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Article ; Online: Regulation, Maintenance, and Remodeling of High Endothelial Venules in Homeostasis, Inflammation, and Cancer.

Ruddle, Nancy H

2023 Volume 36

Abstract: High endothelial venules (HEVs), high walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (aka tertiary lymphoid ... ...

Abstract	High endothelial venules (HEVs), high walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (aka tertiary lymphoid organs). HEV heterogeneity exists between various lymphoid organs in their expression of peripheral node addressin (PNAd) and mucosal vascular addressin adhesion molecule 1(MAdCAM-1). Transcriptomic analyses reveal extensive heterogeneity, plasticity, and regulation of HEV gene expression in ontogeny, acute inflammation, and chronic inflammation within and between lymphoid organs. Rules regulating HEV development are flexible in inflammation. HEVs in tumor tertiary lymphoid structures are diagnostic of favorable clinical outcome and response to Immunotherapy, including immune check point blockade. Immunotherapy induces HEVs and provides an entrance for naïve, central memory, and effector cells and a niche for stem like precursor cells. Understanding HEV regulation will permit their exploitation as routes for drug delivery to autoimmune lesions, rejecting organs, and tumors.
Language	English
Publishing date	2023-08-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2918626-2
ISSN	2468-8673 ; 2468-8681
ISSN (online)	2468-8673
ISSN	2468-8681
DOI	10.1016/j.cophys.2023.100705
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Article ; Online: Posttransplant Tertiary Lymphoid Organs.

Ruddle, Nancy H

Transplantation

2023 Volume 108, Issue 5, Page(s) 1090–1099

Abstract: Tertiary lymphoid organs (TLOs), also known as tertiary or ectopic lymphoid structures or tissues, are accumulations of lymphoid cells in sites other than canonical lymphoid organs, that arise through lymphoid neogenesis during chronic inflammation in ... ...

Abstract	Tertiary lymphoid organs (TLOs), also known as tertiary or ectopic lymphoid structures or tissues, are accumulations of lymphoid cells in sites other than canonical lymphoid organs, that arise through lymphoid neogenesis during chronic inflammation in autoimmunity, microbial infection, cancer, aging, and transplantation, the focus of this review. Lymph nodes and TLOs are compared regarding their cellular composition, organization, vascular components, and migratory signal regulation. These characteristics of posttransplant TLOs (PT-TLOs) are described with individual examples in a wide range of organs including heart, kidney, trachea, lung, artery, skin, leg, hand, and face, in many species including human, mouse, rat, and monkey. The requirements for induction and maintenance of TLOs include sustained exposure to autoantigens, alloantigens, tumor antigens, ischemic reperfusion, nephrotoxic agents, and aging. Several staging schemes have been put forth regarding their function in organ rejection. PT-TLOs most often are associated with organ rejection, but in some cases contribute to tolerance. The role of PT-TLOs in cancer is considered in the case of immunosuppression. Furthermore, TLOs can be associated with development of lymphomas. Challenges for PT-TLO research are considered regarding staging, imaging, and opportunities for their therapeutic manipulation to inhibit rejection and encourage tolerance.
MeSH term(s)	Humans ; Animals ; Tertiary Lymphoid Structures/immunology ; Tertiary Lymphoid Structures/pathology ; Graft Rejection/immunology ; Graft Rejection/prevention & control ; Organ Transplantation/adverse effects
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	208424-7
ISSN	1534-6080 ; 0041-1337
ISSN (online)	1534-6080
ISSN	0041-1337
DOI	10.1097/TP.0000000000004812
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Article: Basics of Inducible Lymphoid Organs.

Ruddle, Nancy H

Current topics in microbiology and immunology

2020 Volume 426, Page(s) 1–19

Abstract: Tertiary lymphoid organs (TLOs), also known as inducible lymphoid organs, tertiary lymphoid structures, tertiary lymphoid tissues, or ectopic lymphoid organs are accumulations of cells in chronic inflammation that have been observed in most tissues in ... ...

Abstract	Tertiary lymphoid organs (TLOs), also known as inducible lymphoid organs, tertiary lymphoid structures, tertiary lymphoid tissues, or ectopic lymphoid organs are accumulations of cells in chronic inflammation that have been observed in most tissues in autoimmunity, infection, and cancer in mouse and man. They share many properties with secondary lymphoid organs (SLOs), particularly lymph nodes, with regard to cellular composition, function, and regulation. TLOs include T and B cells, dendritic cells, follicular dendritic cells, and many other stromal cells, and high endothelial venules (HEVs) and lymphatic vessels. They serve as sites of antigen presentation and tolerance induction; they are harmful in autoimmunity and can be both harmful and beneficial in cancer. SLO induction in ontogeny is mediated by interactions of several cell types, including CD4+ CD3- lymphoid tissue inducer (LTi) RORγt+ cells that express LTαβ and interact with mesenchymal lymphoid tissue organizer (LTo) FAP+ cells in the presence of lymphatic and blood vessels. A variety of inducer cells initiate TLOs, including bona fide LTi cells, T cells, B cells, and NK cells. The mesenchymal organizer cells are less well characterized but can include FAP+ cells. Current challenges include identification of methods to inhibit TLOs in autoimmunity without affecting SLOs, and enhancement of TLOs for defense against tumors.
MeSH term(s)	Animals ; Humans ; Inflammation/immunology ; Lymph Nodes ; Lymphoid Tissue/immunology
Language	English
Publishing date	2020-06-17
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/82_2020_218
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Article: High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation.

Ruddle, Nancy H

Frontiers in immunology

2016 Volume 7, Page(s) 491

Abstract: High endothelial venules (HEVs) and lymphatic vessels (LVs) are essential for the function of the immune system, by providing communication between the body and lymph nodes (LNs), specialized sites of antigen presentation and recognition. HEVs bring in ... ...

Abstract	High endothelial venules (HEVs) and lymphatic vessels (LVs) are essential for the function of the immune system, by providing communication between the body and lymph nodes (LNs), specialized sites of antigen presentation and recognition. HEVs bring in naïve and central memory cells and LVs transport antigen, antigen-presenting cells, and lymphocytes in and out of LNs. Tertiary lymphoid organs (TLOs) are accumulations of lymphoid and stromal cells that arise and organize at ectopic sites in response to chronic inflammation in autoimmunity, microbial infection, graft rejection, and cancer. TLOs are distinguished from primary lymphoid organs - the thymus and bone marrow, and secondary lymphoid organs (SLOs) - the LNs, spleen, and Peyer's patches, in that they arise in response to inflammatory signals, rather than in ontogeny. TLOs usually do not have a capsule but are rather contained within the confines of another organ. Their structure, cellular composition, chemokine expression, and vascular and stromal support resemble SLOs and are the defining aspects of TLOs. T and B cells, antigen-presenting cells, fibroblast reticular cells, and other stromal cells and vascular elements including HEVs and LVs are all typical components of TLOs. A key question is whether the HEVs and LVs play comparable roles and are regulated similarly to those in LNs. Data are presented that support this concept, especially with regard to TLO HEVs. Emerging data suggest that the functions and regulation of TLO LVs are also similar to those in LNs. These observations support the concept that TLOs are not merely cellular accumulations but are functional entities that provide sites to generate effector cells, and that their HEVs and LVs are crucial elements in those activities.
Language	English
Publishing date	2016
Publishing country	Switzerland
Document type	Review ; Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2016.00491
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Article ; Online: Lymphotoxin and TNF: how it all began-a tribute to the travelers.

Ruddle, Nancy H

Cytokine & growth factor reviews

2014 Volume 25, Issue 2, Page(s) 83–89

Abstract: ... to two pioneers in the field who have recently passed away: Byron H. Waksman and Lloyd Old. ...

Abstract	The journey from the discoveries of lymphotoxin (LT) and tumor necrosis factor (TNF) to the present day age of cytokine inhibitors as therapeutics has been an exciting one with many participants and highs and lows; the saga is compared to that in "The Wizard of Oz". This communication summarizes the contributions of key players in the discovery of the cytokines and their receptors, the changes in nomenclature, and the discovery of the LT family's crucial role in secondary and tertiary lymphoid organs. The remarkable advances in therapeutics are detailed as are remaining problems. Finally, special tribute is paid to two pioneers in the field who have recently passed away: Byron H. Waksman and Lloyd Old.
MeSH term(s)	Animals ; Humans ; Lymphoid Tissue/immunology ; Lymphotoxin beta Receptor/metabolism ; Lymphotoxin-alpha/antagonists & inhibitors ; Lymphotoxin-alpha/genetics ; Mice ; Rats ; Receptors, Tumor Necrosis Factor/metabolism ; Signal Transduction ; Tumor Necrosis Factor Inhibitors ; Tumor Necrosis Factors/genetics
Chemical Substances	Lymphotoxin beta Receptor ; Lymphotoxin-alpha ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor Inhibitors ; Tumor Necrosis Factors
Language	English
Publishing date	2014-02-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1330534-7
ISSN	1879-0305 ; 1359-6101
ISSN (online)	1879-0305
ISSN	1359-6101
DOI	10.1016/j.cytogfr.2014.02.001
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Article ; Online: Lymphatic vessels and tertiary lymphoid organs.

Ruddle, Nancy H

The Journal of clinical investigation

2014 Volume 124, Issue 3, Page(s) 953–959

Abstract: 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 ... ...

Abstract	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 sphingosine-1-phosphate (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 insight into therapies for conditions as diverse as lymphedema, autoimmunity, and cancer.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Humans ; Inflammation/pathology ; Lymph Nodes/immunology ; Lymphatic Vessels/immunology ; Lymphatic Vessels/pathology ; Lymphatic Vessels/physiopathology ; Lymphedema/immunology ; Neoplasms/pathology
Language	English
Publishing date	2014-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI71611
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Article ; Online: Lymphotoxin targeted to salivary and lacrimal glands induces tertiary lymphoid organs and cervical lymphadenopathy and reduces tear production.

Truman, Lucy A / Bentley, Kevin L / Ruddle, Nancy H

European journal of immunology

2020 Volume 50, Issue 3, Page(s) 418–425

Abstract: To investigate the role of lymphotoxin (LT) in Sjögren's syndrome (SS) and in mucosal associated lymphoid tissue (MALT)-lymphoma, we made transgenic mice (Amy1-LTαβ) that targeted LTα and LTβ to the salivary and lacrimal glands. Amy1-LTαβ mice developed ... ...

Abstract	To investigate the role of lymphotoxin (LT) in Sjögren's syndrome (SS) and in mucosal associated lymphoid tissue (MALT)-lymphoma, we made transgenic mice (Amy1-LTαβ) that targeted LTα and LTβ to the salivary and lacrimal glands. Amy1-LTαβ mice developed atrophic salivary and lacrimal glands that contained tertiary lymphoid organs (TLOs) and had reduced tear production. Amy1-LTαβ mice developed cervical lymphadenopathy but not MALT-lymphoma. TLO formation in the salivary and lacrimal glands of Amy1-LTαβ was not sufficient to induce autoimmunity as measured by autoantibody titres.
MeSH term(s)	Animals ; Lacrimal Apparatus/pathology ; Lymphadenopathy/genetics ; Lymphadenopathy/pathology ; Lymphoma, B-Cell, Marginal Zone/genetics ; Lymphoma, B-Cell, Marginal Zone/immunology ; Lymphoma, B-Cell, Marginal Zone/pathology ; Lymphotoxin-alpha/genetics ; Lymphotoxin-alpha/metabolism ; Mice ; Mice, Transgenic ; Salivary Glands/pathology ; Sjogren's Syndrome/genetics ; Sjogren's Syndrome/immunology ; Sjogren's Syndrome/pathology ; Tears/metabolism ; Tertiary Lymphoid Structures/genetics ; Tertiary Lymphoid Structures/pathology
Chemical Substances	Lymphotoxin-alpha
Language	English
Publishing date	2020-02-10
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201948300
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Article: Workshop summary: roles of the TNF family in normal development and cancer.

Ruddle, Nancy H

Advances in experimental medicine and biology

2011 Volume 691, Page(s) 3–4

MeSH term(s)	Animals ; Biomarkers, Tumor/metabolism ; Blood Vessels/metabolism ; Disease Progression ; Embryonic Development ; Humans ; Inflammation/metabolism ; Mice ; Multigene Family ; Neoplasms/metabolism ; Neoplasms/pathology ; Phylogeny ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Biomarkers, Tumor ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2011
Publishing country	United States
Document type	Introductory Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4419-6612-4_1
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Article ; Online: The durability of immunity against reinfection by SARS-CoV-2: a comparative evolutionary study.

Townsend, Jeffrey P / Hassler, Hayley B / Wang, Zheng / Miura, Sayaka / Singh, Jaiveer / Kumar, Sudhir / Ruddle, Nancy H / Galvani, Alison P / Dornburg, Alex

The Lancet. Microbe

2021 Volume 2, Issue 12, Page(s) e666–e675

Abstract: Background: Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this ...

Abstract	Background: Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this study is to use data on the durability of immunity among evolutionarily close coronavirus relatives of SARS-CoV-2 to estimate times to reinfection by a comparative evolutionary analysis of related viruses SARS-CoV, MERS-CoV, human coronavirus (HCoV)-229E, HCoV-OC43, and HCoV-NL63. Methods: We conducted phylogenetic analyses of the Findings: We obtained antibody optical density data for six human-infecting coronaviruses, extending from 128 days to 28 years after infection between 1984 and 2020. These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5·1 years after peak antibody response, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans (5-95% quantiles 15 months to 10 years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12 years for HCoV-229E). For SARS-CoV, the 5-95% quantiles were 4 months to 6 years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset. Interpretation: The timeframe for reinfection is fundamental to numerous aspects of public health decision making. As the COVID-19 pandemic continues, reinfection is likely to become increasingly common. Maintaining public health measures that curb transmission-including among individuals who were previously infected with SARS-CoV-2-coupled with persistent efforts to accelerate vaccination worldwide is critical to the prevention of COVID-19 morbidity and mortality. Funding: US National Science Foundation.
MeSH term(s)	Antibodies, Viral/genetics ; COVID-19/epidemiology ; Coronavirus 229E, Human ; Coronavirus NL63, Human ; Coronavirus OC43, Human ; Cross Reactions ; Humans ; Middle East Respiratory Syndrome Coronavirus ; Pandemics ; Phylogeny ; Reinfection/epidemiology ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-10-01
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2666-5247
ISSN (online)	2666-5247
DOI	10.1016/S2666-5247(21)00219-6
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Article ; Online: Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: Parallels with lymph node stroma.

Stranford, Sharon / Ruddle, Nancy H

Frontiers in immunology

2012 Volume 3, Page(s) 350

Abstract: In this communication, the contribution of stromal, or non-hematopoietic, cells to the structure and function of lymph nodes (LNs), as canonical secondary lymphoid organs (SLOs), is compared to that of tertiary lymphoid tissue or organs (TLOs), also ... ...

Abstract	In this communication, the contribution of stromal, or non-hematopoietic, cells to the structure and function of lymph nodes (LNs), as canonical secondary lymphoid organs (SLOs), is compared to that of tertiary lymphoid tissue or organs (TLOs), also known as ectopic lymphoid tissues. TLOs can arise in non-lymphoid organs during chronic inflammation, as a result of autoimmune responses, graft rejection, atherosclerosis, microbial infection, and cancer. The stromal components found in SLOs including follicular dendritic cells, fibroblast reticular cells, lymphatic vessels, and high endothelial venules and possibly conduits are present in TLOs; their molecular regulation mimics that of LNs. Advances in visualization techniques and the development of transgenic mice that permit in vivo real time imaging of these structures will facilitate elucidation of their precise functions in the context of chronic inflammation. A clearer understanding of the inflammatory signals that drive non-lymphoid stromal cells to reorganize into TLO should allow the design of therapeutic interventions to impede the progression of autoimmune activity, or alternatively, to enhance anti-tumor responses.
Language	English
Publishing date	2012-11-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2012.00350
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