Current Molecular Medicine - Volume 4, Issue 1, 2004

Spondyloarthropathies are a group of auto-inflammatory diseases that frequently lead to progressive axial arthritis with significant morbidity and increased mortality. Like other inflammatory arthropathies, these disorders develop in the context of genetic and environmental factors that remain incompletely identified. The first genetic clue discovered 30 years ago, was the major histocompatibility complex (MHC) class I allele now known as HLA-B27. Despite considerable progress in our understanding of the function of MHC class I molecules in immune recognition, the relationship between HLA-B27 and the development of auto-inflammatory disease remains a puzzle. Hypotheses have largely focused on aberrant immunological recognition of a classical form of HLA-B27 since its only known physiologic function is to display peptides to T cells. However, this paradigm is unproven and is not supported by results from animal models. Recent evidence indicates that HLA-B27 misfolds during early stages of assembly inside the cell, and also exists in aberrant dusulfide-linked and β2- microglobulin-free forms on the cell surface. These observations and the possibility that HLA-B27 misfolding may have immunological consequences, have important implications for pathogenic mechanisms. In particular, they raise the question of whether immunological recognition of HLA-B27 is indeed initiating the abnormal inflammatory response. If recognition is required, perhaps there are quantitatively minor forms that serve as stimuli for the aberrant immune response. This issue of Current Molecular Medicine is devoted to a series of reviews on spondyloarthropathies. Our purpose in assembling these articles is to provide readers with an overview of the various disease entities that are classified as spondyloarthropathies and current ideas about pathogenesis. In the first chapter, Baeten and De Keyser review the histopathology of inflammatory lesions. Investigations in this area have been hampered by the inaccessibility of primary lesions that affect axial and sacroiliac joints. These authors highlight recent advances including the identification of a macrophage subset present in early, inflamed synovium and the intestinal mucosa of spondyloarthropathy patients, even in the absence of clinical colitis, thus supporting the link between the gastrointestinal tract and the development of arthritis. Sims et al. review genetic susceptibility to the prototypic spondyloarthropathy, ankylosing spondylitis. Whole genome scans have identified the first non-MHC region of strong linkage on chromosome 16q. With fine mapping to follow, the identification of novel genes that create susceptibility is on the horizon. The remainder of this issue is devoted to articles that focus on possible roles of HLA-B27 in pathogenesis beginning with my review on the immunobiology of HLA-B27, from heavy chain synthesis in the endoplasmic reticulum through various stages of folding and assembly, to events that occur on the cell surface. The central tenet of this review is that despite HLA-B27 functioning normally as an antigen-presenting molecule, it has unusual and perhaps unique characteristics extending beyond the repertoire of peptides it presents, that may play a key role in the pathogenesis of spondyloarthropathies. Breban et al. review animal models of HLA-B27- associated disease that have yielded interesting results challenging the popular view that it is the physiologic antigen-presenting function of this molecule that leads to inflammatory disease. Penttinen et al. review accumulating evidence that expression of HLA-B27 is associated with cell autonomous biological effects unrelated to antigen presentation that may alter sensitivity to activators of NF-κB and cellular bacteriocidal activity. Boyle et al. review their work suggesting that CD4+ T cells can recognize unusual forms of HLA-B27, perhaps including dimers or β2-microglobulin-free forms. Allen and Trowsdale discuss the rapidly developing field of leukocyte receptors that are expressed on many cells of the immune system including natural killer cells, monocytes, macrophages and dendritic cells, and may recognize both normal and abnormal forms of MHC class I molecules including HLA-B27. The recent discovery of additional chromosomal regions harboring susceptibility genes has raised expectations that identifying the critical gene products will help to establish pathogenic mechanisms and identify new targets to improve therapeutic interventions. This optimism, although well founded, remains tempered by the realization that after 30 years we still do not understand the contribution of HLA-B27 to this unique group of diseases.

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.

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.

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.

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 mβ2m° mice, B27 free heavy chain could be implicated in the pathogenesis of arthritis by presenting extracellular peptides to CD4+ T cells.

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.

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.

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.