new players driving inflammation in monogenic ... · (proteostasis), protein misfolding and...

NATURE REVIEWS | RHEUMATOLOGY ADVANCE ONLINE PUBLICATION | 1

Department of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, Epalinges 1066, Switzerland (F.M.). Inflammatory Disease Section, National Human Genome Research Institute, Building 10 Room B2‑5235, 10 Center Drive, MSC 1849, Bethesda, MD 20892‑1849, USA (I.A.).

Correspondence to: I.A. aksentii@ exchange.nih.gov

New players driving inflammation in monogenic autoinflammatory diseasesFabio Martinon and Ivona Aksentijevich

Abstract | Systemic autoinflammatory diseases are caused by abnormal activation of the cells that mediate innate immunity. In the past two decades, single‑gene defects in different pathways, driving clinically distinct autoinflammatory syndromes, have been identified. Studies of these aberrant pathways have substantially advanced understanding of the cellular mechanisms that contribute to mounting effective and balanced innate immune responses. For example, mutations affecting the function of cytosolic immune sensors known as inflammasomes and the IL‑1 signalling pathway can trigger excessive inflammation. A surge in discovery of new genes associated with autoinflammation has pointed to other mechanisms of disease linking innate immune responses to a number of basic cellular pathways, such as maintenance of protein homeostasis (proteostasis), protein misfolding and clearance, endoplasmic reticulum stress and mitochondrial stress, metabolic stress, autophagy and abnormalities in differentiation and development of myeloid cells. Although the spectrum of autoinflammatory diseases has been steadily expanding, a substantial number of patients remain undiagnosed. Next‑generation sequencing technologies will be instrumental in finding disease‑causing mutations in as yet uncharacterized diseases. As more patients are reported to have clinical features of autoinflammation and immunodeficiency or autoimmunity, the complex interactions between the innate and adaptive immune systems are unveiled.

Martinon, F. & Aksentijevich, I. Nat. Rev. Rheumatol. advance online publication 23 September 2014; doi:10.1038/nrrheum.2014.158

IntroductionAutoinflammatory diseases are a distinct group of rheu-matic diseases that are characterized by either periodic or chronic systemic inflammation, often manifesting with unexplained fevers, and with little or no involve-ment of T cells and B cells.1,2 The discovery of disease-causing mutations in genes that have an important role in regulating innate immune responses has established autoinflammation as a spectrum of inflammatory pheno types driven by abnormal activation of mono-cytes, macrophages and granulocytes. In the past, the role of myeloid cells in rheumatic diseases has, to some extent, been overlooked owing to strong interest in the function of T and B cells, which are typically hyper-active in patients with autoimmune diseases. Despite these differences between autoinflammation and auto-immunity, the underlying processes are not mutually exclusive. Some classical autoimmune diseases, such as psoriasis and rheumatoid arthritis (RA), have been associated with alleles in genes that regulate innate immune responses, or can be inferred to have substan-tial innate immune involvement on the basis of thera-peutic res ponse to IL-1 inhibitors. Conversely, patients with auto inflammation might have a dysregulated adap-tive immune system, challenging the clear delineation between au toinflammation and autoimmunity.3

At present, mutations in more than 15 genes mediating several distinct pathways have been associated with auto-inflammatory syndromes (Table 1).4 These studies have expanded the understanding of the molecular mecha-nisms underlying inflammatory responses in a broad spectrum of human diseases, beyond auto inflammation. This is the case, for example, in cryopyrin-associated period ic syndromes (CAPS), a family of syndromes caused by gain-of-function mutations in NLRP3. The initial demonstration of the role of the NLRP3 inflam-masome in the regulation of IL-1β signalling has inspired numerous studies investigating the inflammasome’s contribution to many pathologies, including infections, autoimmune diseases, neurodegenerative disorders, metabolic syndromes and cancer.

In this Review, we discuss the latest developments in research into the pathogenesis of autoinflammation. We present evidence that links the mechanisms of auto-inflammation to some basic and evolutionarily conserved cellular pathways, such as protein misfolding, the endo-plasmic reticulum (ER)-stress response and proteostasis. We also discuss new players, including a secreted growth factor-like protein with a role in macrophage differentia-tion, that have emerged in this field as a result of advances in next-generation sequencing (NGS) technologies. These discoveries have pushed the boundaries of auto-inflammation beyond dysregulation of cytokine signalling and malfunctions limited to intracellular pathways.

Competing interestsThe authors declare no competing interests.

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Mechanisms of inflammatory responsesTNFR1 mutations and protein misfolding Mutations in the TNFRSF1A gene, which encodes TNF receptor 1 protein (TNFR1), were first reported in 1999 as the cause of a dominantly inherited disease known as TNF receptor-associated periodic syndrome (TRAPS).5 This landmark paper defined the term ‘auto-inflammatory syndrome’ and, together with the identi-fication of mutations in MEFV as the cause of familial Mediterranean fever (FMF),6,7 marked the beginning of a new era of research that led to the molecular decipher-ing of many previously uncharacterized inflammatory diseases. Patients with TRAPS experience recurrent epi-sodes of fever lasting several weeks and associated with severe abdominal pain, serositis, skin rashes, ocular inflammation, and myalgia. The inflammatory episodes either occur spontaneously or are provoked by various types of stress. Most TRAPS-associated mutations are subtle missense changes exclusively in the extracellular domain of TNFR1.8

Early studies suggested that TRAPS-associated auto-inflammation was mediated by a defect in the shedding of the soluble extracellular domain of TNFR1; this defect could impair the downregulation of the membrane-bound receptor and diminish the release of a potentially antagonistic TNFR1 molecule.9 However, only a sub set of mutations was found to affect shedding of the recep-tor.10 Moreover, anti-TNF therapy with etanercept, a recombinant human TNFR2–Fc fusion protein com-prising two receptors linked by an immunoglobulin Fc fragment, produced only a modest response in patients with TRAPS, probably reflecting the promiscuous role of TNF in almost all inflammatory cascades.8 These findings suggest that the mechanisms by which TNFR1 mutations drive autoinflammation in TRAPS do not rely on increased bioavailability of TNF or aberrant firing of the receptor induced by its ligand. Indeed, most TRAPS-associated TNFR1 mutants are retained in the ER, which suggests that the mutations most likely affect protein folding and trafficking to the membrane.11–13 Therefore, in TRAPS, mutant TNFR1 does not function as a surface receptor for TNF, but can cooperate with the wild-type protein to drive inflammation.14

Interestingly, the cytosolic domain of the mutant receptor is unaffected, suggesting that it might retain some functionality. The proficiency of mutant TNFR1

Key points

■ Over the past decade, major advances have been made in understanding the molecular link between disease‑causing mutations and inflammation in patients with autoinflammatory diseases

■ A number of alterations in the pathways related to the maintenance of proteostasis have been implicated in monogenic autoinflammatory diseases

■ Next‑generation sequencing technologies have been instrumental in the identification of new disease‑causing genes

■ The identification of ADA2 mutations in patients with inflammation and vasculopathy and/or vasculitis provides evidence that autoinflammation is not limited to the malfunction of intracellular proteins

■ Newly discovered genes and pathways provide further evidence that autoinflammation and autoimmunity are not mutually exclusive processes

to assemble a proinflammatory signalling complex at the ER has not been directly demonstrated, but some studies have suggested that TNFR1 can signal at the ER. TNFR1 has been shown to associate with the ER-anchored serine/threonine-protein kinase/endoribonuclease IRE1 to promote ER-stress-induced activation of c-Jun N-terminal kinases (JNKs),15 a group of kinases that contribute to the transcriptional induction of inflamma-tory mediators such as IL-8 or CC-chemokine ligand 5 (CCL5; also known as RANTES). These observations indicate that TNFR1 can signal within the ER in the context of ER stress. It is tempting to speculate, there-fore, that TNFR1 misfolding and proteostasis deregula-tion within the ER lumen might trigger a response that contributes to the pathophysiology of TRAPS.

Proteostasis deregulationProteostasis refers to the network of biological path-ways within cells that control the biogenesis, fold ing, traf ficking and degradation of proteins (Figure 1). Pertur b ations in these pathways are thought to con-tribute to the development of diseases associated with exces sive protein misfolding and degradation, as well as aggregation- associated degenerative disorders (Box 1).16 Protein mis folding within the ER is a typical deregu lator of proteo stasis and is characterized by the engage ment of stress-response programmes aimed at restor ing homeostasis. These responses have also been associated with spontaneous or exacerbated inflam-mation.17 In mice, a mutation affecting the folding of Muc-2, a mucin expressed in the Paneth and goblet cells, activates hallmarks of ER stress and causes an ulcera-tive colitis-like phenotype.18 As well as in Paneth and goblet cells, hyper-responses to inflammatory stimuli have also been shown in macrophages. In the context of the spondyloarthro pathies, which are a group of polygenic autoinflammatory diseases characterized by HLA-B27 misfolding, mild ER stress caused by accumu-lation of HLA-B27 within the ER has been suggested to con tribute to a hyper- responsive phenotype in macro-phages. These macrophages have enhanced cytokine production and increased release of type I interferon upon stimulation with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide.19

The mechanisms that link protein misfolding and proteostasis regulation with inflammation in auto-inflammatory diseases are still unclear. Patients with TRAPS-associated TNFR1 mutations, for example, have no signs of the unfolded protein response (UPR, the clas-sical ER stress response), such as upregulation of the heat shock protein family chaperone GRP78 (also known as BiP) or the transcription factor C/EBP homologous protein (CHOP, also known as DNA damage-inducible transcript protein 3), but show increased activation of the transcription factor X-box-binding protein 1 (XBP1) and increased production of reactive oxygen species (ROS), two ER-stress-related signalling pathways that could contribute to the inflammatory response.20,21

Different hypotheses could explain the inflamma-tion in protein-misfolding-associated inflammatory

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diseases (Figure 2). For example, signalling pathways stemming from the affected protein within the ER could contribute to the activation of inflammatory pathways. This has been suggested to be the case in patients with TRAPS who show increased activation of JNK and

p38 mitogen-activated protein kinase (MAPK), kinases that can contribute to cytokine expression.20 ER sig-nalling pathways caused by protein misfolding and ER overload could also contribute to inflammation. XBP1 is activated downstream of TLR4 and TLR2, and

Table 1 | Molecular classification of monogenic autoinflammatory diseases

Disease* Gene Protein Mode of inheritance

Mutation type

Mechanism(s) of disease References

Familial Mediterranean fever MEFV Pyrin Autosomal recessive

Gain of function

Inflammasome activationIL‑1β release

6,7,75

TNF receptor‑associated periodic syndrome (TRAPS)

TNFRSF1A TNFRSF1A Autosomal dominant

Gain of function

Unfolded protein responseER stressMAPK activationIncreased production of mROS

5,9,76

Mevalonate kinase deficiency/ hyper IgD syndrome (MKD/HIDS)

MVK Mevalonate kinase Autosomal recessive

Loss of function

Shortage of isoprenoid compoundsActivation of the small GTPase Rac1Inflammasome activationIL‑1β release

77–79

Familial cold autoinflammatory syndome 1 (FCAS1)‡

NLRP3 NLRP3 Autosomal dominant

Gain of function


75,80

Muckle–Wells syndrome (MWS)‡ NLRP3 NLRP3 Autosomal dominant

Gain of function


75,80

Blau syndrome NOD2 NOD2 Autosomal dominant

Gain of function

Constitutive NFκB activation 81,82

Neonatal onset multisystem inflammatory disease (NOMID)‡§

NLRP3 NLRP3 De novo or autosomal dominant

Gain of function


83,84

Pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA)

PSTPIP1 PSTPIP1 Autosomal dominant

Gain of function

Inflammasome activation 85,86

Majeed syndrome LPIN2 Phosphatidate phosphatase LPIN2

Autosomal recessive

Loss of function

Loss of phosphatidate phosphatase activity leads to decreased inhibition of proinflammatory signalling

87,88

Familial cold autoinflammatory syndrome 2 (FCAS2)

NLRP12 NLRP12 (also known as NALP12)

Autosomal dominant

Loss of function

Decreased inhibition of NFκBIncreased processing of caspase 1 and IL‑1 release

75,89,90

Deficiency of IL‑1‑receptor antagonist (DIRA)

IL1RN IL‑1Ra Autosomal recessive

Loss of function

Decreased inhibition of IL‑1α/β signalling

91–93

Early‑onset enterocolitis IL10RAIL10RBIL10

IL‑10RαIL‑10RβIL‑10

Autosomal recessive

Loss of function

Decreased inhibition of IL‑10 signalling

94,95

Deficiency of IL‑36‑receptor antagonist (DITRA)

IL36RN IL‑36Ra Autosomal recessive

Loss of function

Decreased inhibition of IL‑36 signalling

91,96,97

HOIL‑1 deficiency RBCK1 RBCK1 (also known as HOIL‑1)

Autosomal recessive

Loss of function

Decreased activation of NFκBEnhanced sensitivity to IL‑1

56,98

Autoinflammation and PLCγ2‑associated antibody deficiency and immune dysregulation (APLAID)

PLCG2 PLCγ2 Autosomal dominant

Gain of function

Decreased autoinhibition in PLCγ2 signalling

51

Proteasome associated autoinflammatory syndromes (PRAAS)

PSMB8 Immunoproteasome subunit β5i

Autosomal recessive

Loss of function

Impaired degradation of ubiquitinated proteinsCellular stress

41–44

Deficiency of ADA2 (DADA2) CECR1 ADA2 Autosomal recessive

Loss of function

Impaired differentiation of macrophages and endothelial cells

57,58

STING‑associated vasculopathy with onset in infancy (SAVI)

TMEM173 STING Autosomal dominant

Gain of function

Increased STING‑induced interferon activation by TBK1 and IRF‑3 phosphorylation

74

*Diseases are listed in the chronological order in which they were discovered. ‡One of the group of diseases collectively known as the cryopyrin‑associated periodic syndromes (CAPS). §Also known as chronic infantile neurological, cutaneous and articular (CINCA) syndrome. Abbreviations: ADA2, adenosine deaminase 2; ER, endoplasmic reticulum; HOIL‑1, haem‑oxidized IRP2 ubiquitin ligase 1; IL‑1Ra, IL‑10 receptor antagonist; IL‑10R, IL‑10 receptor; IL‑36Ra, IL‑36 receptor antagonist; IRF‑3, interferon regulatory factor 3; MAPK, mitogen‑activated protein kinase; mROS, mitochondrial reactive oxygen species; NOD2, nucleotide‑binding oligomerization domain‑containing protein 2 (also known as CARD15); PLC, phospholipase C; PSTPIP1, PEST phosphatase‑interacting protein 1 (also known as CD2BP1); STING, stimulator of interferon genes protein; TBK1, TANK‑binding kinase 1; TNFRSF1A, TNF receptor superfamily member 1A.

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contributes to the production of cytokines such as IL-6 and TNF.22,23 TLR-driven XBP1 activation is not part of the UPR but synergizes with TLR signalling pathways to optimize cytokine release, suggesting that specific ER sig-nalling pathways can contribute to inflammation in the absence of ER stress. The ER-stress-induced transcription factor CHOP has also been involved in the upregulation

of cytokines, including IL-23, in ER-stressed dendritic cells treated with TLR agonists.24 That transcription factors typically associated with proteostasis deregula-tion can modulate inflammatory responses demonstrates the connection between these stress pathways. However, how this connection contributes to the development of autoinflammatory diseases is poorly understood.

Protein misfolding and inflammation have also been linked to the inflammasome pathway (Figure 2). Inflammasome activation has been observed in macro-phages following treatment with pharmacological activators of ER stress25–27 or upon proteostasis deregu-lation.28 Although aberrant inflammasome activation in autoinflammatory diseases linked to protein misfold-ing remains to be proven, the inflammasome probably has a role in driving these diseases. This hypothesis is supported by the good therapeutic response to IL-1-inhibiting biologic agents in patients with TRAPS. Furthermore, cells expressing TRAPS mutations have increased ROS production and decreased autophagy,20,29 two hallmarks of increased NLRP3 inflammasome acti-vation.30 Whether the inflammasome has a direct role in initiating inflammation in misfolding-mediated auto-inflammation, similar to its role in gout or CAPS,31 needs to be addressed. This question highlights the difficulties in determining the relative contributions of specific and non-specific pathways to the pathogenesis.

Proteasome deficienciesProteostasis within the cell can be affected not only by protein misfolding, but also by proteasome malfunction. Protein degradation is essential for cellular homeostasis and viability, removing proteins that are no longer neces-sary for maintaining the cell cycle, or that are oxidized or otherwise damaged, misfolded or pathogen-derived. The ATP-dependent lysosomal-independent protea-some pathway, also known as the ubiquitin– proteasome system (UPS), has been conserved from archaebacteria to eukaryotes32 and is emerging as a pathway of interest in inflammatory diseases. The proteasome multiprotein complex is expressed in all cell types. Mammalian cells can express an alternative form of the proteasome known as the immunoproteasome (Figure 3a). The immuno-proteasome differs from the proteasome in a subset of subunits, the transcription of which is induced, for example, upon infection.33 Immunoproteasomes have an enhanced ability to generate immunocompetent anti-genic peptides for presentation by MHC class I molecules by degrading immunogenic substrates (Figure 3b).34 Because of its pivotal role in MHC class I ligand gen-eration, the immuno proteasome also shapes cytotoxic T-cell responses and cytokine production in the periph-ery. Mice lacking the three immunoproteasome-specific catalytic subunits have defects in presenting multiple MHC class I epitopes, whereas presentation of MHC class II peptides is unaffected.35 Another type of pro-teasome, termed the thymoproteasome (Figure 3a), is specifically expressed by thymic cortical epithelial cells and is required for the positive selection of MHC-class I-restricted T cells.36

Figure 1 | Proteostasis pathways. Protein homeostasis or ‘proteostasis’ is the process that regulates the production, proper folding, localization, and turnover of proteins, as well as quality controls to get rid of flawed or mislocalized proteins. Different insults and perturbations affect proteostasis pathways and trigger specific stress‑response programs that aim to restore proteostasis function and balance. Transcription factors involved in restoring protein homeostasis include the ER stress‑response factors XBP1 and ATF4. Abbreviations: ATF, activating transcription factor; CHOP, C/EBP homologous protein (also known as DNA damage‑inducible transcript protein 3); HSF1, heat shock factor 1; IRE1, serine/threonine‑protein kinase/endoribonuclease IRE1; NFE2L2, nuclear factor erythroid 2‑related factor 2; PERK, protein kinase RNA‑like endoplasmic reticulum kinase; XBP1; X‑box‑binding protein 1.

Insults and perturbations Stress responses

Translation

Folding

Degradation

Proteostasis

Localization Modi�cation

REDOX imbalanceProteasome de�ciency Temperature changesEnvironmental stress

AgeingDrugs

PathogensDifferentiation

Genetic mutationsCaloric restrictions

ATP de�ciency

Heat shock responseHSF1

Unfolded protein response

IRE1, XBP1ATF6

PERK, ATF4, CHOPOxidative stress

responseNFE2L2

Mitochondrial stress response

Box 1 | Proteostasis in human health

The maintenance of protein homeostasis (proteostasis) is essential to human health. The proteostasis network is a group of pathways that ensures that each protein within the cell will be properly folded, correctly glycosylated and fully functional when it reaches its final destination. This network also ensures that useless, mislocalized or misfolded proteins are, when required, rapidly degraded and cleared to prevent toxicity and cellular damage. Aberrant protein misfolding or aggregation is detected by compartment‑specific stress‑response pathways that orchestrate the activity of effector mechanisms of the proteostasis network in order to restore homeostasis and protein production. Proteostasis surveillance within the ER is mediated by the UPR, also known as the classical ER stress response, which triggers three signalling pathways to cope with the stress. These three branches each have an upstream ER‑anchored sensor: IRE1, ATF6 and PERK, respectively. The synergistic activation of the three branches orchestrates a downstream response that induces chaperone expression, membrane biogenesis, regulators of membrane‑trafficking pathways, and protein degradation mechanisms, as well as regulators of protein translation rates. A growing body of evidence has linked activation of the UPR as well as the engagement of individual ER stress sensors (such as IRE1) with hallmarks of inflammation, including cytokine production, suggesting that inflammation might be a systemic response to the loss of proteostasis. Proteostasis can be perturbed by environmental factors, oxidative stress, ageing and genetic mutations affecting the folding of proteins or genes in the proteostasis pathways. Inflammation might, therefore, contribute to the pathogenesis of diseases associated with proteostasis dysregulation. This mechanism has been proposed for a subset of autoinflammatory diseases characterized by protein misfolding or proteasome defects.Abbreviations: ER, endoplasmic reticulum; IRE1, serine/threonine‑protein kinase/endoribonuclease IRE1; PERK, protein kinase RNA‑like ER kinase; UPR, unfolded protein response.

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The imbalance between proteasome activity and pro-teasome substrate load can produce a buildup of protein aggregates within the cytosol or the ER, or both. This imbalance is associated with numerous diseases, includ-ing neurodegenerative, metabolic and immunoregula-tory disorders.37 Mutations and polymorphisms in genes encoding proteasome subunits (mainly PSMA6 and PSMA7) have been associated with disorders such as type 2 diabetes mellitus, neurodegenerative dis-eases and cardiovascular diseases.37 Polymorphisms in PSMB8, PSMB9 and PSMD7 have been associated with ankylosing spondylitis (AS),38,39 suggesting that immunoproteasome or proteasome functionality might affect HLA-B27-related inflammatory diseases. A poly-morphism in PSMB8 was also associated with juvenile RA.40 However, these studies were not well powered and they need to be replicated in larger cohorts.

Distinct mutations in the immunoproteasome catalytic subunit β5i, encoded by PSMB8, are associated with a spectrum of proteasome-associated autoinflammatory syndromes (PRAAS) known variously as CANDLE (chronic atypical neutrophilic dermatosis with lipo-dystrophy and elevated temperature syndrome), JASL (Japanese autoinflammatory syndrome with lipodys-trophy; also known as Nakajo–Nishimura syndrome), and JMP (joint contractures, muscle atrophy, microcytic anaemia and panniculitis-induced lipodystrophy).41–45

This autosomal recessive autoinflammatory syndrome is characterized by lipodystrophy and systemic multi-organ inflammation leading to progressive joint con-tractures and other disabilities. Disease-associated mutations in PSMB8 might cause either a decrease of the ch ymotrypsin-like catalytic activity of the immuno-proteasome or might affect its assembly.41–45 In these patients, therefore, failure of proteolysis probably leads to the accumulation of damaged proteins, perturbations in proteostasis and a subsequent increase in cytokine production. Findings from cytokine profiling and analy-sis of the transcriptome are consistent with induction of inflammatory mediators such as IL-6 and the interferon pathway.41,44 The mechanisms that link proteasome deficiencies with increased cytokine production are, however, still unclear. It is tempting to speculate that per-turbations in the proteostasis pathways caused by pro-teasome deficiency might induce stress-response factors such as XBP1 (which is known to upregulate inflam-matory mediators including IL-6 and interferon path-ways).46 The mechanism underlying lipodystrophy in proteasome deficiencies is also unclear. Downregulation of PSMB8 has been suggested to alter turnover of specific proteins that regulate adipocyte differentiation.42

The immunoproteasome is involved in generating the repertoire of peptides loaded in the ER for presentation. Alterations in the repertoire possibly affect MHC traf-ficking or stability within the ER, to promote inflam-matory signals. This hypothesis is supported by studies linking ERAP1 polymorphisms with inflammatory conditions such as psoriasis, Behçet disease and AS.47,48 Endoplasmic reticulum aminopeptidase 1 (ERAP1) is involved in trimming peptides within the ER to optimize their length for MHC-I binding (Figure 3b). In AS, pro-inflammatory alterations in ERAP1 are often associated with an interaction with the disease- associated HLA-B27 allele.49 This observation hints that ERAP1 exerts its effect by influencing the stability and processing of HLA-B27. Alterations in ERAP1 or in the immuno-proteasome could, therefore, affect MHC molecules to trigger specific signals within the ER, or ER-stress-related signalling pathways that promote inflammation. Similarly, HLA-B51 is associated with Behcet disease; it would be interesting to investigate whether unstable HLA-B51 could contribute to this disease.50 Further work will be necessary to clarify the mechanisms by which PSMB8, ERAP1, HLA-B27 or HLA-B51 contribute to inflammation in patients.

Novel autoinflammation-associated genesWhole-genome or exome sequencing with the use of massively parallel sequencing technologies (also known as NGS) has proven to be an effective way to iden-tify disease-causing mutations in patients with as-yet uncharac terized diseases, whether they present as spora-dic cases or in the context of a positive family history. NGS strat egies have advanced the field by identifying disease- causing mutations in several genes that other-wise would not have been considered candidate genes for autoinflammatory diseases. Notably, several newly

JNKp38ROS

1

3

2Proteinmisfolding

Stress responsepathways

ER lumen

PERK

IRE1

IL-6, IL-8,CCL5, etc.

CHOP, IL-23, etc.

XBP1ATF4 JNK

Pro-IL-1β IL-1β

Caspase-1

In�ammasome

Nucleus

Figure 2 | Protein‑misfolding‑mediated inflammation. Three distinct pathways have been proposed to contribute to inflammation in the context of protein‑misfolding disorders. Proteostasis regulatory pathways within the ER (1), such as IRE1 and PERK, can activate specific transcription factors (e.g. ATF4, CHOP, XBP1) that can exacerbate inflammatory cytokine production. IRE1 can also trigger JNK, another regulator of inflammatory and stress programmes. Accumulation of misfolded proteins (2) can contribute in an as‑yet undefined way to the accumulation of ROS, p38 and JNK. Proteostasis deregulation has also been suggested to activate the inflammasome (3), a molecular platform that recruits the protease caspase‑1, which cleaves pro‑IL‑1β, thereby activating it and enabling the secretion of mature IL‑1β. Abbreviations: ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein (also known as DNA damage‑inducible transcript protein 3); CCL5, CC‑chemokine ligand 5 (also known as RANTES); ER, endoplasmic reticulum; IRE1, serine/threonine‑protein kinase/endoribonuclease IRE1; JNK, Janus kinase; PERK, protein kinase RNA‑like endoplasmic reticulum kinase; ROS, reactive oxygen species; XBP1, X‑box‑binding protein 1.

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discovered diseases seem to occupy the interface between autoinflammation and immunodeficiency.

PLCγ2 pathwayA hypermorphic mutation in phospholipase Cγ2 (PLCγ2), an enzyme with a critical regulatory role in various immune and inflammatory pathways, was iden-tified as a causal variant in a family with a dominantly inherited systemic inflammatory disease and mild immunodeficiency.51 Patients with the disorder, termed auto inflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID), suf-fered from early-onset recurrent blistering skin lesions, cellulitis, nonspecific interstitial pulmonary dis ease, arthralgia, and inflammatory eye and bowel dis ease. The mis sense mutation in the gene encoding PLCγ2 (PLCG2) affects the function of the autoinhibitory SH2 domain of the enzyme, resulting in enhanced PLCγ2 activity, an increase in the release of intracellular Ca2+ from the ER stores, and activation of ERK signalling in stimulated CD19+ B cells. Similarly, genomic deletions in the regulatory region of PLCG2 result in constitutive phospholipase activity and have been associated with a distinct disease manifested by cold-induced urticaria and various degrees of immunodeficiency and auto-immunity (PLAID).52 However, B cells from patients with PLAID stimulated ex vivo by B-cell-receptor crosslinking had increased ERK signalling only with decreasing temperature. Both genetic defects lead to the near-absence of circulating class-switched memory B cells. The molecular mechanism that underlies inflam-mation and immune defects related to increased signal-ling in the PLCγ2 pathway is not fully understood, but is consistent with murine models of compromised PLCγ2 autoinhibition.53,54 As increased intracellular Ca2+ sig-nalling has been associated with NLRP3 inflammasome activation,55 this link possibly explains an inflammatory phenotype in APLAID. In this instance, a study based on murine cells might help connect apparently distinct pathways in humans.

HOIL‑1 deficiencyHOIL-1 deficiency is another example of a disease that occupies the interface between autoinflammation and immunodeficiency. Loss-of-function mutations in RBCK1, which encodes haem-oxidized IRP2 ubiquitin ligase 1 (HOIL-1), were identified in two families with early-onset recurrent systemic inflammation, hepato-splenomegaly, lymphadenopathy, amylopectin-like deposits in myocytes, and impaired antiviral and anti-bacterial host responses.56 The immunological pheno-type included a paucity of memory B cells. HOIL-1 is one of the three subunits of the linear ubiqui tin chain assembly complex (LUBAC), which attaches ubiqui-tin molecules to various proteins either to mark them for proteasomal degradation or to traffic them to speci fic cellular locations. The most intriguing aspect of the disease pheno type is that HOIL-1 deficiency has pleiotropic effects in various cell types. Whereas HOIL-1-deficient lymphocytes and fibroblasts have

a

MHCclass I

ER lumen

Substrate

20S catalyticcore particle

Proteolyticfragments

Constitutiveproteasome

Immunoproteasome Thymoproteasome

β5 (PSMB5)β2 (PSMB7)β1 (PSMB6)

β5i (PSMB8)β2i (PSMB10)β1i (PSMB9)

β5t (PSMB11) β2i (PSMB10)β1i (PSMB9)

b

ERAP1 or ERAP2

Figure 3 | Composition and function of the proteasome. a | The 20S fraction of the constitutive proteasome, the immunoproteasome and the thymoproteasome is composed of a 28‑subunit 20S proteolytic core. The proteolytic subunits specific to the constitutive proteasome are PSMB5 (β5), PSMB7 (β2) and PSMB6 (β1). The immunoproteasome‑specific subunits are PSMB8 (β5i), PSMB10 (β2i) and PSMB9 (β1i). The thymoproteasome has the same composition as the immunoproteasome except for the catalytic subunit PSMB8 (β5i), which is replaced by PSMB11 (β5t). b | The proteasome degrades polypeptides to the ideal length for binding MHC class I, although further cleavage might occur in the cytoplasm (by aminopeptidases) or upon translocation in the ER (by ERAPs). The binding of high‑affinity peptides to MHC molecules triggers its final folding. Loaded and folded MHC molecules are then transported to the surface of the cell. Abbreviations: ER, endoplasmic reticulum; ERAP, endoplasmic reticulum aminopeptidase; PSMB, proteasome subunits, β‑type.

Box 2 | Monogenic diseases of the purinergic signalling pathway

The purinergic signalling pathway has been implicated in many acute and chronic diseases, including acute lung injury, lung inflammation in asthma, vascular inflammation, multiple sclerosis and IBD.99 Therapeutic agents targeting purinergic signalling are already used to treat patients with rheumatoid arthritis, IBD and other autoimmune diseases. However, few human diseases are known to be caused by single genetic defects in the purinergic signalling pathway. Among the few are SCID caused by ADA1 deficiency (mutations in ADA); ACDC (mutations in NT5E),100 and systemic vasculopathy and/or vasculitis with inflammation caused by deficiency of ADA2 (mutations in ADA2). Patients with SCID have profound defects in the differentiation and function of B cells and T cells, owing to intracellular accumulation of toxic deoxyadenosine nucleotides.101 Surprisingly, the latter two diseases (ACDC and DADA2) are both related to vascular pathology. Deficiency of CD73 leads to a lack of extracellular adenosine and, consequently, an increase in extracellular levels of tissue nonspecific alkaline phosphatase, which in turn promotes calcification in vascular cells.102 Clinical and cellular data in ADA2‑deficient patients suggest various roles for ADA2, a known component of the purinergic pathway. The mechanism of disease is related to an as‑yet uncharacterized function of ADA2 in development and differentiation of endothelial cells and macrophages.Abbreviations: ACDC, arterial calcification due to deficiency of CD73; ADA, adenosine deaminase; DADA2, deficiency of ADA2; IBD, inflammatory bowel disease; SCID, severe combined immunodeficiency disease.

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compromised activation of canonical NFκB signal-ling in response to IL-1β, which is consistent with the observed immuno deficiency, HOIL-1-deficient mono-cytes display enhanced sensitivity to IL-1β and produced large amounts of the cytokines IL-6 and MIP-1α.56 This monocyte-specific effect of HOIL-1 deficiency could explain the clinical auto inflammation in these patients. This study highlights the often-unappreciated variability in the effects of mutations in different cell types.

ADA2 deficiencyThe discovery of loss-of-function mutations in a single gene, CECR1 (encoding the adenosine deaminase 2

protein [ADA2]), in patients with recurrent fever, li vedoid rash, mild immunodeficiency, and a spectrum of symptoms related to vasculopathy and/or vasculitis, points to a new pathway in autoinflammation.57,58 Some patients with deficiency of ADA2 (DADA2) present with early-onset, small, subcortical infarcts in the deep nuclei of the brain, referred to as lacunar strokes, which account for 25% of all ischaemic strokes,59 but are extremely rare in young children.

Analysis of exome-sequencing data from three unre-lated, affected children and their unaffected parents identified recessively inherited deleterious mutations in CECR1.57 A founder mutation was identified in the same gene, guided by suspected homozygosity in several families of Georgian Jewish ancestry affected by multiple cases of childhood-onset polyarteritis nodosa (PAN).58 PAN is a nongranulomatous, necrotizing inflammation of medium-sized or small arteries that results in tissue ischaemia or infarction, or both. Unlike some other vasculitis syndromes (for example, microscopic poly-angiitis or granulomatosis with polyangiitis), PAN is not associated with antineutrophil cytoplasmic anti bodies. Patients with ADA2-associated PAN have varying degrees of cutaneous manifestations, including livedo reticularis, palpable purpura, leg ulcers and some degree of visceral involvement.58

Among the patients with DADA2 studied, those with recurrent stroke and fever typically had compound hetero zygous missense CECR1 mutations, whereas most of those with PAN were homozygous for a muta-tion encoding a Gly47Arg substitution (p.Gly47Arg). The carrier frequency of the p.Gly47Arg variant is high (0.102) in the Georgian-Jewish population58 but lower (0.002) in the Turkish population57 and unreported in the European population, suggesting that the prevalence of childhood-onset PAN is likely to be higher in Middle Eastern and other founder populations. Although the parents of affected patients, who are obligate hetero-zygous carriers, are not clinically affected, two sibling heterozygous carriers (unrelated to the patients already discussed) suffering from late-onset ischaemic lacunar strokes have been reported in the National Heart, Lung, and Blood Institute exome sequencing project data-base.60 This observation indicates that a subtle defi-ciency of ADA2 might be associated with susceptibility to more common cardiovascular diseases, including adult-onset stroke and PAN.

ADA2 has a high level of homology to ADA1, the protein encoded by the adenosine deaminase gene (ADA). ADA1 has been in the spotlight for many years because an inherited deficiency of this protein causes severe combined immunodeficiency disease (SCID; Box 2). Through their catalytic activity, both ADA1 and ADA2 deactivate extracellular adenosine and terminate signalling through various adenosine receptors, with the affinity of ADA2 for adenosine being substantially weaker than that of ADA1 (Figure 4). The relatively low affinity of ADA2 for adenosine has raised the question of whether ADA2 might have other functions independent of its catalytic activity.

ENT1 ENT2

Adenosine

Intracellular

Extracellular

ATP ADP AMP

ACDC

CD39 CD73

SCIDADA1Inosine

Monocytes

ADA2

M1macrophage

M2macrophage

DADA2

ADA2

IL-10, IL-1Ra, VEGF, IL-1R decoy receptors,TGF-β1, MMPs, M2 chemokines

ROS, TNF,IL-1, IL-6, IL-12

Immune suppressionTumour growthTissue repair

Immune stimulationTumour suppression

Tissue injury

Figure 4 | Intracellular and extracellular ADA2 function. Extracellular adenosine is derived sequentially from ATP, ADP, and AMP through the enzymatic activity of two proteins, CD39 and CD73. Adenosine signalling is terminated by uptake of extracellular adenosine into the intracellular space and the subsequent conversion of adenosine to inosine in the presence of ADA1 and ADA2. The affinity of ADA2 for adenosine is roughly 100‑fold less than that of ADA1. Extracellular ADA2 has a unique role in promoting the differentiation of monocytes to macrophages and the subsequent proliferation of macrophages into either M1 or M2 macrophages, depending on the stimuli. M1 and M2 macrophages have opposing functions, providing a balance between proinflammatory and anti‑inflammatory responses. Reduction of ADA2 levels in the blood causes preferential differentiation into M1 macrophages that can cause the release of proinflammatory cytokines. Black rectangles denote diseases caused by single‑gene defects in ADA1, ADA2 and CD73 (see also Box 2). Abbreviations: ACDC, arterial calcification due to deficiency of CD73; ADA, adenosine deaminase; CD39, ectonucleoside triphosphate diphosphohydrolase 1; CD73, ecto‑5'‑nucleotidase; DADA2, deficiency of ADA2; ENT, equilibrative nucleoside transporter; IL‑1R, IL‑1 receptor; IL‑1Ra, IL‑1R antagonist; MMP, matrix metalloproteinase; ROS, reactive oxygen species; SCID, severe combined immunodeficiency; TGF‑β1, transforming growth factor β1; VEGF, vascular endothelial growth factor.

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ADA2 is a secreted protein produced by activated monocytes, macrophages and dendritic cells.61,62 Macro-phages are known to release ADA2 during inflamma-tory responses.63 Increased ADA2 levels are reported in patients with inflammatory conditions such as tuber-culous pleural effusions,64,65 active Crohn disease66 and HIV infection.67 Cultured promonocytic cell lines (THP1 and U937) spontaneously secrete ADA2; how-ever, ADA2 is not found in cultured endothelial cells (HCAEC and HUVEC).57

Disease-associated mutations in ADA2 occur in dif-ferent domains of the protein, affecting the function of catalytic and receptor-binding domains, the protein’s stability or dimerization.68 Consistent with in silico pre-dictions, ADA2-specific adenosine deaminase activity is reduced in monocytes and the mutant protein is present at very low concentration or is nearly absent in the cells and blood of patients with DADA2.57, 58

Partial triplication of the region of human chromo-some 22 that includes the CECR1 gene is associated with a developmental disorder known as cat eye syndrome.69 Studies in Drosophila and frogs, and transgenic expres-sion of ADA2 in mice, suggest an important role for ADA2 during development.70–72 Studies of ADA2 defi-ciency in a zebrafish model suggest that ADA2 has a role in the development of endothelial and haematopoietic cells.57 Equivalent studies in human cells suggest ADA2 acts as a growth factor that is important for the T-cell-dependent differentiation of macrophages, by binding to putative T-cell-specific receptors.62 Absence of ADA2 has been associated with a defect in differentiation of M2 macrophages, which leads to an imbalance of M2 (anti-inflammatory) relative to M1 (proinflammatory) cells57 (Figure 4). Tissue-resident M1 macrophages are known to produce proinflammatory cytokines and can create a hyperinflammatory environment that is damag-ing to blood vessels. Thus, studies of ADA2 mutations associated with autoinflammation have confirmed that this protein has multiple functions depending on its localization: intracellular ADA2 has weak deaminase activity relevant to the purinergic signalling pathway, whereas secreted ADA2 functions in the develop-ment and differentiation of haematopoietic cells and

maintenance of vascular integrity (Figure 4). Further studies are necessary to understand the full spectrum of ADA2 biology.

Conclusions Identification of disease-associated genes in patients with autoinflammation has highlighted the substantial gen-etic heterogeneity of monogenic autoinflammatory dis-eases and has expanded the phenotypic spectrum of these patients. In addition, these studies show that, in some diseases, mutations of a single gene can manifest with very different phenotypes. This knowledge has provided better diagnostic tools and has improved therapies for specific disorders. With new genes being discovered con-tinuously, additional pathways that are important for the homeo stasis of both the innate and the adaptive immune systems will be revealed. For example, type I interferon signalling, which is the hallmark of Aicardi–Goutières syndrome,73 PRAAS, and STING-associated vasculo-pathy with onset in infancy (SAVI),74 might provide a link between auto inflammation and auto immunity. Together, the identification of the molecular and immuno logical mechanisms underlying inflammation in these inherited disorders has shaped our understanding of immunology well beyond autoinflammatory disease.

We have come to a new age, unimaginable 20 years ago, where putative disease-causing genes can be dis-covered in a matter of days owing to major advances in technology. The discovery of new disease-causing genes will contribute insights to further advance pharmaco-logical studies targeting aberrant pathways. This is an exciting time for scientists, physicians and patients as we approach the age of personalized medicine.

Review criteria

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AcknowledgementsF.M. is supported by a grant from the European Research Council (starting grant 281996), a Human Frontier Science Program career development award (CDA00059/2011) and a grant from the Swiss National Science Foundation (31003A‑130476). The authors thank Y. Jamilloux and E. F. Remmers for critical reading of the manuscript, and Q. Zhou and J. Fekecs for help preparing a figure.

Author contributionsBoth authors contributed equally to researching the data for the article, providing a substantial contribution to discussions of the content, writing the article and review and/or editing of the manuscript before submission.

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