CD169+ macrophages in lymph node and spleen critically depend on dual RANK and LTbetaR signaling

CD169+ macrophages reside in lymph node (LN) and spleen and play an important role in the immune defense against pathogens. As resident macrophages, they are responsive to environmental cues to shape their tissue-specific identity. We have previously shown that LN CD169+ macrophages require RANKL for formation of their niche and their differentiation. Here, we demonstrate that they are also dependent on direct lymphotoxin beta (LTβ) receptor (R) signaling. In the absence or the reduced expression of either RANK or LTβR, their differentiation is perturbed, generating myeloid cells expressing SIGN-R1 in LNs. Conditions of combined haploinsufficiencies of RANK and LTβR revealed that both receptors contribute equally to LN CD169+ macrophage differentiation. In the spleen, the Cd169-directed ablation of either receptor results in a selective loss of marginal metallophilic macrophages (MMMs). Using a RANKL reporter mouse, we identify splenic marginal zone stromal cells as a source of RANKL and demonstrate that it participates in MMM differentiation. The loss of MMMs had no effect on the splenic B cell compartments but compromised viral capture and the expansion of virus-specific CD8+ T cells. Taken together, the data provide evidence that CD169+ macrophage differentiation in LN and spleen requires dual signals from LTβR and RANK with implications for the immune response.

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Lymph Node Stromal Cells From Different Draining Areas Distinctly Regulate the Development of Chronic Intestinal Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2020.549473 ◽

2021 ◽

Vol 11 ◽

Author(s):

Marijana Basic ◽

Pia Pascale Peppermüller ◽

Silvia Bolsega ◽

André Bleich ◽

Melanie Bornemann ◽

...

Keyword(s):

Immune Response ◽

Lymph Node ◽

Lymph Nodes ◽

Stromal Cells ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Peripheral Lymph ◽

Intestinal Immune System ◽

Chronic Intestinal Inflammation ◽

Lymph Node Stromal Cells

The balance between the responsiveness of the intestinal immune system and the gut environment is fundamental for the maintenance of intestinal homeostasis, which is required for an adequate recognition of entering antigens. The disruption of this homeostasis by exaggerated immune response to harmless antigens can lead to the development of intestinal disorders such as inflammatory bowel disease. Stromal cells are sessile non-hematopoietic cells that build the backbone of the lymph node, an important site for the immune response induction, but also contribute to immune response and tolerance induction. However, the knowledge about the role of stromal cells in the regulation of inflammatory responses is still limited. Therefore, in this study we analyzed the influence of stromal cells on the development of chronic intestinal inflammation. Here, we show that intestinal inflammation alters the immune activation of the mesenteric lymph node-derived stromal cells. Podoplanin+ and CD21/35+ stromal cells showed increased expression of MHC class II molecules, but CD106 expression on CD21/35+ cells was reduced. Stromal cells secreted cytokines and chemokines such as CCL7 and CXCL16 influenced the gut-homing phenotype and proliferation of CD4+ and CD8+ T cells. Furthermore, stromal cells of peripheral lymph nodes transplanted into the mesentery attenuated colitis severity in B6-Il10-/- mice. The reduced colitis severity in these mice was associated with increased expression of IL4 and distinct activation pattern of stromal cells derived from transplanted peripheral lymph nodes. Altogether, our results demonstrate that lymph node stromal cells impact development of chronic colitis via T cell induction. Moreover, lymph node stromal cells from different draining area due to neonatally imprinted processes distinctly regulate the induction of immune responses.

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Anti-inflammatory and immunomodulating effects of the bacterial lysate in the in vivo models of aseptic lymphadenitis and pneumococcal pneumonia

Medical Immunology (Russia) ◽

10.15789/1563-0625-aai-1758 ◽

2020 ◽

Vol 22 (1) ◽

pp. 111-122

Author(s):

K. L. Kryshen ◽

A. E. Kukharenko ◽

A. S. Vichare ◽

E. A. Gaidai ◽

A. A. Kryshen ◽

...

Keyword(s):

Immune Response ◽

Lymph Node ◽

Therapeutic Dose ◽

Pneumococcal Pneumonia ◽

Inflammatory Diseases ◽

Immune Defense ◽

Control Group ◽

Infectious Agents ◽

Bacterial Lysate ◽

Anti Inflammatory

Bacterial lysates may produce immunoregulatory effects in the inflammatory diseases that are not directly caused by infectious agents; they may also stimulate the immune response against pathogens which are not a part of the lysate composition. Imudon® is a polyvalent bacterial lysate that is available in orodispersible tablets. However, the influence of this drug product on aseptic inflammation and immune defense against the infectious agents, the antigens of which are not contained in this preparation have not been studied so far. The aim of this study, therefore, was to determine the anti-inflammatory and immunomodulating effects of Imudon® using the models of aseptic lymphadenitis (in Wistar rats) and pneumococcal pneumonia (in Balb/c mice), i.e., the conditions not related to the specific components of the bacterial lysate. Lymphadenitis was induced in rats by administration of λ-carrageenan into a cervical lymph node via an open operative approach. Whereas pneumonia was induced in mice by administering Streptococcus pneumoniae suspension intranasally. The choice of pneumococcus was determined by the absence of pneumococcal antigens in Imudon®, i.e., it cannot be a direct inducer of adaptive immune response against pneumococcal infection. Imudon® was administered intragastrically as a crushed tablet suspension following a therapeutic-preventive regimen (for 14 days daily until the induction of inflammation and for 3 [in the lymphadenitis model] or 5 days [in the model of pneumonia] in three doses thereafter). In the lymphadenitis model, Imudon® demonstrated both local and systemic anti-inflammatory responses manifested in the reduced number of circulating leucocytes and lower TNFα levels and by ameliorated histological features of inflammation in the operated lymph node. In rats, the anti-inflammatory effect was most pronounced when the product was administered at a dose of 2.2 mg/kg (equivalent to a human therapeutic dose) and 6.6 mg/kg. In the model of pneumonia, administration of Imudon® at 4.44 mg/kg (equivalent to a human therapeutic dose) and 13.32 mg/kg demonstrated a trend towards increased survival rate as compared to the control group. On Day 5 after infection Imudon® (4.44 and 13.32 mg/kg) decreased significantly the severity of inflammation and bacterial titer in the lungs. The titer of anti-pneumococcal immunoglobulins A in the bronchoalveolar lavage fluid were found to be higher in the Imudon® treated group (13.32 mg/kg) compared to control group. The results of this study showed high antiinflammatory and immunomodulatory activities of Imudon® and provided an insight into the mechanisms that underlie the clinical effects of this drug in various inflammatory diseases.

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Lymph node stromal cells strongly influence immune response suppression

European Journal of Immunology ◽

10.1002/eji.201040681 ◽

2011 ◽

Vol 41 (3) ◽

pp. 624-633 ◽

Cited By ~ 7

Author(s):

Manuela Buettner ◽

Reinhard Pabst ◽

Ulrike Bode

Keyword(s):

Immune Response ◽

Lymph Node ◽

Stromal Cells ◽

Response Suppression ◽

Lymph Node Stromal Cells

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Brief report: Lymph node morphology in stage II colorectal cancer

PLoS ONE ◽

10.1371/journal.pone.0249197 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0249197

Author(s):

Annabelle Greenwood ◽

John Keating ◽

Diane Kenwright ◽

Ali Shekouh ◽

Alex Dalzell ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Immune Response ◽

Lymph Node ◽

Lymph Nodes ◽

B Cell ◽

Stage Ii ◽

Cell Compartments ◽

Stage Ii Colorectal Cancer ◽

Draining Lymph Nodes

Background Colorectal 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. Aim The 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. Methods A 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. Results We 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. Conclusion Variation in B-cell compartments of tumour-draining lymph nodes is associated with clinicopathological risk factors in stage II CRC patients.

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Faculty Opinions recommendation of Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725241262.793528884 ◽

2017 ◽

Author(s):

Theresa Lu ◽

William Shipman ◽

Dragos Dasoveanu

Keyword(s):

Lymph Node ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Stromal Cells ◽

Class Ii ◽

Self Antigen ◽

Lymph Node Stromal Cells

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Detection of follicular regions in actin-stained whole slide images of the human lymph node by shock filter

Biological Chemistry ◽

10.1515/hsz-2020-0178 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Patrick Wurzel ◽

Jörg Ackermann ◽

Hendrik Schäfer ◽

Sonja Scharf ◽

Martin-Leo Hansmann ◽

...

Keyword(s):

Lymph Node ◽

B Cells ◽

Similarity Index ◽

Morphological Differentiation ◽

Development Stage ◽

Immune Defense ◽

Lymphoid Follicles ◽

Shock Filter ◽

Transition Points ◽

Whole Slide Images

Abstract Human lymph nodes play a central part of immune defense against infection agents and tumor cells. Lymphoid follicles are compartments of the lymph node which are spherical, mainly filled with B cells. B cells are cellular components of the adaptive immune systems. In the course of a specific immune response, lymphoid follicles pass different morphological differentiation stages. The morphology and the spatial distribution of lymphoid follicles can be sometimes associated to a particular causative agent and development stage of a disease. We report our new approach for the automatic detection of follicular regions in histological whole slide images of tissue sections immuno-stained with actin. The method is divided in two phases: (1) shock filter-based detection of transition points and (2) segmentation of follicular regions. Follicular regions in 10 whole slide images were manually annotated by visual inspection, and sample surveys were conducted by an expert pathologist. The results of our method were validated by comparing with the manual annotation. On average, we could achieve a Zijbendos similarity index of 0.71, with a standard deviation of 0.07.

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The use of mesenchymal stromal cells in the treatment of coronavirus disease 2019

Journal of Translational Medicine ◽

10.1186/s12967-020-02532-4 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Maurice A. Canham ◽

John D. M. Campbell ◽

Joanne C. Mountford

Keyword(s):

Multiple Sclerosis ◽

Clinical Trial ◽

Immune Response ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Host Response ◽

Distress Syndrome ◽

Graft Versus Host ◽

Immunomodulatory Properties ◽

Efficacious Vaccine

Abstract More than seven months into the coronavirus disease -19 (COVID-19) pandemic, infection from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 21.2 million cases and resulted in over 760,000 deaths worldwide so far. As a result, COVID-19 has changed all our lives as we battle to curtail the spread of the infection in the absence of specific therapies against coronaviruses and in anticipation of a proven safe and efficacious vaccine. Common with previous outbreaks of coronavirus infections, SARS and Middle East respiratory syndrome, COVID-19 can lead to acute respiratory distress syndrome (ARDS) that arises due to an imbalanced immune response. While several repurposed antiviral and host-response drugs are under examination as potential treatments, other novel therapeutics are also being explored to alleviate the effects on critically ill patients. The use of mesenchymal stromal cells (MSCs) for COVID-19 has become an attractive avenue down which almost 70 different clinical trial teams have ventured. Successfully trialled for the treatment of other conditions such as multiple sclerosis, osteoarthritis and graft versus host disease, MSCs possess both regenerative and immunomodulatory properties, the latter of which can be harnessed to reduce the severity and longevity of ARDS in patients under intensive care due to SARS-CoV-2 infection.

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Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells

International Journal of Alzheimer s Disease ◽

10.1155/2012/289412 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Maria Cristina de Vera Mudry ◽

Franziska Regenass-Lechner ◽

Laurence Ozmen ◽

Bernd Altmann ◽

Matthias Festag ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

B Cell ◽

Marginal Zone ◽

Nuclear Translocation ◽

Recovery Period ◽

Functional Characterization ◽

Notch Receptor ◽

Marginal Zone B Cells ◽

Cell Fate Decisions

Theγ-secretase complex is a promising target in Alzheimer’s disease because of its role in the amyloidogenic processing ofβ-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oralγ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.

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