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Patogenesis de espondilitis anquilosante

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Felipe Arias
Felipe Arias

This editorial summarizes recent advances in understanding the pathogenesis of ankylosing spondylitis (AS). Genetic studies have identified genes beyond HLA-B27 that influence AS risk, including genes involved in the IL-23 pathway and antigen processing. The association between ERAP1 and AS provides a molecular basis for the interaction between ERAP1 and HLA-B27. While early hypotheses focused on a role for CD8+ T cells, evidence now points to a central role for the IL-23/IL-17 axis, including the identification of a resident IL-23-responsive T cell population in entheseal tissues. HLA-B27 is now understood to activate the IL-23/IL-17 axis

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Molecular Immunology 57 (2014) 1 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Editorial The pathogenesis of ankylosing spondylitis: HLA-B27 and beyond It is no exaggeration to assert that the last few years witnessed a series of critical discoveries with a revolutionary impact on our perception of the nature and pathogenesis of ankylosing spondylitis (AS) and on the role of HLA-B27 in this disease. These discoveries converge from multiple approaches, from genetics to biochemical, functional and in vivo studies, from animal models to patient-based and translational research, from hypothesis-driven to hypothesisfree strategies, to draw, at last, a coherent and uni?ed picture. In the following articles, some of the major investigators in this ?eld lucidly address the major issues and propose their views on the pathogenetic mechanism of AS. Genetic studies, discussed by Philip Robinson and Matthew Brown, have identi?ed a growing number of genes in?uencing AS. Among these, ERAP1 and other aminopeptidases involved in processing of MHC-I ligands underline the critical role of peptides in AS. Genes involved in the IL-23 pathway provide the genetic evidence for the central position of this cytokine in AS substantiated by functional, animal, and clinical studies. Genes in?uencing the development and differentiation of CD8+ T cells, such as RUNX3, might challenge the idea, arising mainly from animal models, that these cells are irrelevant in the human disease. These issues are developed in depth in subsequent articles. The biology of ERAP1, discussed by Carlos Alvarez-Navarro and myself, provides a molecular basis to explain the epistasis of this gene and HLA-B27 in AS, revealed by genetic studies. ERAP1 has a global effect on the HLA-B27 peptidome that may alter, not only the antigen presenting-properties of the MHC molecule, but also other biological and pathogenetic features. Thus, while supporting a pivotal role of peptides, the association of ERAP1 with AS does not necessarily imply a pathogenetic role of speci?c epitopes, as initially proposed by the arthritogenic peptide hypothesis. But, can we really rule out a role of CD8+ T-cell-mediated antigen recognition in AS? In a very suggestive review Rosa Sorrentino, Rainer B?ckmann and Maria Teresa Fiorillo focused on the structural/dynamic and antigen-presenting properties of HLA-B27 to propose that a predisposition to autoimmunity might be the downside of its high ef?ciency as a restriction element in protective immune responses. Four reviews address what are probably the core issues to our understanding of AS: (1) the nature of the in?ammatory pathways, (2) the relationship between in?ammation and new bone formation, and (3) the pathogenetic role of HLA-B27 in triggering or exacerbating in?ammation and bone remodeling. The in?ammatory pathways in AS are reviewed by Hulda Hreggvidsdottir, Troy Noordenbos and Dominique Baeten. These 0161-5890/$ ¨C see front matter ? 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molimm.2013.08.001 authors highlight the relevance of several proin?ammatory cytokines, in particular membrane-bound TNF and the IL-23/IL-17 axis. In a timely discussion, they examine the relationship between in?ammation and osteoproliferation and the role of these cytokines in driving both processes. The converging evidence towards a central role of IL-23 is lucidly reviewed by Jonathan Sherlock and Daniel Cua, who emphasize the relevance of the entheses as the primary pathological sites. Their hallmark identi?cation of a resident, IL-23-responsive, T-cell population in the entheses helps to explain both enthesitis and local bone remodeling in response to the up-regulation of IL-23. The evidence connecting molecular and biological features of HLA-B27 with its capacity to activate the IL-23/IL-17 axis is a major advance in our understanding of the pathogenetic role of HLA-B27. Atleast two pathways are emerging with increasing clarity. The ?rst one is prompted by HLA-B27 misfolding and subsequent activation of the unfolded protein response. The issue is reviewed by Robert Colbert, Tri Tran and Gerlinde Lay-Schmitt. The authors discuss the evidence, mainly from transgenic animal models, that HLAB27 misfolding leads to induction of IL-23, IFN? and IL-1?, the two latter cytokines modulating osteoclast development. This mechanism would directly connect HLA-B27 with critical in?ammatory and bone remodeling pathways. The second mechanism may be mediated by the capacity of HLA-B27 heavy chain homodimers at the cell surface to induce the production of IL-17 from KIR3DL2+ CD4+ T cells, and possibly also by additional immunomodulatory effects of the homodimer/KIR3DL2 interaction on NK cells. The issue is brightly discussed by Jackie Shaw, Hiroko Hatano and Simon Kollnberger in a dense and timely review of the biochemical an immunological studies dealing with the nature, origin and immunology of HLA-B27 homodimers. In preparing this special issue for Molecular Immunology and reading the articles included in it, I must say that, for the ?rst time in more than 30 years devoted to the study of this disease, a plausible picture of AS pathogenesis and the role of HLA-B27 in it emerged at last in my mind. To be sure, it is still a blurred image, full of insuf?ciencies that must be addressed by future research. Yet, the major questions that resisted the efforts of researchers and clinicians for so many years start to ?t as the solution of a long-sought puzzle. Jos¨¦ A. L¨®pez de Castro E-mail address: aldecastro@cbm.uam.es Available online 27 August 2013

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Patogenesis de espondilitis anquilosante

  • 1. Molecular Immunology 57 (2014) 1 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Editorial The pathogenesis of ankylosing spondylitis: HLA-B27 and beyond It is no exaggeration to assert that the last few years witnessed a series of critical discoveries with a revolutionary impact on our perception of the nature and pathogenesis of ankylosing spondylitis (AS) and on the role of HLA-B27 in this disease. These discoveries converge from multiple approaches, from genetics to biochemical, functional and in vivo studies, from animal models to patient-based and translational research, from hypothesis-driven to hypothesisfree strategies, to draw, at last, a coherent and uni?ed picture. In the following articles, some of the major investigators in this ?eld lucidly address the major issues and propose their views on the pathogenetic mechanism of AS. Genetic studies, discussed by Philip Robinson and Matthew Brown, have identi?ed a growing number of genes in?uencing AS. Among these, ERAP1 and other aminopeptidases involved in processing of MHC-I ligands underline the critical role of peptides in AS. Genes involved in the IL-23 pathway provide the genetic evidence for the central position of this cytokine in AS substantiated by functional, animal, and clinical studies. Genes in?uencing the development and differentiation of CD8+ T cells, such as RUNX3, might challenge the idea, arising mainly from animal models, that these cells are irrelevant in the human disease. These issues are developed in depth in subsequent articles. The biology of ERAP1, discussed by Carlos Alvarez-Navarro and myself, provides a molecular basis to explain the epistasis of this gene and HLA-B27 in AS, revealed by genetic studies. ERAP1 has a global effect on the HLA-B27 peptidome that may alter, not only the antigen presenting-properties of the MHC molecule, but also other biological and pathogenetic features. Thus, while supporting a pivotal role of peptides, the association of ERAP1 with AS does not necessarily imply a pathogenetic role of speci?c epitopes, as initially proposed by the arthritogenic peptide hypothesis. But, can we really rule out a role of CD8+ T-cell-mediated antigen recognition in AS? In a very suggestive review Rosa Sorrentino, Rainer B?ckmann and Maria Teresa Fiorillo focused on the structural/dynamic and antigen-presenting properties of HLA-B27 to propose that a predisposition to autoimmunity might be the downside of its high ef?ciency as a restriction element in protective immune responses. Four reviews address what are probably the core issues to our understanding of AS: (1) the nature of the in?ammatory pathways, (2) the relationship between in?ammation and new bone formation, and (3) the pathogenetic role of HLA-B27 in triggering or exacerbating in?ammation and bone remodeling. The in?ammatory pathways in AS are reviewed by Hulda Hreggvidsdottir, Troy Noordenbos and Dominique Baeten. These 0161-5890/$ ¨C see front matter ? 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molimm.2013.08.001 authors highlight the relevance of several proin?ammatory cytokines, in particular membrane-bound TNF and the IL-23/IL-17 axis. In a timely discussion, they examine the relationship between in?ammation and osteoproliferation and the role of these cytokines in driving both processes. The converging evidence towards a central role of IL-23 is lucidly reviewed by Jonathan Sherlock and Daniel Cua, who emphasize the relevance of the entheses as the primary pathological sites. Their hallmark identi?cation of a resident, IL-23-responsive, T-cell population in the entheses helps to explain both enthesitis and local bone remodeling in response to the up-regulation of IL-23. The evidence connecting molecular and biological features of HLA-B27 with its capacity to activate the IL-23/IL-17 axis is a major advance in our understanding of the pathogenetic role of HLA-B27. Atleast two pathways are emerging with increasing clarity. The ?rst one is prompted by HLA-B27 misfolding and subsequent activation of the unfolded protein response. The issue is reviewed by Robert Colbert, Tri Tran and Gerlinde Lay-Schmitt. The authors discuss the evidence, mainly from transgenic animal models, that HLAB27 misfolding leads to induction of IL-23, IFN? and IL-1?, the two latter cytokines modulating osteoclast development. This mechanism would directly connect HLA-B27 with critical in?ammatory and bone remodeling pathways. The second mechanism may be mediated by the capacity of HLA-B27 heavy chain homodimers at the cell surface to induce the production of IL-17 from KIR3DL2+ CD4+ T cells, and possibly also by additional immunomodulatory effects of the homodimer/KIR3DL2 interaction on NK cells. The issue is brightly discussed by Jackie Shaw, Hiroko Hatano and Simon Kollnberger in a dense and timely review of the biochemical an immunological studies dealing with the nature, origin and immunology of HLA-B27 homodimers. In preparing this special issue for Molecular Immunology and reading the articles included in it, I must say that, for the ?rst time in more than 30 years devoted to the study of this disease, a plausible picture of AS pathogenesis and the role of HLA-B27 in it emerged at last in my mind. To be sure, it is still a blurred image, full of insuf?ciencies that must be addressed by future research. Yet, the major questions that resisted the efforts of researchers and clinicians for so many years start to ?t as the solution of a long-sought puzzle. Jos¨¦ A. L¨®pez de Castro E-mail address: aldecastro@cbm.uam.es Available online 27 August 2013