ReviewTrafficking of antigens from gut to sacroiliac joints and spine in reactive arthritis and spondyloarthropathies: Mainly through lymphatics?
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 P. gingivalis 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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2021, Joint Bone SpineCitation Excerpt :More chronic exposure to PAMPs of Trophyrema Whipplei (Whipple's disease), can also mimic SpA [1]. Other SpA may similarly be triggered by PAMPs from poorly or non-cultivable microorganisms, and repeated silent translocations of PAMPs from gut microbiota (through the portal vein, and/or lymphatics common to gut and sacro-iliac/spine) could contribute to the pathogenesis of SpA [2,3]. Dysbiosis is indeed observed in SpA patients, and is concomitant with chronic mucosal inflammation and gut leakiness.
Translocation of dead or alive bacteria from mucosa to joints and epiphyseal bone-marrow: Facts and hypotheses
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2020, Joint Bone SpineCitation Excerpt :Sugars on the surface of pathogens and self-surface immune glycoproteins, such as TCR, MHC, TLR, and antibodies (including therapeutic monoclonal antibodies) also play a crucial role in leukocytes migration. Some gut bacteria internalized in macrophages only traffic through blood (which could induce metastatic spreading in peripheral joints), while others do so quite exclusively through lymphatics (which would fit with preferential migration of those enterobacteria in sacroiliac joints and spine, since lymphatics from gut are connected to lymphatics of sacroiliac joints and spine through the thoracic duct, which ends near the sterno-clavicular joints and sternum [14]). Lack of development of bacteria following culture of synovial tissue does not preclude infection by slow-growing bacteria only replicating intracellularly.
Gut microbiota and obesity-associated osteoarthritis
2019, Osteoarthritis and CartilageCitation Excerpt :However, the exact source of these organisms is difficult to identify because many species are normal commensal residents both in the intestinal tract and skin66. It seems reasonable to propose the gut as the source of these organisms because impaired gut permeability and mucosal competence have been observed in patients with arthritis66,67, and some living bacteria could be transferred from the gut to the joints/enthesis through the circulatory or lymphatic system68. A hypothesis article proposed the pivotal role of metabolic endotoxemia in cross-sectional associations among gut dysbiosis, systemic inflammation and articular damage in obesity-induced OA69.