Abstract
The vascular–stromal compartment of lymph nodes is important for lymph node function, and high endothelial venules (HEVs) play a critical role in controlling the entry of recirculating lymphocytes. In autoimmune and autoinflammatory diseases, lymph node swelling is often accompanied by apparent HEV expansion and, potentially, targeting HEV expansion could be used therapeutically to limit autoimmunity. In previous studies using mostly flow cytometry analysis, we defined three differentially regulated phases of lymph node vascular–stromal growth: initiation, expansion, and the re-establishment of vascular quiescence and stabilization. In this study, we use optical projection tomography to better understand the morphologic aspects of HEV growth upon immunization with ovalbumin/CFA (OVA/CFA). We find HEV elongation as well as modest arborization during the initiation phase, increased arborization during the expansion phase, and, finally, vessel narrowing during the re-establishment of vascular quiescence and stabilization. We also examine acutely enlarged autoinflammatory lymph nodes induced by regulatory T cell depletion and show that HEVs are expanded and morphologically similar to the expanded HEVs in OVA/CFA-stimulated lymph nodes. These results reinforce the idea of differentially regulated, distinct phases of vascular–stromal growth after immunization and suggest that insights gained from studying immunization-induced lymph node vascular growth may help to understand how the lymph node vascular–stromal compartment could be therapeutically targeted in autoimmune and autoinflammatory diseases.
Highlights
Lymph nodes are sites of immune responses, and the lymph node blood vessels are an integral part of immune function
The results reinforce the concept that there are distinct phases of lymph node vascular growth induced after immunization and demonstrate that acute autoinflammatory lymphadenopathy can be associated with high endothelial venules (HEVs) expansion
As flow cytometry is likely able to detect cells expressing only abluminal peripheral node addressin (PNAd) as well as cells expressing luminal PNAd, we cannot rule out that the additional PNAd+ cells detected by flow cytometry are cells expressing only abluminal PNAd and that elongation seen by Optical projection tomography (OPT) may reflect stretching
Summary
Lymph nodes are sites of immune responses, and the lymph node blood vessels are an integral part of immune function. In addition to the delivery of oxygen and micronutrients, the lymph node blood vessels deliver lymphocytes and other immune cells to the lymph node parenchyma, where these cells can interact with antigen and one another to generate an adaptive immune response. Recirculating lymphocytes enter the lymph node parenchyma at specialized postcapillary venules characterized by cuboidal, rather than flat, endothelial cells that are known as high endothelial venules (HEVs). The HEVs and the vessels in general are suspended within a conduit network consisting of collagen-rich fibrils ensheathed by fibroblastic reticular cells (FRCs). The conduit network is functionally connected to the blood vessels, with FRCs or related pericyte-like cells ensheathing the vessel walls (Gretz et al, 1997; Malhotra et al, 2012). Insight into the events and regulation of HEV alterations during immune responses may lead to new ways by which to therapeutically manipulate immunity
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