11Pathogenesis of ankylosing spondylitis: Current concepts
Section snippets
Histopathology of inflammation in AS
The most common sites of inflammation in AS include sacroiliac joints, entheses, vertebral bodies adjacent to intervertebral discs, peripheral joint synovium, gastrointestinal tract and the eye. Many of these lesions are poorly accessible, so information on histopathology is limited. In early sacroiliitis, there is synovitis with myxoid-appearing bone marrow, and subsequent formation of pannus and granulation tissue.4 T-cells (CD4>CD8) and CD68+ macrophages are accompanied by proliferating
Direct evidence that HLA-B27 is a causative factor in disease
The immunological function of HLA-B27 and other major histocompatibility complex (MHC) class I molecules is to bind peptides derived from proteins degraded in the cytosol, and display them on the cell surface where they can be recognized by CD8+ T-cells. They also bind an accessory molecule, β2-microglobulin (β2m), that helps to maintain the heavy chain in its proper conformation. Building on genetic studies suggesting that HLA-B27 or perhaps a closely linked gene was directly involved in SpA
Immunological requirements for inflammatory disease
Populations of immune system cells have been analysed to discern which cell types are needed for HLA-B27 to exert its effect in B27-Tg rats. HLA-B27-expressing bone marrow cells can transfer disease to a non-Tg animal, indicating that HLA-B27 does not have to be expressed on non-haematopoietic cells, including thymic epithelial cells involved in T-cell education.25 Nevertheless, T-cells are required for disease as B27-Tg nude rats, which lack a thymus (and T-cells), remain healthy.26 Since nude
The role of gastrointestinal microbes
The SpA-like disease seen in B27-Tg rats develops when animals are housed in a probiotic environment present in most conventional animal facilities, even when the environment is free of specific pathogens. In contrast, when raised under entirely germ-free conditions, B27-Tg rats do not develop disease.28 Interestingly, colonization of the gastrointestinal tract with normal gut flora, in particular Bacteroides spp., is sufficient to trigger the development of inflammation.29, 30 The colitis that
Cytokine expression in AS
Another avenue for examining the nature of inflammation in AS/SpA patients has been to examine cytokine production. This line of research has proven fruitful for other arthritic conditions such as RA, but the results have been much more variable and difficult to interpret in SpA.38 Serum cytokines are notoriously difficult to measure because their half-lives are short and differ between cytokines. There has been a trend towards increased TNF-α in some reports39, but not others40, and increased
Existing paradigms to explain the role of HLA-B27 in pathogenesis
The overwhelming genetic evidence together with animal models suggests that HLA-B27 has one or more unique characteristics that can promote the development of inflammation. MHC class I proteins such as HLA-B27 are expressed ubiquitously, but are most abundant on antigen-presenting cells such as macrophages and DCs, and are strongly upregulated by pro-inflammatory stimuli. The peptides they display are normally derived from self-proteins, but when cells are infected with microbes such as viruses
HLA-B27 subtypes
HLA-B27 designates a family of at least 25 closely related alleles, known as subtypes, that differ from the most predominant subtype (B*2705) by anywhere from one to close to 12 residues.108 Most of the common subtypes are associated with AS and other SpA, with two notable exceptions; B*2706 and B*2709.109, 110 Importantly, the HLA-B27 subtypes are distributed unevenly around the world, with B*2709 found primarily in Sardinia and regions of mainland Italy, and B*2706 common in native
Conclusions
Since the discovery of the remarkable relationship between HLA-B27 and AS, much has been learned and many ideas have emerged regarding pathogenesis. AS is a polygenic disorder, with HLA-B27 playing a direct causative role. Animal studies suggest that T-cells, particularly CD4+ cells, are critical, and have provided evidence against a CD8+T-cell-mediated process. Cells of the innate immune system participate in pathogenesis, and evidence for innate immune activation is increasing. Several
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Altered kynurenine pathway metabolism in patients with ankylosing spondylitis
2021, International ImmunopharmacologyCitation Excerpt :The pathogenesis of AS has not been fully elucidated to date, however, it is considered that the complex interaction of genetic susceptibility, environmental factors, and immune responses plays an important role [8]. Increasing evidence has shown that proinflammatory cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) are involved in the pathogenesis of AS [9]. IL-6 is a proinflammatory cytokine generated by T-lymphocytes, B-lymphocytes, activated macrophages and adipocytes, and inflammation is the main stimulator of IL-6 production [10].
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