 to encompass some of the distinct clinicopathologic features of these conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells *[12], [13], [14].
McGonagle and McDermott proposed in 2006 that the majority of inflammatory disorders are situated along an immunologic disease continuum (IDC), with genetic disorders of innate and adaptive immunity located at either end of the spectrum [15]. HPFs are the prototypical genetically determined innate immune-mediated diseases, which may be associated with significant tissue destruction without evidence of adaptive immune responses and are designated as autoinflammatory due to their distinct immunopathological features (Table 1).
There is increasing evidence that a combination of environmental, immunogenic and genetic aetiologies is instrumental in causing polygenic autoinflammatory and autoimmune diseases. Recognition of the central contribution of innate immune-related factors at target sites of disease has led to the idea of classifying some conditions (such as Behçet's syndrome, psoriasis, psoriatic arthritis (PsA) and gout) as having major autoinflammatory components [16], *[17]. Dysregulated innate immunity has been demonstrated in Crohn's disease (CD), a polygenic disorder in which a breach in stability of the intestinal mucosal barrier defences causes abnormal handling of commensal luminal bacteria. CD has been classified as a polygenic autoinflammatory condition [18]. Mutations in the NOD2 (NLRC2) gene encoding nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)(NLRC2 protein), also known as caspase recruitment domain-containing protein 15 (CARD15 or IBD1), are present in about 20% of Caucasian patients with CD [19], [20]. The autophagy pathway has also been linked with CD through association with a coding single-nucleotide polymorphism (SNP) (T300A) in the ATG16L1 gene (chromosome 2q) [21], [22]. ATG16L1 encodes a protein involved in the autophagic mechanism, whereby intracellular bacteria are processed by lysosomal degradation; thus, a defect in this pathway may produce an inappropriate response to gut bacteria.
A number of studies have established the contribution of the interleukin (IL)-23 receptor gene (IL23R) to CD risk [23], [24]. The IL23R gene has also been associated with major histocompatibility complex (MHC) human leukocyte antigen (HLA) class I-related conditions, such as spondyloarthritis [25], psoriasis [26] and Behçet’s disease [27]. Although CD does not usually have HLA class I associations, a genetic overlap exists between CD and some MHC class I-associated diseases, including psoriasis [28].
These aforementioned inflammatory diseases exhibit dysregulated innate immunity and are genetically distinct from autoimmunity, but may demonstrate some evidence of adaptive immune responses [29]. Classical autoimmune diseases, with autoantibody and MHC class II associations, including celiac disease and systemic lupus erythematosus (SLE), have adaptive immune genetic associations, including cytotoxic T-lymphocyte antigen-4 (CTLA4) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) that regulates some signalling pathways in T and B cells.
The proposed IDC classification is relevant to the clinical situation, because innate immune-mediated disorders respond better to cytokine antagonism whereas autoimmune-mediated diseases may respond to anti-T and B cell therapies. Furthermore, some conditions such as systemic juvenile idiopathic arthritis (sJIA) and ankylosing spondylitis (AS) have been reclassified as autoinflammatory diseases primarily based on response to IL-1 antagonism in the case of sJIA [30] and innate immune system abnormalities in the case of AS [31].
Section snippets
Many paths lead to autoinflammation
Masters et al. have proposed a classification scheme for autoinflammatory disorders based on molecular mechanisms rather than clinical classification [13]. They have defined six categories of autoinflammatory disease: IL-1β activation disorders (inflammasomopathies), nuclear factor (NF)-kappaB (NF-κB) activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances of cytokine signalling and macrophage activation syndromes. Therefore, in the 15 years that have
How to recognise autoinflammatory diseases
Inherited or monogenic autoinflammatory syndromes are very rare, apart from FMF, which has a high prevalence in some specific ethnic groups (see below). Even in the case of TRAPS, which is thought to be the most common autosomal-dominant HPF, the estimated prevalence in Europe is only 1 per million [156]. The majority of patients will present in childhood, although in rare instances the first recognised clinical manifestation may occur in adolescence or early adulthood. Therefore, the
Conclusions
Since it was first introduced over a decade ago, autoinflammation has gone from being a somewhat hypothetical concept to a recognised term that embodies an expanding area of clinical practice and medical research. Although the principles of autoinflammation are most clearly evident in the pathogenesis of rare monogenic diseases of the innate immunity, it is the study and understanding of these conditions that has brought us closer to a better understanding of the inflammatory processes that
Conflict of interest statement
None of the authors has any conflicts of interest to declare.
Acknowledgements
S. Savic and M.F. McDermott are supported by Arthritis Research UK, M. Wittmann by the Leeds Foundation for Dermatological Research, and M. Wittmann and M.F. McDermott by the Biomedical and Health Research Centre, University of Leeds. Partial funding by the NIHR-LMBRU.
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