scholarly journals P03.03 Organization, function and gene expression of tertiary lymphoid structures in PDAC resembles lymphoid follicles in secondary lymphoid organs

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A23.1-A23
Author(s):  
M Thelen ◽  
MA García-Márquez ◽  
T Nestler ◽  
S Wagener-Ryczek ◽  
J Lehmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Expression Patterns ◽  
Lymphoid Organs ◽  
Immunofluorescence Staining ◽  
Ductal Adenocarcinoma ◽  
Lymphoid Follicles ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Secondary Lymphoid Organs

BackgroundSecondary lymphoid organs (SLO) are involved in induction and enhancement of anti-tumor immune responses on different tumor entities. Recent evidence suggests that anti-tumor immune responses may also be induced or enhanced in the tumor microenvironment in so called tertiary lymphoid structures (TLS). It is assumed that TLS represent a hotspot for T cell priming, B cell activation, and differentiation, leading to cellular and humoral anti-tumor immune response.MethodsFFPE-slides of 120 primary pancreatic ductal adenocarcinoma (PDAC) patients were immunohistochemically (IHC) stained for CD20, CD3, CD8 and HLA-ABC to analyze spatial distribution of tumor-infiltrating lymphocytes. 5-color immunofluorescence staining was performed to further investigate structural components of TLS in comparison to lymphoid follicles in SLOs. Microscope-based laser microdissection and Nanostring-base RNA expression analysis were used to compare gene expression in PDAC, TLS, SLOs and normal pancreatic tissue.ResultsTLS were frequently detected in PDAC and were mainly localized along the invasive tumor margin. In less than 10% of the cases TLS were infiltrating the tumors. Interestingly, 20% of the patients had no TLS. Results of TLS will be correlated with clinical parameters, Immunoscore and immune escape mechanisms. 5-color Immunofluorescence staining revealed similar organization and function of TLS and SLO. Finally, gene expression analyzed by Nanostring revealed largely overlapping expression patterns in TLS and SLO.ConclusionsThe results clearly demonstrate close similarities between SLO and TLS in terms of composition, distribution and gene expression Patterns.Disclosure InformationM. Thelen: None. M.A. García-Márquez: None. T. Nestler: None. S. Wagener-Ryczek: None. J. Lehmann: None. E. Staib: None. F. Popp: None. F. Gebauer: None. P. Lohneis: None. M. Odenthal: None. S. Merkelbach-Bruse: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlößer: None.

scholarly journals Tertiary lymphoid structures related B-cell IgE isotype switching and secondary lymphoid organs linked IgE production in mouse allergy model

2020 ◽  
Author(s):  
Dmitrii Borisovich Chudakov ◽  
Dmitrii Yur'yevich Ryasantsev ◽  
Daria Sergeevna Tsaregorotseva ◽  
Olga Dmitrievna Kotsareva ◽  
Gulnar Vaisovna Fattakhova
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Genotoxic Stress ◽  
Specific Ige ◽  
Lymphoid Organs ◽  
Antibody Isotype ◽  
Isotype Switching ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Secondary Lymphoid Organs

Abstract Background: Numerous data obtained by different research laboratories around the world indicate that specific IgE production is triggered independently of specific IgG or IgA production and so did not linked to fully matured germinal centers of secondary lymphoid organs. The aim of this study is to clarify whether specific IgE production is triggered by low antigen doses administrated in tertiary lymphoid structure enriched tissues.Methods: OVA in different doses (100 ng or 10 µg) was administrated three times a week for 4–5 weeks intraperitoneally and subcutaneously to female BALB/c mice in the withers region enriched in fat-associated lymphoid clusters and in foot pad region not containing them.Results: OVA-specific IgE was predominantly induced by low but not by high antigen doses and only after immunization in withers. IgE isotype switching was triggered exclusively in withers adipose tissue but not in regional lymph nodes though mature IgE expressing cells were observed both in tissue and lymph nodes. Anti-proliferative genotoxic stress inducing drugs shifted the balance from IgG1 towards IgE production.Conclusion. Tertiary lymphoid structures possess unique environment where B-cell antibody isotype switching to IgE predominantly occurs. These phenomena are explained by hampered proliferation of B-cells in these structures.

MAIDS resistance-associated gene expression patterns in secondary lymphoid organs

2008 ◽  
Vol 60 (9) ◽  
pp. 485-494
Author(s):  
Suprawee Tepsuporn ◽  
Jedediah N. Horwitt ◽  
George W. Cobb ◽  
Sharon A. Stranford
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Lymphoid Organs ◽  
Gene Expression Patterns ◽  
Secondary Lymphoid Organs

scholarly journals Integrative Transcriptomics Reveals Activation of Innate Immune Responses and Inhibition of Inflammation During Oral Immunotherapy for Egg Allergy in Children

2021 ◽  
Vol 12 ◽  
Author(s):  
Piia Karisola ◽  
Kati Palosuo ◽  
Victoria Hinkkanen ◽  
Lukas Wisgrill ◽  
Terhi Savinko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Oral Immunotherapy ◽  
Innate Immune ◽  
Egg Allergy ◽  
Innate Immune Responses ◽  
Open Label

We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1–4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.

Abstract 3853: The anti-tumor immune responses by active and quiescent tertiary lymphoid structures to breast cancer

2020 ◽  
Author(s):  
Pushpamali De Silva ◽  
Soizic Garaud ◽  
Cinzia Solinas ◽  
Grégory Noël ◽  
Mireille Langouo Fontsa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

scholarly journals Delayed but effective induction of mucosal memory immune responses against genital HSV-2 in the absence of secondary lymphoid organs

2012 ◽  
Vol 6 (1) ◽  
pp. 56-68 ◽  
Author(s):  
K L Roth ◽  
S Bhavanam ◽  
H Jiang ◽  
A Gillgrass ◽  
K Ho ◽  
...  
Keyword(s):  
Immune Responses ◽  
Lymphoid Organs ◽  
Secondary Lymphoid Organs

scholarly journals Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ–resident dendritic cells

2013 ◽  
Vol 210 (5) ◽  
pp. 1035-1047 ◽  
Author(s):  
Elodie Segura ◽  
Mélanie Durand ◽  
Sebastian Amigorena
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Lymphoid Organ ◽  
Lymphoid Organs ◽  
Endocytic Pathway ◽  
Soluble Antigen ◽  
Cross Presentation ◽  
Antigen Presenting ◽  
Secondary Lymphoid Organs

Dendritic cells (DCs) represent a heterogeneous population of antigen-presenting cells that initiate and orient immune responses in secondary lymphoid organs. In mice, lymphoid organ–resident CD8+ DCs are specialized at cross-presentation and have developed specific adaptations of their endocytic pathway (high pH, low degradation, and high export to the cytosol). In humans, blood BDCA3+ DCs were recently shown to be the homologues of mouse CD8+ DCs. They were also proposed to cross-present antigens more efficiently than other blood DC subsets after in vitro activation, suggesting that in humans cross-presentation is restricted to certain DC subsets. The DCs that cross-present antigen physiologically, however, are the ones present in lymphoid organs. Here, we show that freshly isolated tonsil-resident BDCA1+ DCs, BDCA3+ DCs, and pDCs all cross-present soluble antigen efficiently, as compared to macrophages, in the absence of activation. In addition, BDCA1+ and BDCA3+ DCs display similar phagosomal pH and similar production of reactive oxygen species in their phagosomes. All three DC subsets, in contrast to macrophages, also efficiently export internalized proteins to the cytosol. We conclude that all freshly isolated lymphoid organ–resident human DCs, but not macrophages, display high intrinsic cross-presentation capacity.

scholarly journals Nerve fibers in the Tumor Microenvironment are co-localized with Tertiary Lymphoid Structures

2020 ◽  
Author(s):  
Lara R. Heij ◽  
Xiuxiang Tan ◽  
Jakob N. Kather ◽  
Jan M. Niehues ◽  
Shivan Sivakumar ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Nerve Fibers ◽  
Ductal Adenocarcinoma ◽  
Fiber Density ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Nerve Fiber Density ◽  
Small Nerve

ABSTRACTBackgroundB cells and tertiary lymphoid structures (TLS) are reported to be important in the improvement of survival of cancer patients. These secondary lymphoid organs have been associated with the generation of an anti-tumor response. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types and the stromal architecture shapes the intratumoral heterogeneity. The stroma of PDAC is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells, endothelial cells and the cancer cells. Besides immune cells and fibroblasts, there is some limited data about the influence of nerve fibers on cancer progression.Patients and methodsNerve Fiber Density (NFD) was analysed in our cohort of 188 patients with Pancreatic Ductal Adenocarcinoma who underwent pancreatic surgery. We used immunohistochemistry and multiplex imaging to phenotype the immune cell infiltrate. The cell detection classifier measured distance from immune cell to cancer gland and with a heat map we could count TLS. By using Machine learning we were able to define the spatial distribution and counting Tertiary Lymphoid Structures.ResultsHigh NFD is significantly associated with prolonged overall survival (HR 1.676 (95%CI 1.126,2.495) for low vs. high NFD, p-value 0.0109). The immune cells surrounding the nerve fibers were phenotyped in B cells, T cells and dendritic follicular cells, matching a TLS. Here we show that small nerve fibers are located at the TLS in Pancreatic Cancer and a high Nerve Fiber Density combined with more than 5 TLS is associated with a better survival (HR 0.388 (95%CI 0.218, 0.689).ConclusionThe co-localization of small nerve fibers with TLS is a new finding which has not been described before. However the precise roles of these TLS and nerve fibers remains unknown. These findings unravel future pathways and has the potential to reach new directions into already existing targeted therapy.

scholarly journals Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging

2021 ◽  
Author(s):  
Sandip Ashok Sonar ◽  
Jennifer L Uhrlaub ◽  
Christopher P Coplen ◽  
Gregory D Sempowski ◽  
Jarrod A Dudakov ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
De Novo ◽  
Functional Decline ◽  
Lymphoid Organs ◽  
Reticular Cell ◽  
Effector Cells ◽  
Age Related ◽  
Secondary Lymphoid Organs

Secondary lymphoid organs (SLO; including the spleen and lymph nodes) are critical both for the maintenance of naive T (TN) lymphocytes and for the initiation and coordination of immune responses. How they age, including the exact timing, extent, physiological relevance, and the nature of age-related changes, remains incompletely understood. We used time-stamping to indelibly mark cohorts of newly generated naive T cells (a.k.a. recent thymic emigrants - RTE) in mice, and followed their presence, phenotype and retention in SLO. We found that SLO involute asynchronously. Skin-draining lymph nodes (LN) atrophied early (6-9 months) in life and deeper tissue-draining LN and the spleen late (18-20 months), as measured by the loss of both TN numbers and the fibroblastic reticular cell (FRC) network. Time-stamped RTE cohorts of all ages entered SLO and successfully completed post-thymic differentiation. However, in older mice, these cells were poorly retained, and those found in SLO exhibited an emigration phenotype (CCR7loS1P1hi). Transfers of adult RTE into recipients of different ages formally demonstrated that the defect segregates with the age of the SLO microenvironment and not with the age of T cells. Finally, upon intradermal immunization, RTE generated in mice as early as 6-7 months of age barely participated in de novo immune responses and failed to produce well-armed effector cells. These results highlight changes in structure and function of superficial secondary lymphoid organs in laboratory mice that are earlier than expected and are consistent with the long-appreciated and pronounced reduction of cutaneous immunity with aging.

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