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PLoS Medicine | www.plosmedicine.org1242 Research in Translation Conceptually, autoimmunity is viewed as a defect of either B or T lymphocyte selection, with aberrant lymphocytic responses to autoantigens [2]. In recent years, an improved genetic understanding of both common and rare diseases, collectively associated with mutations re” ecting immune immune () Problems with the Concept culties with the autoimmunity ammation. These culties include a lack of major Funding: Competing Interests: Citation: cation of the immunological DOI: Copyright: Research in Translation discusses health interventions in the context of translation from basic to clinical Box 1. De“ nitions of ammation Generic De“ nition of Autoimmunity Self-directed in” ammation, whereby aberrant dendritic cell, B and T cell, responses in primary and secondary lymphoid organs lead to breaking of tolerance, with development of immune reactivity towards native antigens. The adaptive immune response plays the predominant role in the eventual clinical c autoantibodies may predate clinical disease expression by years and manifest Proposal for a De“ nition ammation Self-directed in” ammation, whereby local c in” ammation that is independent PLoS Medicine | www.plosmedicine.org1243 ammatory tissue reactions against ammatory tissue reactions against to include tumour necrosis factor (TNF) receptor…associated periodic fever syndrome (TRAPS) [7], familial Mediterranean fever (FMF), hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS), and several others (Table 1). The key breakthrough came in Daniel Kastners laboratory by using a candidate gene approach in families with a rare autosomal dominant HPF termed familial Hibernian fever, initially in the prototypic familial Hibernian fever family from Nottingham, as well as in a series of families drawn from both Europe and the United States. Mutations in the TNF1 receptor, which is widely distributed on both immune and nonimmune cells, were shown in six families. This led the authors to propose the term TNF receptor…associated periodic syndrome (TRAPS) and to coin the term autoin” ammation, in recognition of an ammation, in recognition of an It now appears that TRAPS and other monogenic periodic fever disorders share a common thread. They all show disturbances in pathways associated with innate immune cell function, encompassing abnormal signalling in key cytokine pathways that include TNF and interleukin-1 (IL-1
) (via adaptor molecules collectively termed the in” ammasome [8]), as well as through ammasome [8]), as well as through () Jérôme Galon and colleagues proposed that polygenic diseases sharing clinical features in common with the HPFs and lacking autoantibody or MHC associations could, by default, be termed autoin” ammatory in in of innate immune-related factors at target sites of disease, rather than adaptive immunity, has led to the idea of classifying some conditions (such as Crohn disease and Behçet syndrome) as being autoin” ammatory ammatory cation cation logical consequence of this approach is a resulting two-tiered classi“ cation Autoimmunity versus

ammationThe issues pertaining to cation are compounded by the absence Table 1. ammation Type of DiseaseIn” ammatory DisorderGene/ProteinCellular Distribution/FunctionMonogenic autoimmune diseaseAPS-1 AIRE /AIREThymic epithelium/negative T cell selection FOXP3 /FOXP3Regulatory T cells/immunomodulation FAS /FASWidespread/key role in lymphocyte apoptosis CTLA-4 /CTLA-4Regulation of T lymphocytes activation PTPN22 /PTPN22Regulation of T lymphocytes activationMany disordersMHC associationsMultiple T cell functions, including B cell help ammatory diseaseFMF MEFV /pyrinNeutrophils, early monocyte lineage, stromal ammatory response MVK /mevalonate kinaseWidespread/cholesterol biosynthesis, prenylation TNFRSF1A / TNFR1Widespread/TNF receptor CIAS1/NALP3 // cryopyrin/NALP3Monocytes, stromal cell lineage/regulation of ammation CIAS1/NALP3 CIAS1/NALP3 PSTPIP1 /PSTPIP1Neutrophils and monocytes/regulation of ammation LPIN2 nedWidespread distribution/unde“ ned PSTPIP2 (in mouse)/MAYPMacrophage/regulation of in” ammatory NOD2 /NOD2Macrophages, Paneth cells/bacterial sensing ammatory component NOD2 /NOD2Macrophages, Paneth cells/bacterial sensing DOI: 10.1371/journal.pmed.0030297.t001 This table lists some genes known to be associated with self-directed in” ammation, as well as their distribution and putative functions, where known. All autoimmune disease…associated ammatory diseases are cally play a role in adaptive immunity but are expressed on innate immune cells or with a more widespread nonimmune cell distr ammation. AIRE, autoimmune regulator protein; AITD, autoimmune thyroid disease; ALPS, autoimmune lymphoproliferative syndrome; APS-1, a ammatory syndrome 1; TNFRSF, TNF super family receptor; CINCA, chronic infantile neurologic, cutaneous and articular syndrome; ammatory syndrome; FMF, familial Mediterranean fever; HIDS, hyper-IgD syndrome; IPEX, immune cation of protein encoded by PLoS Medicine | www.plosmedicine.org1244 nition of what ammation in the common polygenic diseases. This is in contrast to polygenic autoimmune disease, where a broad consensus nition exists (Box ammation may simply ned as self-directed tissue ammation, where local factors at disease-prone sites determine activation of the innate immune nition would ammatory mechanisms across the spectrum of immunological disease. Indeed, c factors that could ammation have been recognised (Box S1). nition, many ammatory components could ammatory in nature, although nition of autoin” ammation c boundaries for what ammation. ammatory or ammatory…autoimmune ammation ned by mutations in cells or rst polygenic disease with a genetically ned autoin” ammatory component, ned simultaneously simultaneously cally, the the addition to its expression on cells of the monocyte lineage, the NOD2 protein is also expressed on gut epithelial cells. Moreover, carriage of two copies of the NOD2 mutation is associated with site-speci“ c involvement of the ileum and c involvement of the ileum and Gout is the “ rst common polygenic ammatory diseases. The c deposition in the ammation, despite the ammation, despite the At a molecular level, attacks o

f gout are associated with activation of the IL-1
signalling cascade, via the NALP3 in” ammasone, in a manner similar to ammasone, in a manner similar to Clinical Studies That Helped De“ ne ammatory Diseases Group A: Canonical cytokine pathway ammatory € TRAPS: etanercept € Cryopyrinopathies (chronic infantile ammatory disease, Muckle-Wells € Gout and FMF: colchicine, which may ammasome activation, € Crohn disease: anti-TNF with in” iximab € Ankylosing spondylitis and psoriatic In Group A, anti-TNF (etanercept) or IL-1
ammatory diseases. Colchicine is Group B: Blockade of B and T € SLE: mycophenolate moe“ til, € SLE: rituximab € Sjogren syndrome: rituximab Group C: Blockade of cytokines or € RA: anti-TNF therapy and rituximab € Psoriasis: anti-TNF therapy and In Group C, there is considerable cant ammatory components, as Box 2. The Autoin” ammatory…Autoimmune Continuum PLoS Medicine | www.plosmedicine.org12451245 ammation adjacent to ammation adjacent to in” ammation is extensive, it is often ammation is extensive, it is often Collectively, Crohn disease and the seronegative arthropathies are associated with acneform lesions, skin pustulosis, and occasionally multifocal osteitis. All of these clinical features are variably shared with two recently identi“ ed monogenic ammatory conditions: conditions: molecular basis of these monogenic equivalents of more common polygenic clinical counterparts relates to mutations in proteins associated with innate immune cell functioning rather than with adaptive immunity. This suggests that tissue-speci“ c factors in ammatory in nature (Table ammatory bowel disease, ned tissue-speci“ c factors in Behçet c factors in Behçet In the case of autoimmune diseases such as rheumatoid arthritis (RA), studies by Ai Lyn Tan and colleagues [27] and by Laura Rhodes and colleagues [28] showed that the degree of joint in” ammation, joint c ed in the index “ nger nger of the nger of the show how secondary autoin” ammatory ammatory arthritis, McGonagle and cation c factors related to joint c factors related to joint this dichotomous classi“ cation of Implications for Autoimmunity t the prevailing dogma. ammation to be The case of vasculitis (blood ammation) illustrates the usefulness of a continuum view of immunological disease. The autoimmune-mediated vasculitides can be distinguished clinically by the presence of pathogenic autoantibodies, including Figure 1. The monogenic autoin” ammatoryŽ diseases may be exclusively determined by local tissue- c factors. For rare monogenic autoimmuneŽ conditions, the disease localisation appears ect ammatory and autoimmune factors in disease causation. For ammatory diseases and MHC class cation, these are split up into different categories. This gure does not include all immunologically recognised diseases because of their large number. August 2006 | Volume 3 | Issue 8 | e297 PLoS Medicine | www.plosmedicine.org1246antineutrophil cytoplasmic antibodies (ANCA). It is of note, therefore, that the nonautoantibody-associated vasculitides, including Takayasu arteritis and giant cell arteriti

s, affect particular vascular territories in a patchy manner, thereby illustrating the contribution of local factors to disease pathogenesis (Table S1). c uencing the expression of autoimmune diseases in humans, such as type 1 diabetes, is lacking, but the concept of secondary ammation in autoimmunity offers an alternative perspective on how genetic or environmental factors affecting disease-prone sites could lead to, or alter, clinical disease expression. cation of MHC class c autoantibody cation ammation c factors at disease-prone ammation, immune- eld, renal rejection reactions are c c of MHC class I associations. In certain clinically de“ ned ammatory in in in benign polyarthritis is similar to reactive arthritis, which is a type of seronegative arthritis. Thus, the variable prognosis in diseases such as RA and multiple sclerosis may be related to the predominance of either autoin” ammation or autoimmunity, ammation also has implications ammatory disease; cacy in ammatory ammatory strategies to target lymphocytes are especially effective in autoimmune diseases, such as lupus. In some cases, both anticytokine and antilymphocyte strategies are effective in disorders that lie somewhere along the autoimmune…autoin” ammatory disease continuum Landmark Papers That Set the Scene ammation Spectrum 1. Burnet et al. [1] The seminal work of Burnet and others 2. McDermott et al. [7] This article showed that some ammation directed against self ammation. Since TNF is pivotal rmed that this disease process was 3. Hugot et al. and Ogura Y et al. 3. Hugot et al. and Ogura Y et al. Until this work, Crohn disease was 4. Martinon et al. [18] This paper showed that the molecular ammatory diseases. ned genetic basis, are linked ammation. 5. Matzinger [34] The author argued that the danger ammation. Figure 2. ammation: In early RA, joint disease localisation is to ammatory changes have a widespread c gure shows a contrast- ammation ammatory changes in all tissues. Asterisk, site of diffuse osteitis; arrowhead, orid in” ammatory August 2006 | Volume 3 | Issue 8 | e297 PLoS Medicine | www.plosmedicine.org1247 ammatory ammatory disease along ammatory component could Re“ ning our Understanding ammation has implications for our theoretical understanding of immunology. The two theories of self-directed immunity„the self/nonself discrimination theory and the danger signal theory„place the emphasis on different aspects of how autoimmunity develops and argue for different theoretical rationales for immunological disease. In physics, the nature of matter cannot be readily understood in terms of either particles or waves, so the wave…particle duality arose. Likewise, many aspects of classically recognised autoimmune diseases are best viewed in terms of self/nonself discrimination and, ammatory diseases are best viewed from the c danger signals. For example, uric acid„the causative molecule in gout„is a recognised danger signal [33]. From the standpoint of the danger theory, the ultimate susceptibility to disease lies not with the adaptive immune system but with the targ

et tissue itself, from which danger signals emanate [34]; this hypothesis is closely allied nition ammation. Looking at immunological disease from the autoimmunity perspective, several groups have drawn attention to the c factors in autoimmunity [35]. c ammatory and autoimmune c components, such as cation, then a unifying cation, then a unifying Conversely, the idea that Crohn disease and ulcerative colitis are autoin” ammatory in nature is also ammatory in nature is also to be determined whether the autoantibody association represents secondary autoimmunity or disease heterogeneity, with some cases being predominantly autoimmune and others autoin” ammatory. Conclusions ammatory ned mechanisms ammation ammatory, ne the ammatory disease cation. c factors, c factors in humans. ammation ammatory reactions in ammatory ammatory…autoimmune cation of immunological disease ammation.  Supporting Information ammation versus Pure Table 2. ammation versus Pure Autoimmunity VariableAutoin” ammatoryAutoimmuneInnate immune activationAdaptive immune activation c factors Immunological basisGenetically related to perturbations of innate immune function, ammatory cytokine signalling abnormalities/Cellular basisExpression determined by cells of innate immune system, including DOI: 10.1371/journal.pmed.0030297.t002 This table represents some of the key features that allow differentiation of a pure autoin” ammatory diseaseŽ from a pure autoimmune disease.Ž The rare monogenic HPFs are the ammatory diseases, whereas the prototypes for autoimmune diseases include the polygenic MHC and autoantibody-related diseases, PLoS Medicine | www.plosmedicine.org1248 ammatory ammatory mechanisms in c Factors c Factors 9. Stojanov S, Kastner DL (2005) Familial ammatory diseases: Genetics, 10. Galon J, Aksentijevich I, McDermott MF, ammatory syndromes. 11. Hull KM, Shoham N, Chae JJ, Aksentijevich I, ammatory disorders and 12. Lodes MJ, Cong Y, Elson CO, Mohamath R, agellin is 13. Hugot JP, Chamaillard M, Zouali H, Lesage S, 14. Ogura Y, Bonen DK, Inohara N, Nicolae DL, 15. Strober W, Kitani A, Watababe T (2006) Signalling pathways and molecular interactions 16. Lesage S, Zouali H, Cezard JP, Colombel ammatory 17. Pascual E, Batlle-Gualda E, Martinez A, Rosas uid analysis for 18. Martinon F, Petrilli V, Mayor A, Tardivel A, ammasome. 19. McDermott MF (2004) A common pathway in 20. Wucherpfennig KW (2001) Mechanisms for 21. McGonagle D, Gibbon W, OConnor P, 22. Tan AL, Grainger AJ, Tanner SF, Emery P, 23. McGonagle D, Stockwin L, Isaacs J, Emery 24. Ferguson PJ, Chen S, Tayeh MK, Ochoa L, 25. Ferguson PJ, Bing X, Vasef MA, Ochoa LA, ammatory disorder chronic multifocal 26. Gul A. (2005) Behcets disease as an ammatory disorder. Curr Drug Targets amm Allergy 4: 81…83.27. Tan AL, Tanner SF, Conaghan PG, Radjenovic 28. Rhodes LA, Tan AL, Tanner SF, Radjenovic A, Hensor EM, et al. (2004) Regional variation and differential response to therapy for knee synovitis adjacent to the cartilage-pannus junction and ammatory arthritis: Implications for pathogenesis and treatment. 29. McGonagle D, Gibbon W, Emery P (1998) cation

of in” ammatory arthritis by 30. Ponticelli C (2003) Altruistic living renal 31. McGonagle D, Gibbon W, OConnor P, 32. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle-Wells syndrome and response 33. Shi Y, Evans JE, Rock KL (2003) Molecular cation of a danger signal that alerts 34. Matzinger P (2002) The danger model: a 35. Marrack P, Kappler J, Kotzin BL (2001) 36. Dieterich W, Ehnis T, Bauer M, Donner P, cation of tissue 37. Israeli E, Grotto I, Gilburd B, Balicer RD, ammatory bowel AcknowledgmentsWe would like to acknowledge Paul Emery, Ai 1. Burnet F (1957) A modi“ cation of Jernes theory of antibody production using the concept 2. Davidson A, Diamond B (2001) Autoimmune 3. Rioux JD, Abbas AK (2005) Paths to 4. Rose NR, Bona C (1993) De“ ning criteria for 5. Matzinger P (1994) Tolerance, danger, and 6. Reimann HA (1949) Periodic disease. 7. McDermott MF, Aksentijevich I, Galon J, ne a family of dominantly inherited ammatory syndromes. Cell 97: 133…144.8. Mariathasan S, Newton K, Monack DM, Vucic ammasome by caspase-1 PLoS Medicine | www.plosmedicine.org1244of a precise de“ nition of what constitutes autoin” ammation in the common polygenic diseases. This is in contrast to polygenic autoimmune disease, where a broad consensus on a generic de“ nition exists (Box 1). Autoin” ammation may simply be de“ ned as self-directed tissue in” ammation, where local factors at disease-prone sites determine activation of the innate immune c boundaries for what ammatory or are de“ ned by mutations in cells or For example, Crohn disease is the “ rst polygenic disease with a genetically ned autoin” ammatory component, ned simultaneously simultaneously cally, the the addition to its expression on cells of the monocyte lineage, the NOD2 protein is also expressed on gut epithelial cells. Moreover, carriage of two copies of the NOD2 mutation is associated with site-speci“ c involvement of the ileum and c involvement of the ileum and Gout is the “ rst common polygenic autoin” ammatory diseases. The for site-speci“ c deposition in the lead to in” ammation, despite the ammation, despite the At a molecular level, attacks of gout are associated with activation of the IL-1
signalling cascade, via the NALP3 in” ammasone, in a manner similar to ammasone, in a manner similar to Clinical Studies That Helped De“ ammatory Diseases Crohn disease is closely Group A: Canonical cytokine pathway € TRAPS: etanercept € Cryopyrinopathies (chronic infantile in” ammatory disease, Muckle-Wells € Gout and FMF: colchicine, which may ammasome activation, € Crohn disease: anti-TNF with in” € Ankylosing spondylitis and psoriatic In Group A, anti-TNF (etanercept) or IL-1
autoin” ammatory diseases. Colchicine is Group B: Blockade of B and T € SLE: mycophenolate moe“ € SLE: rituximab € Sjogren syndrome: rituximab Group C: Blockade of cytokines or € RA: anti-TNF therapy and rituximab € Psoriasis: anti-TNF therapy and In Group C, there is considerable autoin” ammatory components, as Box 2. The Autoin” ammatory…Autoimmune Continuum nition, many in” ammatory component

s could autoin” ammatory in nature, although this de“ nition of autoin” nition would ammatory mechanisms across the spectrum of immunological disease. Indeed, several tissue-speci“ c factors that could contribute to in” ammation have been S1). PLoS Medicine | www.plosmedicine.org1248 This table represents key features that allow and autoin” ammatory mechanisms in DOI: 10.1371/journal.pmed.0030297.st001 Text S1. c Factors Found at DOI:10.1371/journal. 9. Stojanov S, Kastner DL (2005) Familial autoin” ammatory diseases: Genetics, 10. Galon J, Aksentijevich I, McDermott MF, ammatory syndromes. 11. Hull KM, Shoham N, Chae JJ, Aksentijevich I, of systemic autoin” ammatory disorders and 12. Lodes MJ, Cong Y, Elson CO, Mohamath R, agellin is 13. Hugot JP, Chamaillard M, Zouali H, Lesage S, 14. Ogura Y, Bonen DK, Inohara N, Nicolae DL, 15. Strober W, Kitani A, Watababe T (2006) Signalling pathways and molecular interactions 16. Lesage S, Zouali H, Cezard JP, Colombel 17. Pascual E, Batlle-Gualda E, Martinez A, Rosas J, Vela P (1999) Synovial ” uid analysis for 18. Martinon F, Petrilli V, Mayor A, Tardivel A, 19. McDermott MF (2004) A common pathway in 20. Wucherpfennig KW (2001) Mechanisms for 21. McGonagle D, Gibbon W, OConnor P, 22. Tan AL, Grainger AJ, Tanner SF, Emery P, 23. McGonagle D, Stockwin L, Isaacs J, Emery 24. Ferguson PJ, Chen S, Tayeh MK, Ochoa L, 25. Ferguson PJ, Bing X, Vasef MA, Ochoa LA, autoin” ammatory disorder chronic multifocal 26. Gul A. (2005) Behcets disease as an autoin” ammatory disorder. Curr Drug Targets In” amm Allergy 4: 81…83. 27. Tan AL, Tanner SF, Conaghan PG, Radjenovic 28. Rhodes LA, Tan AL, Tanner SF, Radjenovic A, Hensor EM, et al. (2004) Regional variation and differential response to therapy for knee synovitis adjacent to the cartilage-pannus junction and ammatory arthritis: Implications for pathogenesis and treatment. 29. McGonagle D, Gibbon W, Emery P (1998) Classi“ cation of in” ammatory arthritis by 30. Ponticelli C (2003) Altruistic living renal 31. McGonagle D, Gibbon W, OConnor P, 32. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle-Wells syndrome and response 33. Shi Y, Evans JE, Rock KL (2003) Molecular cation of a danger signal that alerts 34. Matzinger P (2002) The danger model: a 35. Marrack P, Kappler J, Kotzin BL (2001) 36. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, et al. (1997) Identi“ cation of tissue 37. Israeli E, Grotto I, Gilburd B, Balicer RD, ammatory bowel We would like to acknowledge Paul Emery, Ai References 1. Burnet F (1957) A modi“ cation of Jernes theory of antibody production using the concept 2. Davidson A, Diamond B (2001) Autoimmune 3. Rioux JD, Abbas AK (2005) Paths to 4. Rose NR, Bona C (1993) De“ ning criteria for 5. Matzinger P (1994) Tolerance, danger, and 6. Reimann HA (1949) Periodic disease. 7. McDermott MF, Aksentijevich I, Galon J, de“ ne a family of dominantly inherited autoin” ammatory syndromes. Cell 97: 133…144. 8. Mariathasan S, Newton K, Monack DM, Vucic activation of the in” ammasome by caspa