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1.
Proc Natl Acad Sci U S A ; 119(29): e2205378119, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858347

RESUMO

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell-derived interleukin (IL)-21 upregulated B-cell-homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti-PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.


Assuntos
Envelhecimento , Linfócitos T CD4-Positivos , Quimiocina CXCL13 , Inibidores de Checkpoint Imunológico , Doenças do Sistema Imunitário , Imunoterapia , Neoplasias , Receptor de Morte Celular Programada 1 , Envelhecimento/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL13/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Doenças do Sistema Imunitário/etiologia , Imunoterapia/efeitos adversos , Ativação Linfocitária , Camundongos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores
2.
Proc Natl Acad Sci U S A ; 119(25): e2202780119, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35696572

RESUMO

Exposure to stress is a risk factor for poor health and accelerated aging. Immune aging, including declines in naïve and increases in terminally differentiated T cells, plays a role in immune health and tissue specific aging, and may contribute to elevated risk for poor health among those who experience high psychosocial stress. Past data have been limited in estimating the contribution of life stress to the development of accelerated immune aging and investigating mediators such as lifestyle and cytomegalovirus (CMV) infection. This study utilizes a national sample of 5,744 US adults over age 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naïve and terminally differentiated T cell percentages and the ratio of CD4+ to CD8+ cells. Experiencing life trauma and chronic stress was related to a lower percentage of CD4+ naïve cells. Discrimination and chronic stress were each associated with a greater percentage of terminally differentiated CD4+ cells. Stressful life events, high lifetime discrimination, and life trauma were related to a lower percentage of CD8+ naïve cells. Stressful life events, high lifetime discrimination, and chronic stress were associated with a higher percentage of terminally differentiated CD8+ cells. High lifetime discrimination and chronic stress were related to a lower CD4+:CD8+ ratio. Lifestyle factors and CMV seropositivity partially reduced these effects. Results identify psychosocial stress as a contributor to accelerating immune aging by decreasing naïve and increasing terminally differentiated T cells.


Assuntos
Envelhecimento , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por Citomegalovirus , Aposentadoria , Estresse Psicológico , Adulto , Idoso , Envelhecimento/imunologia , Relação CD4-CD8 , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aposentadoria/psicologia , Estresse Psicológico/imunologia
3.
Science ; 376(6594): 694-695, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35549427
4.
Sci Immunol ; 7(71): eabk0018, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35522725

RESUMO

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+ stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1+ stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people.


Assuntos
Envelhecimento , Centro Germinativo , Receptor 4 Toll-Like , Idoso , Envelhecimento/imunologia , Animais , Moléculas de Adesão Celular , Humanos , Camundongos , Células Estromais , Vacinação
5.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35131902

RESUMO

Weather-related disasters are increasing in frequency and severity, leaving survivors to cope with ensuing mental, financial, and physical hardships. This adversity can exacerbate existing morbidities, trigger new ones, and increase the risk of mortality-features that are also characteristic of advanced age-inviting the hypothesis that extreme weather events may accelerate aging. To test this idea, we examined the impact of Hurricane Maria and its aftermath on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. A cross section of macaques was sampled 1 to 4 y before (n = 435) and 1 y after (n = 108) the hurricane. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes, and these effects were correlated with age-associated alterations in gene expression. We further found that individuals exposed to the hurricane had a gene expression profile that was, on average, 1.96 y older than individuals that were not-roughly equivalent to an increase in 7 to 8 y of a human life. Living through an intense hurricane and its aftermath was associated with expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. Together, our findings illuminate potential mechanisms through which the adversity unleashed by extreme weather and potentially other natural disasters might become biologically embedded, accelerate age-related molecular immune phenotypes, and ultimately contribute to earlier onset of disease and death.


Assuntos
Envelhecimento/imunologia , Macaca/imunologia , Sobreviventes/psicologia , Fatores Etários , Animais , Estudos Transversais , Tempestades Ciclônicas , Desastres , Desastres Naturais/mortalidade , Fatores de Risco
6.
J Immunol ; 208(5): 1001-1005, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121642

RESUMO

Advanced age is a main risk factor for severe COVID-19. However, low vaccination efficacy and accelerated waning immunity have been reported in this age group. To elucidate age-related differences in immunogenicity, we analyzed human cellular, serological, and salivary SARS-CoV-2 spike glycoprotein-specific immune responses to the BNT162b2 COVID-19 vaccine in old (69-92 y) and middle-aged (24-57 y) vaccinees compared with natural infection (COVID-19 convalescents, 21-55 y of age). Serological humoral responses to vaccination excee-ded those of convalescents, but salivary anti-spike subunit 1 (S1) IgA and neutralizing capacity were less durable in vaccinees. In old vaccinees, we observed that pre-existing spike-specific CD4+ T cells are associated with efficient induction of anti-S1 IgG and neutralizing capacity in serum but not saliva. Our results suggest pre-existing SARS-CoV-2 cross-reactive CD4+ T cells as a predictor of an efficient COVID-19 vaccine-induced humoral immune response in old individuals.


Assuntos
Envelhecimento/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , SARS-CoV-2/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Casas de Saúde , Saliva/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Adulto Jovem
7.
Immunity ; 55(2): 210-223, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35139351

RESUMO

Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease.


Assuntos
Dietoterapia , Imunidade , Envelhecimento/imunologia , Restrição Calórica , Humanos , Inflamação , Corpos Cetônicos/biossíntese , Corpos Cetônicos/imunologia , Desnutrição/imunologia , Microbiota/imunologia , Fenômenos Fisiológicos da Nutrição/imunologia
8.
Elife ; 112022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35129436

RESUMO

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.


Assuntos
Diversidade de Anticorpos/imunologia , Fundulidae/imunologia , Imunossenescência/imunologia , Imunidade Adaptativa/imunologia , Envelhecimento/imunologia , Animais , Linfócitos B/imunologia , Humanos , Longevidade/imunologia , Microbiota/imunologia , Modelos Animais
9.
Adv Drug Deliv Rev ; 183: 114175, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35202770

RESUMO

Vaccination is the most effective measure to protect against infections. However, with increasing age, there is a progressive decline in the ability of the immune system to both protect against infection and develop protective immunity from vaccination. This age-related decline of the immune system is due to age-related changes in both the innate and adaptive immune systems. With an aging world population and increased risk of pandemics, there is a need to continue to develop strategies to increase vaccine responses in the elderly. Here, the major age-related changes that occur in both the innate and adaptive immune responses that impair the response to vaccination in the elderly will be highlighted. Existing and future strategies to improve vaccine efficacy in the elderly will then be discussed, including adjuvants, delivery methods, and formulation. These strategies provide mechanisms to improve the efficacy of existing vaccines and develop novel vaccines for the elderly.


Assuntos
Envelhecimento/imunologia , Imunidade Adaptativa , Idoso , Animais , Humanos , Imunidade Inata
10.
Nat Commun ; 13(1): 907, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35173150

RESUMO

Population antibody surveillance helps track immune responses to COVID-19 vaccinations at scale, and identify host factors that may affect antibody production. We analyse data from 212,102 vaccinated individuals within the REACT-2 programme in England, which uses self-administered lateral flow antibody tests in sequential cross-sectional community samples; 71,923 (33.9%) received at least one dose of BNT162b2 vaccine and 139,067 (65.6%) received ChAdOx1. For both vaccines, antibody positivity peaks 4-5 weeks after first dose and then declines. At least 21 days after second dose of BNT162b2, close to 100% of respondents test positive, while for ChAdOx1, this is significantly reduced, particularly in the oldest age groups (72.7% [70.9-74.4] at ages 75 years and above). For both vaccines, antibody positivity decreases with age, and is higher in females and those with previous infection. Antibody positivity is lower in transplant recipients, obese individuals, smokers and those with specific comorbidities. These groups will benefit from additional vaccine doses.


Assuntos
Envelhecimento/imunologia , Anticorpos Antivirais/sangue , /imunologia , SARS-CoV-2/imunologia , Fatores Etários , Idoso , Formação de Anticorpos/imunologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Estudos Transversais , Inglaterra/epidemiologia , Feminino , Humanos , Programas de Imunização , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais , Vacinação
11.
Front Immunol ; 13: 806906, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154123

RESUMO

Memory CD8+ T cells accumulate with aging, while the naïve T cell compartment decreases, leading to an increased susceptibility to infections and a decreased vaccine efficiency. To get deeper insights into the underlying mechanisms, this study aims to determine the age-dependent expression profile of total versus memory CD8+ T cells from young and old donors. Total CD8+ and CD8+CD45RA- memory T cells isolated from young (<30 years) and old (>60 years) donors were stimulated with anti-CD3 and anti-CD28 antibodies for 48h before analyzing the cytokine secretion and activation markers by flow cytometry and changes in the expression profiles using RNA sequencing. Gene ontology (GO) term enrichment analyses were performed for up-regulated and uniquely expressed transcripts identified in the T cell populations of both age groups. Total and memory CD8+ T cells from old donors expressed significantly higher CD25 levels and have an increased cytokine secretion. While approximately 1,500 up-regulated transcripts were identified in all groups, CD8+CD45RA- memory T cells of old donors had approximately 500 more uniquely expressed transcripts. Four GO terms related to the JAK-STAT pathway were identified for up-regulated transcripts in the total CD8+ T cells of old donors, whereas CD8+CD45RA- memory T cells GO terms related to adjacent pathways, like JNK and MAPK/ERK, were found. Additionally, the unique transcripts of CD8+CD45RA- memory T cells of old donors were related to the JNK, MAPK and IL-12 pathways. For both T cell populations of the old donors, cytokine and JAK-STAT pathway transcripts were up-regulated. Thus, an age-dependent effect was observed on the transcriptomes of total and memory CD8+ T cells. The CD8+ CD45RA- memory T cells from old donors maintained the increased cytokine secretion of the total CD8+ T cell population and the increased JAK-STAT pathway transcripts, which have an impact on inflammation and senescence.


Assuntos
Envelhecimento , Doadores de Sangue , Linfócitos T CD8-Positivos/imunologia , Perfilação da Expressão Gênica/métodos , Memória Imunológica/imunologia , Antígenos Comuns de Leucócito/genética , /imunologia , Adulto , Fatores Etários , Idoso , Envelhecimento/imunologia , Doadores de Sangue/estatística & dados numéricos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/classificação , Citocinas , Feminino , Citometria de Fluxo , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Cell Rep ; 38(7): 110363, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35172147

RESUMO

Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.


Assuntos
Envelhecimento/imunologia , Antígenos/imunologia , Imunidade , Tolerância a Antígenos Próprios/imunologia , Linfócitos T/imunologia , Animais , Antioxidantes/farmacologia , Apolipoproteínas B/metabolismo , Atrofia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Catalase/metabolismo , Suplementos Nutricionais , Imunidade/efeitos dos fármacos , Epitopos Imunodominantes/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/imunologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Tolerância a Antígenos Próprios/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/enzimologia , Linfócitos T/efeitos dos fármacos , Timo/patologia
13.
Emerg Microbes Infect ; 11(1): 368-383, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34989330

RESUMO

Older individuals are at higher risk of SARS-CoV-2 infection and severe outcomes, but the underlying mechanisms are incompletely understood. In addition, how age modulates SARS-CoV-2 re-infection and vaccine breakthrough infections remain largely unexplored. Here, we investigated age-associated SARS-CoV-2 pathogenesis, immune responses, and the occurrence of re-infection and vaccine breakthrough infection utilizing a wild-type C57BL/6N mouse model. We demonstrated that interferon and adaptive antibody response upon SARS-CoV-2 challenge are significantly impaired in aged mice compared to young mice, which results in more effective virus replications and severe disease manifestations in the respiratory tract. Aged mice also showed increased susceptibility to re-infection due to insufficient immune protection acquired during the primary infection. Importantly, two-dose COVID-19 mRNA vaccination conferred limited adaptive immune response among the aged mice, making them susceptible to SARS-CoV-2 infection. Collectively, our findings call for tailored and optimized treatments and prevention strategies against SARS-CoV-2 among older individuals.


Assuntos
Fatores Etários , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Envelhecimento/imunologia , Animais , Anticorpos Antivirais/imunologia , COVID-19/patologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Vacinação , Replicação Viral
14.
Biochem J ; 479(2): 161-183, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35098992

RESUMO

The nuclear factor-κB (NF-κB) signaling pathway is one of the most well-studied pathways related to inflammation, and its involvement in aging has attracted considerable attention. As aging is a complex phenomenon and is the result of a multi-step process, the involvement of the NF-κB pathway in aging remains unclear. To elucidate the role of NF-κB in the regulation of aging, different systems biology approaches have been employed. A multi-omics data-driven approach can be used to interpret and clarify unknown mechanisms but cannot generate mechanistic regulatory structures alone. In contrast, combining this approach with a mathematical modeling approach can identify the mechanistics of the phenomena of interest. The development of single-cell technologies has also helped clarify the heterogeneity of the NF-κB response and underlying mechanisms. Here, we review advances in the understanding of the regulation of aging by NF-κB by focusing on omics approaches, single-cell analysis, and mathematical modeling of the NF-κB network.


Assuntos
Envelhecimento/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Biologia de Sistemas/métodos , Envelhecimento/genética , Envelhecimento/imunologia , Animais , Senescência Celular/fisiologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Cinética , Modelos Teóricos , NF-kappa B/genética , Análise de Célula Única/métodos , Transcriptoma
15.
Clin Sci (Lond) ; 136(1): 61-80, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34985109

RESUMO

Massive CD4+ T-cell depletion as well as sustained immune activation and inflammation are hallmarks of Human Immunodeficiency Virus (HIV)-1 infection. In recent years, an emerging concept draws an intriguing parallel between HIV-1 infection and aging. Indeed, many of the alterations that affect innate and adaptive immune subsets in HIV-infected individuals are reminiscent of the process of immune aging, characteristic of old age. These changes, of which the presumed cause is the systemic immune activation established in patients, likely participate in the immuno-incompetence described with HIV progression. With the success of antiretroviral therapy (ART), HIV-seropositive patients can now live for many years despite chronic viral infection. However, acquired immunodeficiency syndrome (AIDS)-related opportunistic infections have given way to chronic diseases as the leading cause of death since HIV infection. Therefore, the comparison between HIV-1 infected patients and uninfected elderly individuals goes beyond the sole onset of immunosenescence and extends to the deterioration of several physiological functions related to inflammation and systemic aging. In light of this observation, it is interesting to understand the precise link between immune activation and aging in HIV-1 infection to figure out how to best care for people living with HIV (PLWH).


Assuntos
Envelhecimento/imunologia , Infecções por HIV/imunologia , HIV-1 , Linfócitos T CD4-Positivos/imunologia , Progressão da Doença , Infecções por HIV/fisiopatologia , Humanos , Inflamação/imunologia
16.
Cancer Cell ; 40(1): 103-108.e2, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-34990570

RESUMO

Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses in a subset. Neutralization of alpha, beta, gamma, and delta SARS-CoV-2 variants is impaired relative to wildtype, regardless of vaccine type. Regardless of viral variant, mRNA1273 is the most immunogenic, followed by BNT162b2, and then Ad26.COV2.S. Neutralization of more variants (breadth) is associated with a greater magnitude of wildtype neutralization, and increases with time since vaccination; advancing age associates with a lower breadth. The concentrations of anti-spike protein antibody are a good surrogate for breadth (positive predictive value of =90% at >1,000 U/mL). Booster SARS-CoV-2 vaccines confer enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with the current vaccines increases the breadth of responses against variants.


Assuntos
Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Neoplasias/imunologia , SARS-CoV-2/imunologia , Idoso , Envelhecimento/imunologia , Antígenos Virais/imunologia , Feminino , Humanos , Imunização Secundária , Hospedeiro Imunocomprometido , Imunogenicidade da Vacina , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
17.
Diabetes ; 71(1): 23-30, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34995348

RESUMO

Age-related immunosenescence, defined as an increase in inflammaging and the decline of the immune system, leads to tissue dysfunction and increased risk for metabolic disease. The elderly population is expanding, leading to a heightened need for therapeutics to improve health span. With age, many alterations of the immune system are observed, including shifts in the tissue-resident immune cells, increased expression of inflammatory factors, and the accumulation of senescent cells, all of which are responsible for a chronic inflammatory loop. Adipose tissue and the immune cell activation within are of particular interest for their well-known roles in metabolic disease. Recent literature reveals that adipose tissue is an organ in which signs of initial aging occur, including immune cell activation. Aged adipose tissue reveals changes in many innate and adaptive immune cell subsets, revealing a complex interaction that contributes to inflammation, increased senescence, impaired catecholamine-induced lipolysis, and impaired insulin sensitivity. Here, we will describe current knowledge surrounding age-related changes in immune cells while relating those findings to recent discoveries regarding immune cells in aged adipose tissue.


Assuntos
Tecido Adiposo/patologia , Microambiente Celular/fisiologia , Senescência Celular/fisiologia , Inflamação/patologia , Leucócitos/fisiologia , Tecido Adiposo/metabolismo , Idoso , Envelhecimento/sangue , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Microambiente Celular/imunologia , Feminino , Humanos , Imunossenescência/fisiologia , Inflamação/metabolismo , Macrófagos/fisiologia , Masculino , Camundongos
18.
Int J Biol Sci ; 18(2): 617-636, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35002513

RESUMO

Among numerous studies on coronavirus 2019 (COVID-19), we noted that the infection and mortality rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increased with age and that fetuses known to be particularly susceptible to infection were better protected despite various mutations. Hence, we established the hypothesis that a new immune system exists that forms before birth and decreases with aging. Methods: To prove this hypothesis, we established new ex-vivo culture conditions simulating the critical environmental factors of fetal stem cells (FSCs) in early pregnancy. Then, we analyzed the components from FSCs cultivated newly developed ex-vivo culture conditions and compared them from FSCs cultured in a normal condition. Results: We demonstrated that immunoglobulin M (IgM), a natural antibody (NAb) produced only in early B-1 cells, immunoglobulins (Igs) including IgG3, which has a wide range of antigen-binding capacity and affinity, complement proteins, and antiviral proteins are induced in FSCs only cultured in newly developed ex-vivo culture conditions. Particularly we confirmed that their extracellular vesicles (EVs) contained NAbs, Igs, various complement proteins, and antiviral proteins, as well as human leukocyte antigen G (HLA-G), responsible for immune tolerance. Conclusion: Our results suggest that FSCs in early pregnancy can form an independent immune system responding to unlearned antigens as a self-defense mechanism before establishing mature immune systems. Moreover, we propose the possibility of new solutions to cope with various infectious diseases based on the factors in NAbs-containing EVs, especially not causing unnecessary immune reaction due to HLA-G.


Assuntos
Envelhecimento/imunologia , COVID-19/imunologia , Células-Tronco Fetais/fisiologia , Imunidade/fisiologia , SARS-CoV-2 , Afinidade de Anticorpos , Antígenos Virais , Proteínas do Sistema Complemento , Feminino , Células-Tronco Fetais/virologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Humanos , Imunoglobulinas/metabolismo , Gravidez
20.
J Immunol ; 208(3): 562-570, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35031578

RESUMO

Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunocompetência/efeitos dos fármacos , Metabolismo dos Lipídeos , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Linfócitos T CD8-Positivos/metabolismo , COVID-19/imunologia , Vacinas Anticâncer/imunologia , Divisão Celular , Feminino , Fenofibrato/farmacologia , Glucose/metabolismo , Antígeno HLA-A2/imunologia , Humanos , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Influenza Humana/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Ativação Linfocitária , Antígeno MART-1/química , Antígeno MART-1/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Rosiglitazona/farmacologia , Método Simples-Cego , Vacinação , Vacinas Virais/imunologia , Adulto Jovem
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