scholarly journals Lymph-Borne Chemokines and Other Low Molecular Weight Molecules Reach High Endothelial Venules via Specialized Conduits While a Functional Barrier Limits Access to the Lymphocyte Microenvironments in Lymph Node Cortex

2000 ◽  
Vol 192 (10) ◽  
pp. 1425-1440 ◽  
Author(s):  
J. Elizabeth Gretz ◽  
Christopher C. Norbury ◽  
Arthur O. Anderson ◽  
Amanda E.I. Proudfoot ◽  
Stephen Shaw
Keyword(s):  
Lymph Node ◽  
Basement Membranes ◽  
High Endothelial Venules ◽  
Reticular Fibers ◽  
Lymph Node Enlargement ◽  
Subcapsular Sinus ◽  
Sinus Floor ◽  
Draining Lymph Node ◽  
Reticular Cells ◽  
Draining Lymph Nodes

Lymph-borne, soluble factors (e.g., chemokines and others) influence lymphocyte recirculation and endothelial phenotype at high endothelial venules (HEVs) in lymph node cortex. Yet the route lymph-borne soluble molecules travel from the subcapsular sinus to the HEVs is unclear. Therefore, we injected subcutaneously into mice and rats a wide variety of fluorophore-labeled, soluble molecules and examined their distribution in the draining lymph nodes. Rather than percolating throughout the draining lymph node, all molecules, including microbial lipopolysaccharide, were very visible in the subcapsular and medullary sinuses but were largely excluded from the cortical lymphocyte microenvironments. Exclusion prevailed even during the acute lymph node enlargement accompanying viral infection. However, low molecular mass (MW) molecules, including chemokines, did gain entry into the cortex, but in a very defined manner. Low MW, fluorophore-labeled molecules highlighted the subcapsular sinus, the reticular fibers, and the abluminal and luminal surfaces of the associated HEVs. These low MW molecules were in the fibers of the reticular network, a meshwork of collagen fibers ensheathed by fibroblastic reticular cells that connects the subcapsular sinus floor and the HEVs by intertwining with their basement membranes. Thus, low MW, lymph-borne molecules, including chemokines, traveled rapidly from the subcapsular sinus to the HEVs using the reticular network as a conduit.

scholarly journals Neutrophils recruited through high endothelial venules of the lymph nodes via PNAd intercept disseminating Staphylococcus aureus

2018 ◽  
Vol 115 (10) ◽  
pp. 2449-2454 ◽  
Author(s):  
Ania Bogoslowski ◽  
Eugene C. Butcher ◽  
Paul Kubes
Keyword(s):  
Staphylococcus Aureus ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Systemic Circulation ◽  
Skin Infections ◽  
High Endothelial Venules ◽  
Novel Treatments ◽  
Subcapsular Sinus ◽  
Draining Lymph Node ◽  
Peripheral Node

Staphylococcus aureus is a skin- and respiratory tract-colonizing bacterium and is the leading cause of community-acquired skin infections. Dissemination of these bacteria into systemic circulation causes bacteremia, which has a high mortality rate. Therefore, understanding the immunologic barriers that prevent dissemination is critical to developing novel treatments. In this study, we demonstrate that an S. aureus breach across skin leads to some migration of the pathogen to the draining lymph node, but no further. While subcapsular sinus (SCS) macrophage in lymph nodes were important in detaining S. aureus, a rapid complement-dependent neutrophil recruitment (independent of the SCS macrophage) via high endothelial venules (HEVs) resulted in high numbers of neutrophils that intercepted the bacteria in the lymph nodes. Peripheral Node Addressin together with its two ligands, L-selectin and platelet P-selectin, are critical for recruiting neutrophils via the HEVs. Almost no neutrophils entered the lymph nodes via lymphatics. Neutrophils actively phagocytosed S. aureus and helped sterilize the lymph nodes and prevent dissemination to blood and other organs.

scholarly journals Altering the Cellular Location of an Antigen Expressed by a DNA-Based Vaccine Modulates the Immune Response

1999 ◽  
Vol 73 (12) ◽  
pp. 10214-10223 ◽  
Author(s):  
P. J. Lewis ◽  
S. van Drunen Littel-van den Hurk ◽  
L. A. Babiuk
Keyword(s):  
Lymph Node ◽  
Immune Responses ◽  
Dna Vaccines ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
Bovine Herpesvirus 1 ◽  
Draining Lymph Node ◽  
Herpesvirus 1 ◽  
Draining Lymph Nodes ◽  
Node Immunization

ABSTRACT The potential for DNA vaccines encoding mutated versions of the same antigen to modulate immune responses in C3H/HeN mice was investigated. We created expression plasmids that encoded several versions of glycoprotein D (gD) from bovine herpesvirus 1, including authentic membrane-anchored glycoprotein (pSLRSV.AgD), a secreted glycoprotein (pSLRSV.SgD), and an intracellular protein (pSLRSV.CgD). Immunization of an inbred strain of mice with these plasmids resulted in highly efficacious and long-lasting humoral and cell-mediated immunity. We also demonstrated that the cell compartment in which plasmid-encoded gD was expressed caused a deviation in the serum immunoglobulin (Ig) isotype profile as well as the predominant cytokines secreted from the draining lymph node. Immunization of C3H/HeN mice with DNA vaccines encoding cell-associated forms of gD resulted in a predominance of serum IgG2a and gamma interferon-secreting cells within the spleens and draining lymph nodes. In contrast, mice immunized with a secreted form of this same antigen displayed immune responses characterized by greater levels of interleukin 4 in the draining lymph node and IgG1 as the predominant serum isotype. We also showed evidence of compartmentalization of distinct immune responses within different lymphoid organs.

The chemokine receptor CCR7 and α4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2977-2984 ◽  
Author(s):  
Kathleen J. Till ◽  
Ke Lin ◽  
Mirko Zuzel ◽  
John C. Cawley
Keyword(s):  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
Lymph Nodes ◽  
Lymph Node Involvement ◽  
Lymphocytic Leukemia ◽  
Lymphocyte Migration ◽  
High Endothelial Venules ◽  
Lymph Node Enlargement ◽  
Node Involvement

Abstract Malignant lymphocyte migration into lymph nodes is an important aspect of chronic lymphocytic leukemia (CLL), yet little is known about the processes involved. Here we demonstrate that CLL cells migrate across vascular endothelium in response to at least 3 chemokines, namely, CCL21, CCL19, and CXCL12. Moreover, transendothelial cell migration (TEM) in response to CCL21 and CCL19 was significantly higher for the malignant B cells of patients who had clinical lymph node involvement as compared with those of patients lacking such organomegaly. Furthermore, the expression of CCR7, the receptor for both CCL21 and CCL19, correlated with clinical lymphadenopathy, and blocking of CCR7 inhibited CLL cell TEM. By using immunohistochemistry we demonstrated that CCL21 and CCL19, but not CXCL12, are located in high endothelial venules and are, therefore, in an appropriate location to induce TEM. Regarding the adhesion receptors involved in TEM, α4 (most likely in association with β1) and αLβ2 were shown to be important in CLL cell TEM in vitro, but only the level of α4 expression correlated with the presence of clinical lymphadenopathy. The present studies are the first to shed light on the factors determining CLL cell entry into nodes and define the phenotype of circulating malignant cells likely to determine the pattern of lymph node enlargement in the disease.

scholarly journals Lymph Node Morphology in Stage II Colorectal Cancer

2020 ◽  
Author(s):  
Annabelle Greenwood ◽  
John Keating ◽  
Diane Kenwright ◽  
Ali Shekouh ◽  
Alex Dalzell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Lymph Node ◽  
Lymph Nodes ◽  
B Cell ◽  
Stage Ii ◽  
Cell Compartments ◽  
Stage Ii Colorectal Cancer ◽  
Draining Lymph Node ◽  
Draining Lymph Nodes

ABSTRACTBackgroundColorectal cancer is one of the leading causes of cancer-associated morbidity and mortality worldwide. The local anti-tumour immune response is particularly important for patients with stage II where the tumour-draining lymph nodes have not yet succumbed to tumour spread. The lymph nodes allow for the expansion and release of B cell compartments such as primary follicles and germinal centres. A variation in this anti-tumour immune response may influence the observed clinical heterogeneity in stage II patients.AimThe aim of this study was to explore tumour-draining lymph node histomorphological changes and tumour pathological risk factors including the immunomodulatory microRNA-21 (miR-21) in a small cohort of stage II CRC.MethodsA total of 23 stage II colorectal cancer patients were included. Tumour and normal mucosa samples were analysed for miR-21 expression levels and B-cell compartments were quantified from Haematoxylin and Eosin slides of lymph nodes. These measures were compared to clinicopathological risk factors such as perforation, bowel obstruction, T4 stage and high-grade.ResultsWe observed greater follicle density in patients with a lower tumour T stage and higher germinal centre density in patients with higher pre-operative carcinoembryonic antigen levels. Trends were also detected between tumours with deficiency in mismatch repair proteins, lymphatic invasion and both the density and size of B-cell compartments. Lastly, elevated tumour miR-21 was associated with decreased follicle and germinal centre size.ConclusionVariation in B-cell compartments of tumour-draining lymph nodes is associated with clinicopathological risk factors in stage II CRC patients.What does this paper add to the literature?This study demonstrates the variability of tumour draining lymph node morphological features in stage II CRC patients. This provides new scope for biomarker discovery in stage II CRC patients which is a research priority for this patient group.

scholarly journals Tumor pre-conditioning of draining lymph node stroma by lactic acid

2018 ◽  
Author(s):  
Angela Riedel ◽  
Jonathan Swietlik ◽  
David Shorthouse ◽  
Lisa Haas ◽  
Tim Young ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Transcriptional Profiling ◽  
Structure And Function ◽  
Tumor Site ◽  
Primary Tumor Site ◽  
Draining Lymph Node ◽  
Reticular Cells ◽  
And Function ◽  
Activated Fibroblasts ◽  
Draining Lymph Nodes

Communication between tumors and the stroma of tumor draining lymph nodes (TDLNs) exists before metastasis arises, altering structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRCs), the dominant stromal population of the LN, revealed reprogramming of these cells in immune related pathways, but also in fibroblast activation and mitochondrial function. However, tumor derived factors driving the changes in FRCs remained to be identified. Taking an unbiased approach, we show that lactate, a metabolite released by cancer cells, elicits upregulation of Pdpn and Thy1 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we show that tumor-derived lactate alters mitochondrial function of FRCs of TDLNs. Thus, our results demonstrate a novel mechanism by which a tumor-derived metabolite modulates the function of fibroblasts in TDLNs.

scholarly journals Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 211
Author(s):  
Tove Bekkhus ◽  
Teemu Martikainen ◽  
Anna Olofsson ◽  
Mathias Franzén Boger ◽  
Daniel Vasiliu Bacovia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Stromal Cells ◽  
Nodal Metastasis ◽  
Organ Donors ◽  
High Endothelial Venules ◽  
Tumor Invasiveness ◽  
Non Invasive ◽  
Reticular Cells ◽  
Draining Lymph Nodes

The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.

scholarly journals Characterization of Leptin Receptor+ Stromal Cells in Lymph Node

2022 ◽  
Vol 12 ◽  
Author(s):  
Liwei Jiang ◽  
Mine Yilmaz ◽  
Mayuko Uehara ◽  
Cecilia B. Cavazzoni ◽  
Vivek Kasinath ◽  
...  
Keyword(s):  
Lymph Node ◽  
Stromal Cells ◽  
Leptin Receptor ◽  
Inflammatory Responses ◽  
Conditional Knockout ◽  
High Endothelial Venules ◽  
Stromal Compartment ◽  
Leptin Signaling ◽  
Cell Dysfunction ◽  
Reticular Cells

Lymph node (LN)-resident stromal cells play an essential role in the proper functioning of LNs. The stromal compartment of the LN undergoes significant compensatory changes to produce a milieu amenable for regulation of the immune response. We have identified a distinct population of leptin receptor-expressing (LepR+) stromal cells, located in the vicinity of the high endothelial venules (HEVs) and lymphatics. These LepR+ stromal cells expressed markers for fibroblastic reticular cells (FRCs), but they lacked markers for follicular dendritic cells (FDCs) and marginal reticular cells (MRCs). Leptin signaling deficiency led to heightened inflammatory responses within the LNs of db/db mice, leakiness of HEVs, and lymphatic fragmentation. Leptin signaling through the JAK/STAT pathway supported LN stromal cell survival and promoted the anti-inflammatory properties of these cells. Conditional knockout of the LepR+ stromal cells in LNs resulted in HEV and extracellular matrix (ECM) abnormalities. Treatment of ob/ob mice with an agonist leptin fusion protein restored the microarchitecture of LNs, reduced intra-LN inflammatory responses, and corrected metabolic abnormalities. Future studies are needed to study the importance of LN stomal cell dysfunction to the pathogenesis of inflammatory responses in type 2 diabetes (T2D) in humans.

scholarly journals Optimal CD4T Cell Priming in Lymph Nodes Requires Repertoire Scanning by CD301b+ Migratory cDC2 Cells

2020 ◽  
Author(s):  
Naoya Tatsumi ◽  
Alicia L Codrington ◽  
Yosuke Kumamoto
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Activation Mechanism ◽  
Th2 Cells ◽  
List Type ◽  
Antigen Specificity ◽  
High Endothelial Venules ◽  
Cell Clones ◽  
Draining Lymph Node ◽  
Cd4t Cell

SummaryActivation of CD4T cells by conventional dendritic cells (cDC) is pivotal in adaptive immunity. However, while the activation mechanism of antigen-specific CD4T cells has been extensively studied, the cellular mechanism that leads to the selection of cognate CD4T cell clones out of the polyclonal pool is incompletely understood. Here, we show that, in the reactive lymph nodes, newly homed naive polyclonal CD4T cells are temporarily retained before leaving the lymph node. This stop-and-go traffic of CD4T cells provides an adequate time window for efficient scanning and timely priming of antigen-specific clones. Mechanistically, upon immunization, CD301b+ DCs, a major subset of migratory cDC2 cells, quickly migrate to the draining lymph node and settle in the areas near the high endothelial venules, where they retain incoming polyclonal CD4T cells through MHCII-dependent but antigen-independent mechanisms while concurrently providing cognate stimuli to prime antigen-specific CD4T cells. These results indicate that CD301b+ DCs function as an immunological “display window” for CD4T cells to efficiently scan their antigen specificity.Graphical AbstractHighlightsNewly homed polyclonal CD4T cells are temporarily retained in the reactive lymph nodes.Depletion of CD301b+ DCs results in shorter dwell time of CD4T cells in the draining lymph node and delayed priming of antigen-specific clones.The transient retention of polyclonal CD4T cells in the draining lymph node requires MHCII expression on CD301b+ DCs but not cognate antigen.CD301b+ DCs are required for robust expansion of rare antigen-specific CD4T cell clones and their skewing toward Th2 cells.

scholarly journals Characterization of lumbar lymph node, a CNS-specific draining lymph node, after spinal cord injury in rats

2019 ◽  
Author(s):  
Hadi Askarifirouzjaei ◽  
Leila Khajoueinejad ◽  
Mehdi Fazeli ◽  
Taki Tiraihi ◽  
Ali Akbar Pourfathollah
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Thoracic Spinal Cord ◽  
Intact Control ◽  
Thoracic Spinal ◽  
Cord Injury ◽  
Draining Lymph Node ◽  
Draining Lymph Nodes

Abstract Regional tissue-draining lymph nodes are the major active site after inflammation that generate primary immune responses according to lymphatic system pathways. However, CNS specific draining lymph nodes have not characterized individually after spinal cord injury (SCI). Therefore, we examined the morphofunctional state of the Lumbar lymph node, the closest CNS-draining lymph node adjacent to the lesion site in thoracic spinal cord injury. Findings: Lumbar lymph nodes isolated 7 days after low thoracic spinal cord injury were compared with sham control and intact control rats. The significant enlargement was observed in lumbar lymph nodes in SCI group accompanied by increased total cell number, while there was a significantly higher cell death rate. Besides, the proliferation test performed on lymphocytes lumbar lymph nodes one week after SCI revealed accelerated proliferation rate compared to sham and intact control groups, which was associated with significant elevation of IFN-γ/IL4 ratio, which confirms adaptive immunity is biased towards the Th1 pro-inflammatory responses. Conclusions: Accordingly, we conclude that the lumbar lymph node is an important CNS-draining lymph node for understanding the immunopathology of SCI, which needs to be considered as a major active lymphoid organ adjacent to the lesion site.

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