Preface [Hot topic: HLA-B27 and Spondyloarthropathies Thirty Years Later (Executive Editor: Robert A. Colbert)]

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.