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Article ; Online: B Cells from Aged Mice Do Not Have Intrinsic Defects in Affinity Maturation in Response to Immunization.

Lee, Jia Le / Innocentin, Silvia / Silva-Cayetano, Alyssa / Guillaume, Stephane M / Linterman, Michelle A

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 211, Issue 10, Page(s) 1506–1515

Abstract: Affinity maturation, the progressive increase in serum Ab affinity after vaccination, is an essential process that contributes to an effective humoral response against vaccines and infections. Germinal centers are key for affinity maturation, because ... ...

Abstract	Affinity maturation, the progressive increase in serum Ab affinity after vaccination, is an essential process that contributes to an effective humoral response against vaccines and infections. Germinal centers are key for affinity maturation, because they are where B cells undergo somatic hypermutation of their Ig genes in the dark zone before going through positive selection in the light zone via interactions with T follicular helper cells and follicular dendritic cells. In aged mice, affinity maturation has been shown to be impaired after immunization, but whether B cell-intrinsic factors contribute to this defect remains unclear. In this study, we show that B cells from aged BCR transgenic mice are able to become germinal center B cells, which are capable of receiving positive selection signals to a similar extent as B cells from young adult mice. Consistent with this, aging also does not impact the ability of B cells to undergo somatic hypermutation and acquire affinity-enhancing mutations. By contrast, transfer of B cells from young adult BCR mice into aged recipients resulted in the impaired acquisition of affinity-enhancing mutations, demonstrating that the aged microenvironment causes altered affinity maturation.
MeSH term(s)	Mice ; Animals ; B-Lymphocytes ; Germinal Center ; Immunization ; Vaccination ; Mice, Transgenic
Language	English
Publishing date	2023-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300318
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Article ; Online: Stromal cell control of conventional and ectopic germinal centre reactions.

Silva-Cayetano, Alyssa / Linterman, Michelle A

Current opinion in immunology

2020 Volume 64, Page(s) 26–33

Abstract: The germinal centre (GC) is a specialized cellular structure that forms in response to antigenic stimulation. It generates long-term humoral immunity through the production of memory B cells and long-lived antibody-secreting plasma cells. Conventional ... ...

Abstract	The germinal centre (GC) is a specialized cellular structure that forms in response to antigenic stimulation. It generates long-term humoral immunity through the production of memory B cells and long-lived antibody-secreting plasma cells. Conventional GCs form within secondary lymphoid organs, where networks of specialised stromal cells that form during embryogenesis act as the stage upon which the various GC immune cell players are brought together, nurtured and co-ordinated to generate a productive response. In non-lymphoid organs, ectopic GCs can form in response to persistent antigenic and inflammatory stimuli. Unlike secondary lymphoid tissues, non-lymphoid organs do not have a developmentally programmed stromal cell network capable of supporting the germinal centre reaction; therefore, the local tissue stroma must be remodelled by inflammatory stimuli in order to host a GC reaction. These ectopic GCs produce memory B cells and plasma cells that form a critical component of the humoral immune response.
MeSH term(s)	Antigens ; Germinal Center ; Humans ; Immunity, Humoral ; Plasma Cells ; Stromal Cells
Chemical Substances	Antigens
Language	English
Publishing date	2020-04-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2020.03.007
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Zs.A 2773: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Targeting TLR4 during vaccination boosts MAdCAM-1

Denton, Alice E / Dooley, James / Cinti, Isabella / Silva-Cayetano, Alyssa / Fra-Bido, Sigrid / Innocentin, Silvia / Hill, Danika L / Carr, Edward J / McKenzie, Andrew N J / Liston, Adrian / Linterman, Michelle A

Science immunology

2022 Volume 7, Issue 71, Page(s) eabk0018

Abstract: The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re) ... ...

Abstract	The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule-1 (MAdCAM-1)-expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1
MeSH term(s)	Aged ; Aging/immunology ; Animals ; Cell Adhesion Molecules ; Germinal Center ; Humans ; Mice ; Stromal Cells ; Toll-Like Receptor 4 ; Vaccination
Chemical Substances	Cell Adhesion Molecules ; TLR4 protein, human ; Tlr4 protein, mouse ; Toll-Like Receptor 4
Language	English
Publishing date	2022-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abk0018
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Heterochronic faecal transplantation boosts gut germinal centres in aged mice.

Stebegg, Marisa / Silva-Cayetano, Alyssa / Innocentin, Silvia / Jenkins, Timothy P / Cantacessi, Cinzia / Gilbert, Colin / Linterman, Michelle A

Nature communications

2019 Volume 10, Issue 1, Page(s) 2443

Abstract: Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome ... ...

Abstract	Ageing is a complex multifactorial process associated with a plethora of disorders, which contribute significantly to morbidity worldwide. One of the organs significantly affected by age is the gut. Age-dependent changes of the gut-associated microbiome have been linked to increased frailty and systemic inflammation. This change in microbial composition with age occurs in parallel with a decline in function of the gut immune system; however, it is not clear whether there is a causal link between the two. Here we report that the defective germinal centre reaction in Peyer's patches of aged mice can be rescued by faecal transfers from younger adults into aged mice and by immunisations with cholera toxin, without affecting germinal centre reactions in peripheral lymph nodes. This demonstrates that the poor germinal centre reaction in aged animals is not irreversible, and that it is possible to improve this response in older individuals by providing appropriate stimuli.
MeSH term(s)	Aging/immunology ; Animals ; Cholera Toxin/immunology ; Dysbiosis/immunology ; Fecal Microbiota Transplantation ; Female ; Gastrointestinal Microbiome/immunology ; Germinal Center/immunology ; Immunization ; Immunoglobulin A/immunology ; Mice ; Nitrophenols/immunology ; Peyer's Patches/immunology ; Phenylacetates/immunology
Chemical Substances	Immunoglobulin A ; Nitrophenols ; Phenylacetates ; 4-hydroxy-5-nitrophenyl acetic acid (10463-20-4) ; Cholera Toxin (9012-63-9)
Language	English
Publishing date	2019-06-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10430-7
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Article ; Online: Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging.

Silva-Cayetano, Alyssa / Fra-Bido, Sigrid / Robert, Philippe A / Innocentin, Silvia / Burton, Alice R / Watson, Emily M / Lee, Jia Le / Webb, Louise M C / Foster, William S / McKenzie, Ross C J / Bignon, Alexandre / Vanderleyden, Ine / Alterauge, Dominik / Lemos, Julia P / Carr, Edward J / Hill, Danika L / Cinti, Isabella / Balabanian, Karl / Baumjohann, Dirk /

Espeli, Marion / Meyer-Hermann, Michael / Denton, Alice E / Linterman, Michelle A

Nature immunology

2023 Volume 24, Issue 7, Page(s) 1124–1137

Abstract: The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular ... ...

Abstract	The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (T
MeSH term(s)	Animals ; Mice ; T-Lymphocytes, Helper-Inducer ; B-Lymphocytes ; T Follicular Helper Cells ; Germinal Center ; Aging ; Vaccines
Chemical Substances	Vaccines
Language	English
Publishing date	2023-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01519-9
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Article ; Online: Regulation of the Germinal Center Response.

Stebegg, Marisa / Kumar, Saumya D / Silva-Cayetano, Alyssa / Fonseca, Valter R / Linterman, Michelle A / Graca, Luis

Frontiers in immunology

2018 Volume 9, Page(s) 2469

Abstract: The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo ... ...

Abstract	The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity. However, this mutation process can also be dangerous, as it can create autoreactive clones that can cause autoimmunity. Because of this, regulation of GC reactions is critical to ensure high affinity antibody production and to enforce self-tolerance by avoiding emergence of autoreactive B cell clones. A productive GC response requires the collaboration of multiple cell types. The stromal cell network orchestrates GC cell dynamics by controlling antigen delivery and cell trafficking. T follicular helper (Tfh) cells provide specialized help to GC B cells through cognate T-B cell interactions while Foxp3
MeSH term(s)	Animals ; Autoimmunity ; B-Lymphocytes/immunology ; Cell Differentiation ; Cellular Microenvironment ; Clonal Selection, Antigen-Mediated ; Germinal Center/immunology ; Humans ; Immunity, Humoral ; Lymphocyte Subsets/immunology ; Self Tolerance ; T-Lymphocytes, Helper-Inducer/immunology
Language	English
Publishing date	2018-10-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.02469
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Article ; Online: Heterochronic faecal transplantation boosts gut germinal centres in aged mice

Marisa Stebegg / Alyssa Silva-Cayetano / Silvia Innocentin / Timothy P. Jenkins / Cinzia Cantacessi / Colin Gilbert / Michelle A. Linterman

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 13

Abstract: Microbiota impacts all major aspects of physiology, but little is known about its effects on age-related changes in immune responses. Here the authors show that gut microbiota transfer between adult and old mice increases local but not systemic germinal ... ...

Abstract	Microbiota impacts all major aspects of physiology, but little is known about its effects on age-related changes in immune responses. Here the authors show that gut microbiota transfer between adult and old mice increases local but not systemic germinal centre responses regardless of age directionality.
Keywords	Science ; Q
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Heterochronic faecal transplantation boosts gut germinal centres in aged mice

Marisa Stebegg / Alyssa Silva-Cayetano / Silvia Innocentin / Timothy P. Jenkins / Cinzia Cantacessi / Colin Gilbert / Michelle A. Linterman

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 13

Abstract	Microbiota impacts all major aspects of physiology, but little is known about its effects on age-related changes in immune responses. Here the authors show that gut microbiota transfer between adult and old mice increases local but not systemic germinal centre responses regardless of age directionality.
Keywords	Science ; Q
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination.

Stebegg, Marisa / Bignon, Alexandre / Hill, Danika Lea / Silva-Cayetano, Alyssa / Krueger, Christel / Vanderleyden, Ine / Innocentin, Silvia / Boon, Louis / Wang, Jiong / Zand, Martin S / Dooley, James / Clark, Jonathan / Liston, Adrian / Carr, Edward / Linterman, Michelle A

eLife

2020 Volume 9

Abstract: Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the ...

Abstract	Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.
MeSH term(s)	Adolescent ; Adoptive Transfer ; Adult ; Aged ; Aging ; Animals ; B-Lymphocytes ; Bone Marrow Cells ; CD11 Antigens/genetics ; CD11 Antigens/metabolism ; Chimera ; Female ; Germinal Center/physiology ; Humans ; Immunity, Humoral ; Immunologic Memory ; Influenza Vaccines/administration & dosage ; Influenza Vaccines/immunology ; Influenza, Human/prevention & control ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Orthomyxoviridae Infections/prevention & control ; Orthomyxoviridae Infections/veterinary ; Receptor, Interferon alpha-beta/genetics ; Receptor, Interferon alpha-beta/metabolism ; T Follicular Helper Cells/physiology ; T-Lymphocytes, Helper-Inducer/physiology ; Vaccination ; Young Adult
Chemical Substances	CD11 Antigens ; Ifnar1 protein, mouse ; Influenza Vaccines ; Itgax protein, mouse ; Receptor, Interferon alpha-beta (156986-95-7)
Language	English
Publishing date	2020-03-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.52473
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Article ; Online: A booster dose enhances immunogenicity of the COVID-19 vaccine candidate ChAdOx1 nCoV-19 in aged mice.

Silva-Cayetano, Alyssa / Foster, William S / Innocentin, Silvia / Belij-Rammerstorfer, Sandra / Spencer, Alexandra J / Burton, Oliver T / Fra-Bidó, Sigrid / Le Lee, Jia / Thakur, Nazia / Conceicao, Carina / Wright, Daniel / Barrett, Jordan / Evans-Bailey, Nicola / Noble, Carly / Bailey, Dalan / Liston, Adrian / Gilbert, Sarah C / Lambe, Teresa / Linterman, Michelle A

Med (New York, N.Y.)

2020 Volume 2, Issue 3, Page(s) 243–262.e8

Abstract: Background: The spread of SARS-CoV-2 has caused a worldwide pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection and may enable the ... ...

Abstract	Background: The spread of SARS-CoV-2 has caused a worldwide pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection and may enable the relaxation of social-distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection; therefore, it is desirable that any new vaccine candidates elicit a robust immune response in older adults. Methods: Here, we use in-depth immunophenotyping to characterize the innate and adaptive immune response induced upon intramuscular administration of the adenoviral vectored ChAdOx1 nCoV-19 (AZD-1222) COVID-19 vaccine candidate in mice. Findings: A single vaccination generates spike-specific Th1 cells, Th1-like Foxp3 Conclusions: This study shows that ChAdOx1 nCoV-19 induces both cellular and humoral immunity in adult and aged mice and suggests a prime-boost strategy is a rational approach to enhance immunogenicity in older persons. Funding: This study was supported by BBSRC, Lister institute of Preventative Medicine, EPSRC VaxHub, and Innovate UK.
MeSH term(s)	Aged ; Aged, 80 and over ; Animals ; CD8-Positive T-Lymphocytes ; COVID-19/prevention & control ; COVID-19 Vaccines ; ChAdOx1 nCoV-19 ; Humans ; Mice ; SARS-CoV-2
Chemical Substances	COVID-19 Vaccines ; ChAdOx1 nCoV-19 (B5S3K2V0G8)
Language	English
Publishing date	2020-12-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-6340
ISSN (online)	2666-6340
DOI	10.1016/j.medj.2020.12.006
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