The development of lymphoid organs can be viewed as a continuum. At one end are the ‘canonical’ secondary lymphoid organs, including lymph nodes and. Abstract: The development of lymphoid organs can be viewed as a continuum. At one end are the ‘canonical’ secondary lymphoid organs, including lymph. Lymphoid organ development: from ontogeny to neogenesis. (English). 1 reference. stated in · Europe PubMed Central · PubMed ID · · retrieved.

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Review Series Free access Find articles by Ruddle, Developmennt. First published March 3, – More info. Tertiary lymphoid organs TLOs are accumulations of lymphoid cells in chronic inflammation that resemble LNs in their cellular content and organization, high endothelial venules, and lymphatic vessels LVs. Although acute inflammation can result in defective LVs, TLO LVs appear to function normally in that they drain fluid and transport cells that respond to chemokines and sphingosinephosphate S1P gradients.

Molecular regulation of TLO LVs differs from lymphangiogenesis in ontogeny with a dependence on cytokines and hematopoietic cells. Ongoing work to elucidate the function and molecular regulation of LVs in TLOs is providing neognesis into therapies for conditions as diverse as lymphedema, autoimmunity, and cancer.

Nancy Ruddle, PhD > Immunobiology | Yale School of Medicine

The initial thin-walled vessels, called capillaries, progress to collecting vessels and then to larger vessels such as the thoracic duct. Although other cell types can express some of these markers, none except LVs express the entire range. Fluid is transported through the LVs by means of extrinsic contraction of tissue forces and intrinsic pumping through lymphatic muscle 3.

Lymphatic valves prevent backflow and have higher expression of PROX1 than do the cells in the walls of the vessels. LVs have many functions in homeostasis. They maintain fluid balance, preventing edema by providing drainage of interstitial fluid, provide lipid transport, and serve in an immune capacity by carrying antigen and cells throughout the immune system and regulating this transport through production of chemokines and sphingosinephosphate S1P 4.

LVs are also found at sites of chronic inflammation, referred to as ectopic or tertiary lymphoid organs TLOs. Cells are directed to their various locations through the activity of chemokines produced by several different types of stromal cells — fibroblast reticular cells, marginal reticular cells, and endothelial cells 5.

Naive cells enter LNs through specialized blood vessels, called high endothelial venules HEVsand leave after interaction with antigen, which enters into LNs via LVs. Conduits are very fine microvessels consisting of ECM scaffolding produced by fibroblast reticular cells. They transport low-molecular-weight antigens from the cortex to the paracortex and into the parenchyma of LNs, where they can contact the HEVs 6.

The organization of LNs and their vascular features are presented in Figure 1. The signals that organize LNs in ontogeny are tightly regulated, which results in the development of individual LNs on a precise temporal and anatomical schedule 7.

The role of stromal cells in SLO development and maintenance is froom better understood 10 as is the response of these cells to neuronal signals, including retinoic acid DCs accumulate in the subcapsular sinus and transmigrate through the floor of that sinus into the T cell zone, while T cells access the parenchyma of the LN through the peripheral medullary sinuses Efferent LVs drain activated cells from the LN, which then travel through afferent vessels to the next LN in the series, into the thoracic duct, and into the bloodstream via the subclavian veins.

Markers that distinguish efferent from afferent vessels are not yet known. S1P is found in high concentrations in the blood jeogenesis lymph, where lymphocytes express low levels of the receptor, S1PR1.

The receptor is re-expressed at higher levels in the LN, where S1P levels are low. Conditional inducible knockouts regulated by PROX1 will provide insight into this question. TLOs, also referred to as ectopic lymphoid tissues, are accumulations of cells in chronic inflammation reviewed in ref. SLOs arise during development at key locations in the body under the control of a precise developmental program, but chronic immune activity in the adult can give rise to similarly organized accumulations of lymphoid cells in almost any non-lymphoid tissue through a process that is not preprogrammed but rather the result of induction by factors in the environment that could elicit the same signals that contribute to LN development reviewed in refs.

It has been suggested that TLOs differ from SLOs by the absence of a capsule; however, TLOs in a variety of chronic kidney diseases are in contact with a fibrous capsule As noted above, the latter arise at predefined locations as a result of stromal and endothelial organizers.


Even though most of these elements are also present in TLOs 5the order in which they populate the TLO may differ from the precise temporal aspect of LNs. The general neogwnesis of a capsule may have consequences for trafficking patterns that could differ in TLOs from what is seen in LNs, in which the DCs and T cells migrate through the peripheral medullary nwogenesis to the parenchyma TLOs arise in several instances of chronic inflammation, including autoimmunity, chronic graft rejection, persistent infection summarized in ref.

They can be induced experimentally by tissue-specific expression of certain inflammatory mediators summarized in ref. As noted above, lymphoid chemokines regulate trafficking of lymphocytes and DCs to and within LNs, and their expression 2030 is one criterion that defines TLOs.

TLOs likely function as local sites of antigen presentation and lymphocyte activation, including somatic hypermutation and class switching in B cells 31which suggests that they facilitate local antimicrobial responses as well as otnogeny spreading 3233 and autoimmune exacerbation.

TLOs can progress from a relatively benign to a destructive phase and lose their lymphoid organ characteristics. For example, in the non-obese diabetic NOD mouse model of type 1 diabetes mellitus T1DMinitial pancreatic infiltrates are characterized by HEV development and minimal islet destruction, whereas later stages demonstrate frank islet destruction and diabetes The presence of high proportions of regulatory T cells in some TLOs 2535 suggests that immune regulation occurs in these locations.

Thin-walled vessels with typical lymphatic markers, including LYVE1 and PROX1, are apparent in the TLOs arising in both clinical settings autoimmune disease and chronic graft rejection and experimental models summarized in ref.

They are also found in TLOs associated with some tumors The functions of the LVs in TLOs have not been thoroughly investigated but are worthy of analysis with regard to fluid balance and transport of antigen and naive, activated, and memory lymphocytes.

Fluid balance is a critical function of LVs in the body. Since edema is a frequent occurrence in acute inflammation, it is likely that LVs associated with that process serve a drainage function.

Lymphangiogenesis accompanies acute inflammation with enhanced lymph flow Seeger and colleagues suggest that inflammation occurs before lymphangiogenesis and gives rise to that process Lymphangiogenesis at early times after immunization or during acute inflammation may be the result of the presence of excess fluid, but the LVs are unable to transport APCs 13 due to defects in lymphatic contraction Thaunat and colleagues have suggested that the existence of edema in an injured tissue results in an insufficient lymphatic outflow that then gives rise to chronic inflammation at the local site They suggest that defective lymphatic drainage is a prerequisite for the development of TLOs and have provided data supporting this concept in chronic graft rejection.

EBSCOhost | | Lymphoid organ development: from ontogeny to neogenesis.

Techniques to measure fluid accumulation are available 46 but have not been employed in the local region of a TLO. Future research could take advantage of measurements of interstitial fluid pressure in the local vicinity of a TLO to evaluate whether edema occurs and the LVs are functional.

This may be more feasible and meaningful in a clinical setting, in which a relatively accessible TLO such as the joint in rheumatoid arthritis RA provides a logical study site. For example, proteins such as insulin in the pancreatic islet are in immediate proximity to or even a part of the TLO in T1DM.

Thus, the necessity for antigen transport to the TLO through an extensive LV system might not be necessary, and the LVs may not serve that function.

The presentation of self-antigen in LNs 19 that has been suggested as a mechanism for self-tolerance has not been investigated in TLOs and is an important area for future research.

LVs that are packed with lymphocytes are prominent in some TLOs ref. Diagrammatic rendering of actual staining of a TLO from a mouse salivary gland. A Giemsa staining of TLO reveals the presence of leukocytes. TLO-associated LVs may also function in an efferent capacity by transporting activated lymphocytes to the periphery.

This is only effective if the mice have already developed pancreatic TLOs Treatment results in additional accumulation of lymphocytes in the pancreatic TLOs, which is reversed upon cessation, resulting in rapid islet destruction and diabetes 23 These data are also consistent with the observation that FTY also prevents egress from inflamed tissues into afferent lymphatics 5556 and raise the exciting possibility that inhibitors of LV function could prevent diabetes and other autoimmune diseases systemically by preventing trafficking from the TLO to the LNs.

During ontogeny, LVs develop after the embryonic blood vessels have formed, sprouting from the cardinal vein The involvement of additional cell types is suggested by the existence of lymphangioblasts, which are distinct from blood endothelial cells, in developing tadpoles Studies in chickens 6162 and mice 63 — 65 support a role for mesodermal cells that express macrophage and lymphatic markers that become, integrate into, or support LVs through their production of VEGFs.


Regulation of lymphangiogenesis in TLOs is poorly understood. Angiogenesis occurs in inflammation and platelets are present, which indicates that the important players in embryonic lymphangiogenesis may participate.

Thus, the possibility, though remote, exists that a recapitulation of the developmental program could occur — that is, that LVs in inflammation could arise from veins as they do in development. On the other hand, the presence of blood vessels and their nearby LVs in TLOs suggests that lymphangiogenesis in inflammation occurs by sprouting from existing LVs. But what are the cells that signal these events?

DCs, macrophages, and T and B cells have been implicated in the regulation of LVs in acute inflammation 1366 — Different cells may be important at different times in various tissues.

Nancy Ruddle, PhD

For example, B cells appear to be important in the lymphangiogenesis that occurs in LNs during inflammation, but only at the early stages after immunization 13 The participation of macrophages in lymphangiogenesis in acute inflammation has been well documented, although the precise nature of their role is a subject of considerable controversy. Data in a model of corneal transplant lymphangiogenesis suggest that macrophages can actually transdifferentiate into LECs 70 ; that is, that macrophages themselves are precursors to LECs 616264 The expression of LYVE1 by macrophages could be interpreted as evidence that this is the case.

On the other hand, the expression of this marker on both cell types may be a red herring. Kerjaschki and colleagues demonstrated the presence of host bone marrow—derived precursors in association with LVs in the TLOs of chronically rejecting kidneys Osteoclast precursors, which include cells with macrophage properties, participate in lymphangiogenesis in a model of TNF transgene— and serum-mediated RA During low-dose, streptozotocin-induced pancreatic inflammation, there is a marked increase in macrophages in and around the islets.

Lineage-tracing experiments might resolve this controversy. Cytokines contribute to lymphangiogenesis in acute inflammation, although there have been few studies evaluating their roles in the chronic inflammation—associated TLOs. The question of LT participation is of particular interest given both its crucial role in lymphoid organ development and its ability to induce TLOs.

The plasticity of LVs is a reflection of their environment, which influences their function, especially in the case of inflammation.

CCL21 is particularly sensitive to inflammation. Immunofluorescence and microarray studies that compare LECs from acutely inflamed and resting mouse skin reveal increased expression of CCL21 and several other inflammatory genes Interestingly, there is downregulation of other genes, including Vegfr3 and Prox1.

Extension of these studies to LVs in TLOs may reveal differences due to the chronic nature of stimulation, and data from a mouse corneal model of recurrent inflammation suggest that this is the case The authors suggest that, in chronic inflammation, LVs retain memory in their accelerated development of a network of functional LVs The ability to isolate LVs on the basis of their antigen expression 77 or transgene induced fluorescence 79 will allow their molecular analysis and comparison to vessels from resting LNs, activated LNs, and TLOs.

As noted above, new techniques allowing isolation, purification, and single-cell in situ analysis will provide the tools for determination of gene expression. Are there any genes that are differentially expressed in LVs from TLOs compared with those in the rest of the body? If so, it will be possible to preferentially affect those vessels with inhibitors of their function while leaving remaining LVs intact.

Analysis of lymphocyte, DC, and antigen-trafficking patterns in TLOs in real time in vivo is now possible with the use of mice that express fluorescent markers for HEVs 80 and LVs 79 Although the technique of in vivo imaging is well established for analysis of trafficking in LNs 82addressing this issue in TLOs is a greater challenge.

The key is to study TLOs in tissues that are amenable to these techniques, which will allow the evaluation of questions concerning LV insufficiency, memory, and plasticity in LVs in TLOs, and on a functional level, to determine whether valves and muscles occur in these vessels.

The analysis of TLOs in mice whose LVs are conditionally deleted or induced through PROX1 regulation will provide information regarding the importance of fluid drainage functions of LVs in ontogemy context. Finally, the influence of the local environment on the LVs in TLOs in different organs must be analyzed.

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