POINT OF VIEWNew pathogenic hypotheses for spondyloarthropathies
Section snippets
Role for genetic factors
The HLA-B27 gene confers increased susceptibility to spondyloarthropathies: it is found in 90 to 95% of patients with ankylosing spondylitis, 50 to 75% of those with reactive arthritis, and 20% of those with spondyloarthropathy associated with Crohn’s disease or SAPHO syndrome 〚1〛. However, some B27 subtypes (including B2706 and B2709) do not seem associated with spondyloarthropathies 〚1〛, and these diseases can develop in patients who do not carry the HLA-B27 gene. Other susceptibility genes
Role for environmental factors
The role for environmental factors in the pathogenesis of spondyloarthropathies is firmly established. Epidemiological studies in humans showed that outbreaks of infections with microorganisms such as Salmonella and Campylobacter can be followed in genetically susceptible individuals by joint symptoms and enthesitis, which can become chronic and eventually lead to a diagnosis of spondyloarthropathy 〚11〛. For instance, in an outbreak of salmonella infection, 96% of a cohort of Swedish physicians
Initial deficiency in the control of some intracellular bacteria located within the mucous membranes, followed by migration to target sites of either bacterial antigens or infected macrophages or dendritic cells
The process that eventually leads to spondyloarthropathy may be initiated by defective control of mucous membrane infection related in part to genetic factors 〚5〛 and in part to a large size of the bacterial inoculum or to virulence gene expression by the bacteria. A deficiency in the initial response may allow these organisms to persist within the mucosa-associated lymphoid tissue. The deficiency may be related to the effector cells (NK or Tγδ cells) and to an imbalance in the gut flora with
The HLA-b27 molecule may promote the development of spondyloarthropathy by facilitating persistence of some pathogens within macrophagic or dendritic cell lines
Strong support for a functional deficiency in antigen-presenting cells (macrophages or dendritic cells) has come from studies of the role of HLA-B27 in the pathogenesis of spondyloarthropathies in transgenic murine models. The possibility remains that HLA-B27 may promote an excessive immune response via cross-reactions with, or excessive presentation of, self-antigens and that this may explain some of the aspects of spondyloarthropathies 〚6〛. However, the pathogenic effect of HLA-B27 seems
In the absence of chaperone molecules, the HLA-B27 heavy chains tend to misfold, to form dimers, and to accumulate within the cytoplasm instead of being expressed at the cell surface
Yet, in transgenic murine models, only the strains that express very large amounts of transgene develop manifestations of spondyloarthropathy (and inflammatory colonic disease). Recent data explain and reconcile these apparently contradictory findings. Studies 27, 28, 29 have shown that, as compared to other Class I HLA molecules, the HLA-B27 heavy chain has a greater tendency to form homodimers within the endoplasmic reticulum in the absence of chaperone molecules (such as calnexin,
Consistency of this scenario with most of the available experimental data
This scenario may explain why the addition of peptides that bind to the HLA-B27 pocket but not to chaperone molecules decreases the frequency of spondyloarthropathy manifestations in transgenic rats (but does not affect the frequency of colitis). The mechanism probably involves stabilization of the HLA-B27 heavy chains with inhibition of dimer formation 〚4〛. Conversely, the development of spondyloarthropathy may be facilitated by functional deficiencies in peptide transporters that delay the
The next step may be migration of macrophagic or dendritic cells previously infected by dormant bacteria to tissues where these presenting cells may undergo ‘reactivation’
The distinctive features of spondyloarthropathies is selective involvement of the entheses and, in ankylosing spondylitis, the risk of involvement of other tissues such as the uvea, proximal aorta, lung apices (retractile fibrosis), and dural sac (nerve root pain and, eventually, adherence to the spinal canal walls) 〚1〛. The classic hypothesis involved a cross-reaction between bacterial peptides and a self-peptide present at all these sites. This hypothesis remains consistent with the scenario
High TGF-β (and IL-10) levels within entheses may contribute to the pathogenesis of spondyloarthropathies and to the selective involvement of entheses
The body sites affected by spondyloarthropathies are fibrillin-rich structures subjected to pulling forces: insertion of the tendons at the entheses, of the aorta on the aortic valve ring, of the lens on the uvea, of the lung apices on the apical pleura, and of the dural sac on the spinal canal (by ligaments not found at other spinal sites) 〚1〛. These traction zones must resist rupture in the event of inflammation, even upon release of large amounts of cytokines or enzymes capable of damaging
Consequences of macrophage activation near the entheses or within the joints
Reactivation of intracellular organisms within entheses and joints in patients with spondyloarthropathies may induce marked local release of TNFα then of PGE2, explaining the efficacy of anti-TNFα agents and of nonsteroidal anti-inflammatory drugs in the treatment of spondyloarthropathies 64, 65. In a transgenic TNFα murine model, a disease closely similar to ankylosing spondylitis develops 〚66〛. Bacterial reactivation may also enhance a T-cell response against bacterial peptides and self
Conclusion
These new hypotheses hold considerable appeal because they reconcile apparently conflicting hypotheses about the pathogenesis of spondyloarthropathy. However, they need to be confirmed by further experimental work. There is no doubt that additional insights into the pathogenesis of spondyloarthropathies will be gained by an improved understanding of the mechanisms used by bacteria to evade the immune system and to persist in a dormant state within cells despite the antibiotic therapy 〚16〛.
References (67)
- et al.
Jekyll and Hyde: the transformation of HLA-B27
Immunol Today
(2000) Animal models and in vitro models for the study of aetiopathogenesis of the spondylarthropathies
Baillieres. Clin Rheumatol
(1998)- et al.
Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease
Hum Immunol
(2000) Evasion of host cell defense mechanisms by pathogenic bacteria
Curr Opin Immunol
(2001)- et al.
Host cytokine response and resistance to Salmonella infection
Microbes Infect
(1999) - et al.
Identification and characterization of a new latent transforming growth-factor-beta-binding protein, LTBP-4
J Biol Chem
(1998) TGF-beta in infections and infectious diseases
Microbes Infect
(1999)- et al.
Growth factor and cytokine gene expression in mechanically strained human osteoblast-like cells : implications for distraction osteogenesis
Oral Surg Oral Med Oral Pathol Oral Radio Endod
(2000) Atypical clinical presentation of ankylosing spondylitis
Semin Arthritis Rheum
(1999)- et al.
The effects of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis
Arthritis Rheum
(1998)
The genetics of des spondyloarthropathies
Rev Rhum 〚Engl Ed〛
Inflammatory disease in HLA-B27 transgenic rats
Immunol Rev
Ankylosing spondylitis in monozygotic twins : studies on immunological parameters
Ann Rheum Dis
HLA-B27 and immunogenetics of spondylarthropathies
Curr Opin Rheumatol
Reiter's syndrome associated with HLA-B51
Intern M
Genome-wide screen for susceptibility loci in ankylosing spondylitis
Arthritis Rheum
LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative caucasian and mexican Mestizo patients with ankylosing spondylitis
J Rheumatol
Clinical aspects, outcome assessment, and management of ankylosing spondylitis and postenteric reactive arthritis
Curr Opin Rhumatol
Reactive arthritis after Salmonella among medical doctors-Study of an outbreak
J Rheumatol
Somatic serogroups, capsular types, and species of fecal Klebsiella in patients with ankylosing spondylitis
J Clin Microbiol
Micro-organismes impliqués dans les arthrites réactionnelles
Réflexions Rhumatologiques
Correlation of cecal microflora of HLA-B27 transgenic rats with inflammatory bowel disease
Infect Immun
Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human b2microglobulin transgenic rats
J Clin Invest
Inhibition of murine splenic and mucosal lymphocyte function by enteric products
Infect Immun
Persistent Chlamydia trachomatis infections resist apoptotic stimuli
Infect Immun
Ankylosing spondylitis : time to focus on ankylosis
J Rheumatol
Transfer of the inflammatory disease of HLA-B27 transgenic rats by bone marrow engraftment
J Exp M
Animal models of the spondylarthropathies
Curr Rheumatol Rep
Spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta-2 microglobulin : a model of human spondylarthropathies
J Exp M
Presentation of HLA class I-derived peptides: potential involvement in allo-recognition and HLA-B27-associated arthritis
Immunol Rev
HLA-B27 misfolding and spondylarthropathies: not so groovy after all?
J Rheumatol
Cutting edge: HLA-B27 can form a novel beta-2-microglobulin-free heavy chain homodimer structure
J Immunol
The role of HLA-B27 in spondyloarthritis
Immunogenetics
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Translocation of dead or alive bacteria from mucosa to joints and epiphyseal bone-marrow: Facts and hypotheses
2020, Revue du Rhumatisme (Edition Francaise)Essential role for CD103+ cells in the pathogenesis of spondyloarthritides
2015, Joint Bone SpineCitation Excerpt :A marked increase in CD8+ CD103+ T cells was found in joint fluid samples from patients with the enthesis-related arthritis subtype of juvenile idiopathic arthritis (mean, 17.4% versus 4% in the bloodstream, with a joint fluid/blood ratio greater than 1 in 90% of cases and a memory phenotype in 82% of cases [47]). Migration of dendritic cells or infected M2 macrophages [30,48] and/or CD103+ T cells (both CD4+ and CD8+) to the joints, dermis, and/or ocular tissues may also contribute to the topographic distribution of sites targeted by reactive arthritides and SpAs [49]. Some bacteria may be able to subvert the regulatory capabilities of dendritic cells or CD4+ CD103+ T cells within mucosal tissues and perhaps even at peripheral sites involved by SpAs, where they may persist in a latent state (Fig. 3) [48].
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