Current
Volume 4, Number 1, 2004
Contents
HLA-B27
and Spondyloarthropathies Thirty Years Later
Executive
Editor: Robert A. Colbert
The Histopathology of Spondyloarthropathy Pp.1-12
Dominique
Baeten and Filip De Keyser
Genetic Susceptibility to Ankylosing
Spondylitis Pp.13-20
Anne-Marie
Sims, B. Paul Wordsworth and Matthew A. Brown
The Immunobiology of HLA-B27: Variations on a
Theme Pp.21-30
Robert
A. Colbert
Animal Models of HLA-B27-Associated Diseases Pp.31-40
Maxime
Breban, Cecile Hacquard-Bouder and
Geraldine Falgarone
Non-Antigen Presenting Effects of HLA-B27 Pp.41-49
Markus
A. Penttinen, Paivi Ekman and Kaisa Granfors
The Recognition of Abnormal Forms of HLA-B27
by CD4+ T Cells Pp.51-58
Louise H. Boyle, Jane C. Goodall and J.S. Hill Gaston
Recognition of Classical and Heavy Chain
Forms of HLA-B27 by Leukocyte Receptors Pp.59-65
Rachel
L Allen and John Trowsdale
Abstracts
[Back to top] The Histopathology of Spondyloarthropathy
Dominique
Baeten and Filip De Keyser
An extensive
histopathological analysis of diseased tissues and organs is a crucial step in
our understanding of how specific molecular and cellular events described in
vitro or in animal models might by relevant to the clinical presentation of a
specific disease in humans. Although in spondyloarthropathy (SpA) such an
approach is hampered by the fact that some target tissues are not readily
accessible for biopsy sampling (the sacroiliac joint, the axial skeleton, the
enthesis, and the eye), numerous histological studies of the synovial membrane
of the peripheral joint, the gut, and the skin have contributed to new insights
into the cellular and molecular base of SpA. Firstly, the peripheral synovitis
is characterized by an extensive hypervascularity and the presence of specific
macrophage and T cell subsets. Secondly, the fact that the same subsets of
macrophages and T cells can be identified in the gut mucosa, even before
histological inflammation is present, point to a role for early immune
alterations of the gut in the development of the disease. Thirdly, macrophages
and macrophage-derived cytokines such as the pro-inflammatory TNFalpha and the
anti-inflammatory IL-10 appear to be crucial mediators of the tissue
inflammation. Therefore, neovascularization, recirculation of inflammatory
cells between gut and synovium, and macrophage-derived cytokines are all
potential targets for immunotherapy. As a proof of concept, anti-TNFalpha
treatment has been demonstrated to have an impressive clinical effect as well
as a major impact on the histological tissue inflammation. Further research
should benefit from the combination of classical histopathology with newer
molecular techniques (genomics, proteomics) to unravel the molecular and
cellular base of the different disease presentations and should aim to
translate these basic findings into clinical applications such as
histopathological differential diagnosis and follow-up of targeted therapies.
[Back to top] Genetic Susceptibility to Ankylosing
Spondylitis
Anne-Marie
Sims, B. Paul Wordsworth and Matthew A. Brown
Ankylosing
spondylitis is a highly heritable, common rheumatic condition, primarily affecting
the axial skeleton. The association with HLA-B27 has been demonstrated
worldwide, and evidence for a role of HLA-B27 in disease comes from linkage and
association studies in humans, and transgenic animal models. However, twin
studies indicate that HLA-B27 contributes only 16% of the total genetic risk
for disease. Furthermore, there is compelling evidence that non-B27 genes, both
within and outwith the major histocompatability complex, are involved in
disease aetiology. In this post-genomic era we have the tools to help elicit
the genetic basis of disease. This review describes methods for genetic
investigation of ankylosing spondylitis, and summarises the status of current
research in this exciting area.
[Back to top] The Immunobiology of HLA-B27: Variations on a
Theme
Robert
A. Colbert
In the thirty
years since the initial discovery of a striking association between HLA-B27 and
susceptibility to ankylosing spondylitis, numerous hypotheses have been proposed
to explain the role of this molecule in the pathogenesis of
spondyloarthropathies. In the past few years the focus has shifted from one
centered largely on the physiological peptide-presenting function of HLA-B27,
to include ideas based on aberrant aspects of its immunobiology. This has been
driven in part by results from animal models of HLA-B27-associated disease
where CD8+ T cells do not appear to be playing a major role in pathogenesis. In
addition, the HLA-B27 heavy chain is unusual in that it has a tendency to
misfold in the endoplasmic reticulum and to form disulfide linked heavy chain
dimers that can be expressed on the cell surface. Although the data suggest
misfolding and cell surface dimerization are fundamentally different processes,
it appears that certain structural features of the heavy chain are common to
both. Potential links between these aberrant characteristics of HLA-B27 and
inflammatory disease are discussed in this and other reviews in this issue.
Herein we consider how protein misfolding affects cell function through the
activation of an ‘unfolded protein response’ and/or an ‘ER overload response’,
and the potential impact on the immune system. Despite significant advances in
the treatment of spondyloarthropathies over the past few years, a better
understanding of pathogenesis is likely to improve outcome by identifying ways
to provide greater and more sustained clinical responses.
[Back to top] Animal Models of HLA-B27-Associated Diseases
Maxime
Breban, Cecile Hacquard-Bouder and
Geraldine Falgarone
The HLA-B27
molecule is strongly associated with the spondyloarthropathies (SpA), a group
of inflammatory conditions affecting the skeleton, the skin and several
mucosae. The mechanism of this association remains unknown, largely because the
HLA-B27 molecule displays normal function. A disease that closely mimicks SpA
arises spontaneously in HLA-B27 transgenic rats. This disease is dependent on
the presence of a normal bacterial flora and implicates the immune system. The
presence of both CD4+ T cells and antigen presenting cells (APCs) expressing
high levels of HLA-B27, seems of critical importance in its pathogenesis,
whereas CD8+ T cells are dispensable. The T cell stimulatory function of APCs
is disturbed by the HLA-B27 molecule. This disease could result from a failure
of tolerance, related in part to high level of B27 expression in professional
APCs and to the immune response to gut bacteria. In contrast, HLA-B27
transgenic mice have usually remained healthy. However, two types of
inflammatory conditions afffecting the skeleton, which arise in mice of
susceptible background after exposure to a conventional bacterial flora, are
increased by an HLA-B27 transgene. The first is ANKENT, a spontaneous ankylosing
enthesitis that affects ankle and/or tarsal joints of ageing mice; the second
is a spontaneous arthritis of hindpaws developing in mice lacking endogenous
mβ2m. As in rats, the absence of CD8+ T cells in the latter model, argues
against the "arthritogenic peptide" hypothesis. In these mβ2m0 mice,
B27 free heavy chain could be implicated in the pathogenesis of arthritis by
presenting extracellular peptides to CD4+ T cells.
[Back to top] Non-Antigen Presenting Effects of HLA-B27
Markus A. Penttinen, Paivi Ekman and Kaisa Granfors
Spondyloarthropathies
(SpA) are a group of chronic rheumatic diseases, which show a strong
asoociation with human leukocyte antigen (HLA)-B27. Although the association
between HLAB27 and the susceptibility to SpA was discovered thirty years ago,
the exact mechanism by which HLA-B27 predisposes to disease development remains
unclear. The classical role of MHC class I molecules is to present peptides for
CD8+ T cells. Therefore, it has been proposed that the antigen presenting
function of HLA-B27 is somehow altered in the patients developing SpA. However,
despite extensive research, the attempts to create a comprehensive theory that
would explain the role of HLA-B27 as an antigen presenting molecule in the
development of SpA have been unsuccessful. Reactive arthritis (ReA) belongs to
the group of SpA. It is a joint inflammation developing after certain bacterial
infections e.g. Salmonella, Yersinia, and Chlamydia. Several unrelated
observations indicate that HLA-B27 modulates the interaction between
ReA-triggering bacteria and host cell. These findings suggest that HLA-B27 may
possess functions, which are unrelated to antigen presentation. In this paper,
we summarize these findings and discuss their potential impact in the
development of SpA.
[Back to top] The Recognition of Abnormal Forms of HLA-B27
by CD4+ T Cells
Louise
H. Boyle, Jane C. Goodall and J.S. Hill Gaston
The MHC class I
molecule, HLA-B27 can be expressed as a number of non-conventional forms, in
addition to conventional HLA-B27 heterodimers presenting peptide. This has lead
to new avenues of research to explain the association of this molecule with
SpA. Surprisingly, HLA-B27 transgenic animal models implicated CD4+ T cells,
which conventionally interact with MHC class II molecules, not MHC class I
molecules, in the pathogenesis of SpA. One hypothesis to explain these finding
is that non-conventional forms of HLA-B27, specifically HLA-B27 homodimers,
might mimic MHC class II molecules and be recognised by CD4+ T cells. We
investigated whether CD4+ T cells from AS patients can interact with HLA-B27,
discovering that indeed CD4+ T cells can interact with various forms of
HLA-B27. Here we discuss how such interactions between HLA-B27 and CD4+ T cells
could occur in vivo and potential contributions of such interactions to the
pathogenesis of SpA.
[Back to top] Recognition of Classical and Heavy Chain
Forms of HLA-B27 by Leukocyte Receptors
Rachel
L Allen and John Trowsdale
As an MHC class I
protein, the disease association of HLA-B27 with inflammatory arthritis has
been widely assumed to imply a role for the T cell antigen receptor (TCR) in
disease. However, in addition to their classical antigen-presenting role, HLA
class I proteins are recognised by members of the killer immunoglobulin
receptor (KIR) and leukocyte immunoglobulin-like receptor (LILR/ILT/LIR)
families. Unusual properties of HLA-B27 include an ability of free heavy chains
(FHC) to reach the cell surface in the absence of β2m and to maintain their
peptide-binding groove in vitro. This review describes immunomodulatory
receptors that recognise HLA class I, and the recognition of HLA-B27 in both
the classical β2m-associated and β2m-independent forms by members of the KIR
and LILR families. Alternative recognition of different forms of HLA-B27 by
leukocyte receptors could influence the function of cells from both innate and
adaptive immune systems, and may indicate a role for various leukocyte
populations in HLA-B27-associated inflammatory disease.