This editorial summarizes recent discoveries that have revolutionized the understanding of ankylosing spondylitis (AS) pathogenesis and the role of HLA-B27. Genetic studies have identified additional genes influencing AS beyond HLA-B27, including ERAP1 and genes in the IL-23 pathway. ERAP1 provides a molecular basis for its epistatic interaction with HLA-B27 in AS. While supporting a role for peptides, the association of ERAP1 does not necessarily implicate specific epitopes. Reviews discuss evidence that inflammatory pathways like IL-23/IL-17 and membrane-bound TNF drive both inflammation and new bone formation in AS. HLA-B27 may activate these pathways through misfolding and

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 unified picture. In
the following articles, some of the major investigators in this field
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 identified a growing number of genes influencing
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 influencing 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 specific 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 Böckmann 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 efficiency 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 inflammatory pathways,
(2) the relationship between inflammation and new bone formation, and (3) the pathogenetic role of HLA-B27 in triggering or
exacerbating inflammation and bone remodeling.
The inflammatory pathways in AS are reviewed by Hulda
Hreggvidsdottir, Troy Noordenbos and Dominique Baeten. These
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authors highlight the relevance of several proinflammatory
cytokines, in particular membrane-bound TNF and the IL-23/IL-17
axis. In a timely discussion, they examine the relationship between
inflammation 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 identification 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 first
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 inflammatory
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 first 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
insufficiencies 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 fit as the solution of a long-sought
puzzle.
José A. López de Castro
E-mail address: aldecastro@cbm.uam.es
Available online 27 August 2013