Elsevier

Joint Bone Spine

Volume 83, Issue 5, October 2016, Pages 485-490
Joint Bone Spine

Review
Trafficking of antigens from gut to sacroiliac joints and spine in reactive arthritis and spondyloarthropathies: Mainly through lymphatics?

https://doi.org/10.1016/j.jbspin.2015.10.015Get rights and content

Abstract

Bacterial trafficking from gut to mesenteric lymph nodes is physiologic only for a few commensal species, like Alcaligenes which produces antimicrobial-substances inhibiting growth of pathogenic bacteria. In reactive arthritis, some living bacteria transiently manage to travel from gut to joints/enthesis within dendritic cells and/or macrophages. Migration of dead or dormant bacteria outside the gut in spondyloarthropathies, including those associated with Crohn's disease, can occur either through blood or lymphatics. Migration through lymphatics instead of blood depends on the host, but also on the subset of pathogen, as shown for Salmonella. Retrograde trafficking within lymphatics of immune cells infected by dormant or dead bacteria, from mesenteric lymph nodes or thoracic duct to sacroiliac joint and spine, might contribute to axial involvement in some spondyloarthropathies and related disorders, since: 1- large influxes of pathogens can overwhelm lymph nodes, and Yersinia can even replicate within lymph nodes; 2- Whipple cells have been shown to circulate in thoracic duct lymph; 3- expansion of lymphatics is a prominent feature of gastro-intestinal inflammation, and obstruction of gut lymphatics a hallmark of Crohn's disease; 4- lymph reflux has been demonstrated in models of mesenteric lymph vessel obstruction; 5- reflux to sacroiliac has been observed in patients with chyluria undergoing lymphography; 6- lymphatics are present in the outer periosteum and paraspinal ligaments surrounding intervertebral discs and connected to thoracic duct. Accordingly, further studies on the trafficking of dendritic cells, macrophages and lymphocytes from gut to joints and spine in animal models of reactive arthritis or spondyloarthropathies should also focus on lymphatic routes.

Section snippets

Physiologic role of gut lymphatics

The importance of lymphatics in disease is gaining renewal of interest in acute and chronic inflammation, especially in gut inflammation. Indeed, the gastro-intestinal absorptive surface is immense (> 200 m2), and, whereas total lymph formation in humans is approximately 1–4 liters/day, most is formed in the gastro-intestinal tract [10]. Lymphatic vessels constitute a ubiquitous countercurrent system to the blood vasculature that returns interstitial fluid, salts, small molecules, resorbed fat,

Gut bacteria can invade the host by blood or lymphatic routes

Some indigenous intestinal bacteria can invade distant organs, either by blood or lymphatic routes. This remote bacterial translocation can be indirectly estimated in animal models by using labeled bacteria, blood culture, and detection of microbial DNA or endotoxin [13]. In humans, transient bacterial translocation from the digestive tract also seems a frequent event: in a study on eighteen patients with esophageal cancer, where MLN were also harvested from the jejunal mesentery both before

Trafficking through blood

The mDCs that are elevated in the blood as a result of low-grade bacteremia, often do not trigger a productive immune response. They can however disseminate the pathogen throughout the host, accelerating some systemic inflammatory disease progression [15]. Analysis of the blood mDC microbiome by 16S rDNA sequencing showed Porphyromonas gingivalis and other species. The survival of the anaerobe Pgingivalis under aerobic conditions was enhanced within mDCs [16]. It has been shown that DCs can

Trafficking through lymphatics

The firewalls for lymphatic routes are the MLNs (Fig. 1), where some commensal bacteria unexpectedly contribute to prevent systemic diffusion of pathogenic gut bacteria. Indeed, bacterial translocation to MLNs is more common than previously thought [19], but most of the bacteria found in MLNs are commensal, and more beneficial than detrimental for the host [20], through their production of antimicrobial-substances inhibiting the growth of pathogenic bacteria. Indeed, some commensal bacteria

Factors enhancing bacterial translocation

The space between luminal intestinal cells is sealed by tight junctions (Box 1). Some commensal strains of bacteria lead to an increase in tight junction proteins at the cell boundaries, thus regulating the permeability of the intestinal barrier, and preventing the ingress of pathogenic bacteria. Some pathogenic bacteria can conversely enhance overall gut permeability. This explains why dysbiosis induced by antibiotic treatment can have effect negative effect on host defense mechanisms [27],

Mesenteric fat as a possible place to hide before further migration of bacterial antigens

Mesenteric fat hyperplasia is a hallmark of Crohn's disease [38], which is not surprising since lymph factor(s) stimulate adipose tissue to proliferate. Adipocytes are tolerogenic cells, and a favourable place to hide for some bacteria escaped from MLNs firewalls. Bacterial translocation to mesenteric fat was indeed observed in 13% of healthy and 27% of Crohn's disease subjects, and is increased in experimental colitis and ileitis. As human mesenteric adipocytes constitutively express mRNA for

Obstruction of lymphatics in inflammatory bowel diseases

Increased density of lymphatic vessels is a constant feature of inflammatory bowel diseases (IBD), and is present in non-inflamed areas. It is trans-mural in Crohn's disease, and confined to the mucosa in ulcerative colitis [45]. The fundamental alteration in Crohn's disease occurs in regional lymphatics of the intestine, with failure of lymphatic pumps produced by several inflammatory mediators [10]. Consequently, Crohn's disease can be seen a lymphocytic and granulomatous lymphangitis,

Retrograde trafficking from lymph-node and thoracic duct to sacro-iliac, spine and thorax in reactive arthritis and axial SpA

Sacroiliitis, inflammation of lumbar and thoracic spine, aortitis, and sternal osteitis, all can be observed in SpA, but not in RA, and hip involvement is also more frequent in SpA. Retrograde trafficking of DC cells carrying bacterial antigens from MLNs to sacro-iliac joints and from thoracic duct to spine and thorax through lymphatics, could contribute to explain some of those anatomical differences between RA and SpA.

Although metastatic tumor spread to the spine usually does not occur by

Conclusion

The connections between immune responses in gut and joints have been recently highlighted as more important than previously thought [59], [60]. Further studies on the translocation of DC and bacteria or their antigens (including bacteria in dormancy [3]), from gut to sacroiliac joints and spine, through MLNs, in animal models of ReA and SpA, could shed new lights on the pathogenesis of those disorders. Those studies should not be restricted to blood, but rather focus on trafficking in

Disclosure of interest

The authors declare that they have no competing interest.

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