New pathogenic hypotheses for spondyloarthropathies

doi:10.1016/S1297-319X(02)00371-8

Joint Bone Spine

Volume 69, Issue 2, March 2002, Pages 114-122

https://doi.org/10.1016/S1297-319X(02)00371-8 Get rights and content

Abstract

Pathogenic hypotheses for spondyloarthropathies are evolving. Several candidates have been added to the list of inciting microorganisms, and genes other than HLA-B27 are under scrutiny. Above all, the chiefly ‘immunological’ theory of spondyloarthropathies incriminating a cross-reaction between self-proteins and bacterial peptides is giving way to a more ‘microbiological’ concept in which latent bacteria residing within macrophagic or dendritic cells undergo reactivation through a process facilitated by HLA-B27. This molecule is prone to misfolding, which decreases the presentation of bacterial peptides to the immune system and stimulates the Nf-KB inflammation pathway within infected macrophages and/or dendritic cells. Migration of these infected cells from the mucous membranes to the tissues targeted by spondyloarthropathies, particularly the bone marrow located near entheses, may facilitate transient reactivation of dormant intracellular bacteria by creating a favorable cytokine environment. This environment may include high levels of TGFβ and IL-10, noted also at other sites that enjoy immune privilege, such as the eye. The reactivation may be stopped by a local response of CD4+ and/or CD8+ T cells at the expense of local inflammation responsible for clinical manifestations. This scenario seems consistent with results from studies of murine models transgenic for the HLA-B27 antigen: exposure to bacteria is necessary to the development of spondyloarthropathy, but the disease occurs even when only the heavy chain of HLA-B27 is present (i.e., beta2-microgloblin is not indispensable). Improved understanding of the mechanisms that confer to some bacterial strains a strong potential for persisting within cells, including macrophagic cells, may open the way toward new treatment approaches capable of complementing antagonists of TNF-α and other monokines, which merely suspend the disease process, and antibiotic therapy, which fails to kill dormant bacteria located within cells.

Pathogenic hypotheses for spondyloarthropathies are evolving. This review presents the most recent concepts. These concepts have not all received confirmation from experimental data. However, the high degree of consistency among them prompted us to consolidate them into a single picture. Although this approach may yield a motley composite of fact and speculation, it may open up new avenues of thought for rheumatologists interested in the links between chronic intracellular infections and inflammatory joint disease.

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〛.

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Essential role for CD103+ cells in the pathogenesis of spondyloarthritides
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Citation 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].
The clinical features of spondyloarthritides include extraarticular manifestations involving the skin, eyes, and gastrointestinal tract. At these sites, a membrane integrin can be acquired by virtue of the presence of CD4+ T cells and specific dendritic cells and correlates with a regulatory behavior of these cells. This membrane integrin conjugates the beta7 subunit and the alphaE subunit, also known as CD103. CD103 expression requires high levels of TGF-beta and retinoic acid; in addition, expression of CD103 by T cells requires antigen recognition. Whether CD103 is found in the entheses has not yet been investigated. CD103 is expressed at high levels in the skin, eyes, and bowel but it is found in only very low levels in the bloodstream. CD8+ CD103+ T cells differ markedly from other CD103+ cells in that they are resident cells with no tendency to migrate and usually exert predominantly cytotoxic functions as opposed to regulatory functions. Several bacteria, such as Salmonella, can become dormant within the mucous membranes and/or their lymph nodes, where they use CD103+ dendritic cells and CD4+ CD103+ regulatory T cells (Tregs) to evade the immune response. This phenomenon could be studied in other tissues targeted by spondyloarthritides, where dormant microorganisms can migrate by using M2 macrophages as Trojan horses, since M2 macrophages express the CD103 ligand E-cadherin. Microorganism peptide recognition by CD8+ CD103+ T cells (which are overrepresented in psoriasis and joint fluid in some forms of spondyloarthritis) induces an inflammatory response that may be sufficient to transiently reverse the regulatory function of the CD103+ dendritic cells and CD4+ CD103+ T cells during disease flares. The sensitivity of these diseases to retinoids further supports a pathogenic role for transient CD103+ cell failure.
Importance of CD103+ cells in the pathogenesis of spondyloarthritis
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Les spondyloarthrites s’accompagnent d’atteintes cutanées oculaires et digestives. Ces tissus sont propices à l’acquisition, par les lymphocytes TCD4 et certaines cellules dendritiques, d’une intégrine de membrane dont la présence est corrélée à un comportement régulateur de ces cellules. Cette intégrine conjugue les sous-unités bêta 7 et alpha-E, aussi appelée CD103. L’expression de CD103, encore non recherchée dans les enthèses, requière de fortes concentrations de TGF-bêta et d’acide rétinoïque, ainsi, pour les lymphocytes T, que la reconnaissance d’un antigène. Elle est forte dans la peau, l’œil et l’intestin, mais très faible dans le sang. Les lymphocytes TCD8+ CD103+ s’opposent aux autres cellules CD103+, car elles sont très résidentes, non migratrices, et ont une fonction en général plus cytotoxique que régulatrice. Certaines bactéries comme les salmonelles peuvent, dans les muqueuses et/ou leurs ganglions, adopter un état dormant et se servir des cellules dendritiques CD103+ et des TCD4+ CD103+ régulateurs pour échapper à la réponse immune. Ceci pourrait être étudié dans d’autres tissus cibles des SpA, où certains germes dormants migrent en se servant du cheval de Troie des macrophages M2, lesquels expriment le ligand de CD103 (la E-cadhérine). La reconnaissance de peptides microbiens par les TCD8+ CD103+ (sur-représentés dans les psoriasis et dans les liquides articulaires de certaines SpA) induit une inflammation qui pourrait être suffisante à renverser transitoirement la fonction régulatrice des cellules dendritiques CD103+ et des lymphocytes TCD4+CD103+ lors des poussées de ces pathologies. Leur sensibilité aux rétinoïdes est un autre argument pour suspecter qu’une défaillance temporaire de cellules CD103+ participe à leur pathogénie.
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Citation Excerpt :
The etiologic role of Chlamydia species and enterobacteria in reactive arthritis has been posited to also apply to AS pathogenesis.113,114 Transgenic HLA-B27 murine models have also demonstrated that the introduction of bacteria is necessary for the development of spondyloarthropathy.115 Inflammation in the gut has been consistently observed in spondyloarthritis.116
Correlations among clinical, radiographic and sonographic scores for enthesitis in ankylosing spondylitis
2011, Revue du Rhumatisme (Edition Francaise)
Rechercher les corrélations entre les scores cliniques, radiographiques et échographiques d’enthésite au cours de la spondylarthrite ankylosante (SA).
Étude prospective portant sur 60 patients, atteints de SA, répondant aux critères de New York modifiés. Nous avons utilisé le BASDAI, le BASFI, l’ASQoL et l’échelle visuelle analogique (Eva) au niveau des enthèses pour l’évaluation clinique de la SA, ainsi que les indices spécifiques d’enthésite : le Maastrich Ankylosing spondylitis Enthesitis Score (MASES) et le Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Cinq sites enthésiques ont été explorés de façon bilatérale par des radiographies et par des échographies-Doppler (insertion rotulienne du quadriceps, insertions proximale et distale du tendon rotulien, insertion du tendon d’Achille et de l’aponévrose plantaire superficielle), à l’aide d’un échographe Philips HD 11^TM utilisant une sonde à balayage linéaire de haute fréquence.
Cette étude a porté sur 48 hommes et 12 femmes, leur âge moyen était de 36 ± 11ans. L’étude des corrélations entre les scores cliniques, radiographique et échographiques a montré que le score radiographique était corrélé avec l’Eva douleur des enthèses, le BASDAI et le BASFI. Le score échographique d’enthésite aigue était corrélé uniquement avec le MASES. Le score échographique d’enthésite chronique n’était corrélé avec aucun score clinique. Le score Doppler était corrélé avec l’Eva douleur, le BASDAI, le BASFI et l’ASQoL. Enfin, le score échographique global était corrélé avec le MASES et le SPARCC.
Une bonne concordance a été notée entre les scores cliniques et échographiques d’enthésite alors que le score radiographique semble plus lié aux paramètres généraux de la SA. Des études de plus grande envergure sont nécessaires pour mieux apprécier la place des radiographies et de l’échographie des enthèses dans la démarche diagnostique et le suivi des malades sous traitement.

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POINT OF VIEWNew pathogenic hypotheses for spondyloarthropathies

Abstract

Section snippets

Role for genetic factors

Role for environmental factors

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 HLA-b27 molecule may promote the development of spondyloarthropathy by facilitating persistence of some pathogens within macrophagic or dendritic cell lines

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

Consistency of this scenario with most of the available experimental data

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’

High TGF-β (and IL-10) levels within entheses may contribute to the pathogenesis of spondyloarthropathies and to the selective involvement of entheses

Consequences of macrophage activation near the entheses or within the joints

Conclusion

Immunol Today

Baillieres. Clin Rheumatol

Hum Immunol

Curr Opin Immunol

Microbes Infect

J Biol Chem

Microbes Infect

Oral Surg Oral Med Oral Pathol Oral Radio Endod

Semin Arthritis Rheum

The effects of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis

Arthritis Rheum

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

POINT OF VIEW
New pathogenic hypotheses for spondyloarthropathies