Key Points
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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
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A number of alterations in the pathways related to the maintenance of proteostasis have been implicated in monogenic autoinflammatory diseases
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Next-generation sequencing technologies have been instrumental in the identification of new disease-causing genes
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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
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Newly discovered genes and pathways provide further evidence that autoinflammation and autoimmunity are not mutually exclusive processes
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.
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References
Kastner, D. L., Aksentijevich, I. & Goldbach-Mansky, R. Autoinflammatory disease reloaded: a clinical perspective. Cell 140, 784–790 (2010).
Ozen, S. & Bilginer, Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat. Rev. Rheumatol. 10, 135–147 (2014).
Savic, S., Dickie, L. J., Wittmann, M. & McDermott, M. F. Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives. Best Pract. Res. Clin. Rheumatol. 26, 505–533 (2012).
Goldbach-Mansky, R. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin. Exp. Immunol. 167, 391–404 (2012).
McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).
The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).
French, F. M. F. C. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, 25–31 (1997).
Cantarini, L. et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun. Rev. 12, 38–43 (2012).
Galon, J., Aksentijevich, I., McDermott, M. F., O'Shea, J. J. & Kastner, D. L. TNFRSF1A mutations and autoinflammatory syndromes. Curr. Opin. Immunol. 12, 479–486 (2000).
Kimberley, F. C., Lobito, A. A., Siegel, R. M. & Screaton, G. R. Falling into TRAPS—receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. Arthritis Res. Ther. 9, 217 (2007).
Lobito, A. A. et al. Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). Blood 108, 1320–1327 (2006).
Rebelo, S. L. et al. Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheum. 54, 2674–2687 (2006).
Todd, I. et al. Mutant tumor necrosis factor receptor associated with tumor necrosis factor receptor-associated periodic syndrome is altered antigenically and is retained within patients' leukocytes. Arthritis Rheum. 56, 2765–2773 (2007).
Simon, A. et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc. Natl Acad. Sci. USA 107, 9801–9806 (2010).
Yang, Q. et al. Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep. 7, 622–627 (2006).
Powers, E. T., Morimoto, R. I., Dillin, A., Kelly, J. W. & Balch, W. E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959–991 (2009).
Hasnain, S. Z., Lourie, R., Das, I., Chen, A. C. & McGuckin, M. A. The interplay between endoplasmic reticulum stress and inflammation. Immunol. Cell Biol. 90, 260–270 (2012).
Heazlewood, C. K. et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008).
Colbert, R. A., Tran, T. M. & Layh-Schmitt, G. HLA-B27 misfolding and ankylosing spondylitis. Mol. Immunol. 57, 44–51 (2014).
Bulua, A. C. et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J. Exp. Med. 208, 519–533 (2011).
Dickie, L. J. et al. Involvement of X-box binding protein 1 and reactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome. Ann. Rheum. Dis. 71, 2035–2043 (2012).
Qiu, Q. et al. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J. 32, 2477–2490 (2013).
Martinon, F., Chen, X., Lee, A. H. & Glimcher, L. H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418 (2010).
Goodall, J. C. et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc. Natl Acad. Sci. USA 107, 17698–17703 (2010).
Lerner, A. G. et al. IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250–264 (2012).
Menu, P. et al. ER stress activates the NLRP3 inflammasome via an UPR-independent pathway. Cell Death Dis. 3, e261 (2012).
Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012).
Shin, J. N., Fattah, E. A., Bhattacharya, A., Ko, S. & Eissa, N. T. Inflammasome activation by altered proteostasis. J. Biol. Chem. 288, 35886–35895 (2013).
Bachetti, T. et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann. Rheum. Dis. 72, 1044–1052 (2013).
Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).
Jesus, A. A. & Goldbach-Mansky, R. IL-1 blockade in autoinflammatory syndromes. Annu. Rev. Med. 65, 223–244 (2014).
Dahlmann, B. et al. The multicatalytic proteinase (prosome) is ubiquitous from eukaryotes to archaebacteria. FEBS Lett. 251, 125–131 (1989).
Basler, M., Kirk, C. J. & Groettrup, M. The immunoproteasome in antigen processing and other immunological functions. Curr. Opin. Immunol. 25, 74–80 (2013).
Sijts, E. J. & Kloetzel, P. M. The role of the proteasome in the generation of MHC class I ligands and immune responses. Cell. Mol. Life Sci. 68, 1491–1502 (2011).
Kincaid, E. Z. et al. Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat. Immunol. 13, 129–135 (2012).
Groettrup, M., Kirk, C. J. & Basler, M. Proteasomes in immune cells: more than peptide producers? Nat. Rev. Immunol. 10, 73–78 (2010).
Gomes, A. V. Genetics of proteasome diseases. Scientifica (Cairo) 2013, 637629 (2013).
Fraile, A. et al. Association of large molecular weight proteasome 7 gene polymorphism with ankylosing spondylitis. Arthritis Rheum. 41, 560–562 (1998).
Niu, Z. et al. A polymorphism rs17336700 in the PSMD7 gene is associated with ankylosing spondylitis in Chinese subjects. Ann. Rheum. Dis. 70, 706–707 (2011).
Prahalad, S. et al. Polymorphism in the MHC-encoded LMP7 gene: association with JRA without functional significance for immunoproteasome assembly. J. Rheumatol. 28, 2320–2325 (2001).
Agarwal, A. K. et al. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am. J. Hum. Genet. 87, 866–872 (2010).
Kitamura, A. et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J. Clin. Invest. 121, 4150–4160 (2011).
Arima, K. et al. Proteasome assembly defect due to a proteasome subunit β type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo–Nishimura syndrome. Proc. Natl Acad. Sci. USA 108, 14914–14919 (2011).
Liu, Y. et al. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 64, 895–907 (2012).
Kluk, J. et al. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature. Br. J. Dermatol. 170, 215–217 (2014).
Martinon, F. & Glimcher, L. H. Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr. Opin. Immunol. 23, 35–40 (2011).
Alvarez-Navarro, C. & López de Castro, J. A. ERAP1 structure, function and pathogenetic role in ankylosing spondylitis and other MHC-associated diseases. Mol. Immunol. 57, 12–21 (2014).
Kirino, Y. et al. Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).
Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).
Masters, S. L. & O'Neill, L. A. Disease-associated amyloid and misfolded protein aggregates activate the inflammasome. Trends Mol. Med. 17, 276–282 (2011).
Zhou, Q. et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91, 713–720 (2012).
Ombrello, M. J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012).
Everett, K. L. et al. Characterization of phospholipase C gamma enzymes with gain-of-function mutations. J. Biol. Chem. 284, 23083–23093 (2009).
Yu, P. et al. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase Cγ2 that specifically increases external Ca2+ entry. Immunity 22, 451–465 (2005).
Lee, G. S. et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123–127 (2012).
Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178–1186 (2012).
Zhou, Q. et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N. Engl. J. Med. 370, 911–920 (2014).
Navon Elkan, P. et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N. Engl. J. Med. 370, 921–931 (2014).
Sacco, S. et al. A population-based study of the incidence and prognosis of lacunar stroke. Neurology 66, 1335–1338 (2006).
National Heart, Lung, and Blood Institute. NHLBI Exome Sequencing Project (ESP) [online], (2014).
Iwaki-Egawa, S., Yamamoto, T. & Watanabe, Y. Human plasma adenosine deaminase 2 is secreted by activated monocytes. Biol. Chem. 387, 319–321 (2006).
Zavialov, A. V., Gracia, E., Glaichenhaus, N., Franco, R. & Lauvau, G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J. Leukoc. Biol. 88, 279–290 (2010).
Conlon, B. A. & Law, W. R. Macrophages are a source of extracellular adenosine deaminase-2 during inflammatory responses. Clin. Exp. Immunol. 138, 14–20 (2004).
Valdés, L., Pose, A., San Jose, E. & Martinez Vazquez, J. M. Tuberculous pleural effusions. Eur. J. Intern. Med. 14, 77–88 (2003).
Inase, N. et al. Adenosine deaminase 2 in the diagnosis of tuberculous pleuritis [Japanese]. Kekkaku 80, 731–734 (2005).
Maor, I., Rainis, T., Lanir, A. & Lavy, A. Adenosine deaminase activity in patients with Crohn's disease: distinction between active and nonactive disease. Eur. J. Gastroenterol. Hepatol. 23, 598–602 (2011).
Chittiprol, S. et al. Plasma adenosine deaminase activity among HIV1 Clade C seropositives: relation to CD4 T cell population and antiretroviral therapy. Clin. Chim. Acta 377, 133–137 (2007).
Zavialov, A. V., Yu, X., Spillmann, D. & Lauvau, G. Structural basis for the growth factor activity of human adenosine deaminase ADA2. J. Biol. Chem. 285, 12367–12377 (2010).
Riazi, M. A. et al. The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome. Genomics 64, 277–285 (2000).
Dolezal, T., Dolezelova, E., Zurovec, M. & Bryant, P. J. A role for adenosine deaminase in Drosophila larval development. PLoS Biol. 3, e201 (2005).
Iijima, R. et al. The extracellular adenosine deaminase growth factor, ADGF/CECR1, plays a role in Xenopus embryogenesis via the adenosine/P1 receptor. J. Biol. Chem. 283, 2255–2264 (2008).
Riazi, A. M., Van Arsdell, G. & Buchwald, M. Transgenic expression of CECR1 adenosine deaminase in mice results in abnormal development of heart and kidney. Transgen. Res. 14, 333–336 (2005).
Rice, G. I. et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46, 503–509 (2014).
Liu, Y. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507–518 (2014).
Masters, S. L., Simon, A., Aksentijevich, I. & Kastner, D. L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27, 621–668 (2009).
Park, H., Bourla, A. B., Kastner, D. L., Colbert, R. A. & Siegel, R. M. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat. Rev. Immunol. 12, 570–580 (2012).
Van der Burgh, R., Ter Haar, N. M., Boes, M. L. & Frenkel, J. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin. Immunol. 147, 197–206 (2013).
Houten, S. M. et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat. Genet. 22, 175–177 (1999).
Drenth, J. P. et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat. Genet. 22, 178–181 (1999).
Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305 (2001).
Sfriso, P. et al. Blau syndrome, clinical and genetic aspects. Autoimmun. Rev. 12, 44–51 (2012).
Miceli-Richard, C. et al. CARD15 mutations in Blau syndrome. Nat. Genet. 29, 19–20 (2001).
Feldmann, J. et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 71, 198–203 (2002).
Aksentijevich, I. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46, 3340–3348 (2002).
Veillette, A., Rhee, I., Souza, C. M. & Davidson, D. PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders. Immunol. Rev. 228, 312–324 (2009).
Wise, C. A. et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Mol. Genet. 11, 961–969 (2002).
Sharma, M. & Ferguson, P. J. Autoinflammatory bone disorders: update on immunologic abnormalities and clues about possible triggers. Curr. Opin. Rheumatol. 25, 658–664 (2013).
Ferguson, P. J. et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J. Med. Genet. 42, 551–557 (2005).
Jeru, I. et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc. Natl Acad. Sci. USA 105, 1614–1619 (2008).
Borghini, S. et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 63, 830–839 (2011).
Cowen, E. W. & Goldbach-Mansky, R. DIRA, DITRA, and new insights into pathways of skin inflammation: what's in a name? Arch. Dermatol. 148, 381–384 (2012).
Aksentijevich, I. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360, 2426–2437 (2009).
Reddy, S. et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N. Engl. J Med. 360, 2438–44 (2009).
Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).
Glocker, E. O., Kotlarz, D., Klein, C., Shah, N. & Grimbacher, B. IL-10 and IL-10 receptor defects in humans. Ann. NY Acad. Sci. 1246, 102–107 (2011).
Onoufriadis, A. et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am. J. Hum. Genet. 89, 432–437 (2011).
Marrakchi, S. et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N. Engl. J. Med. 365, 620–628 (2011).
Ombrello, M. J., Kastner, D. L. & Milner, J. D. HOIL and water: the two faces of HOIL-1 deficiency. Nat. Immunol. 13, 1133–1135 (2012).
Eltzschig, H. K., Sitkovsky, M. V. & Robson, S. C. Purinergic signaling during inflammation. N. Engl. J. Med. 367, 2322–2333 (2012).
St Hilaire, C. et al. NT5E mutations and arterial calcifications. N. Engl. J. Med. 364, 432–42 (2011).
Hershfield, M. in Immunologic Disorders in Infants and Children 5th edn (eds Stiehm, E. R. et al.) 480–504 (W. B. Saunders, Philadelphia, 2004).
Markello, T. C. et al. Vascular pathology of medial arterial calcifications in NT5E deficiency: implications for the role of adenosine in pseudoxanthoma elasticum. Mol. Genet. Metab. 103, 44–50 (2011).
Acknowledgements
F.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.
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Martinon, F., Aksentijevich, I. New players driving inflammation in monogenic autoinflammatory diseases. Nat Rev Rheumatol 11, 11–20 (2015). https://doi.org/10.1038/nrrheum.2014.158
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DOI: https://doi.org/10.1038/nrrheum.2014.158
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