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Annual Review of Cell and Developmental... Oct 2020Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more... (Review)
Review
Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.
Topics: Animals; Antibody Formation; B-Lymphocytes; Gastrointestinal Microbiome; Humans; Immunosenescence; Inflammation; Polymorphism, Single Nucleotide
PubMed: 33021823
DOI: 10.1146/annurev-cellbio-011620-034148 -
Cell Jan 2023Antibody responses are characterized by increasing affinity and diversity over time. Affinity maturation occurs in germinal centers by a mechanism that involves repeated...
Antibody responses are characterized by increasing affinity and diversity over time. Affinity maturation occurs in germinal centers by a mechanism that involves repeated cycles of somatic mutation and selection. How antibody responses diversify while also undergoing affinity maturation is not as well understood. Here, we examined germinal center (GC) dynamics by tracking B cell entry, division, somatic mutation, and specificity. Our experiments show that naive B cells continuously enter GCs where they compete for T cell help and undergo clonal expansion. Consistent with late entry, invaders carry fewer mutations but can contribute up to 30% or more of the cells in late-stage germinal centers. Notably, cells entering the germinal center at later stages of the reaction diversify the immune response by expressing receptors that show low affinity to the immunogen. Paradoxically, the affinity threshold for late GC entry is lowered in the presence of high-affinity antibodies.
Topics: Antibody Affinity; Germinal Center; B-Lymphocytes; Antibody Formation; Antigens
PubMed: 36565698
DOI: 10.1016/j.cell.2022.11.032 -
Immunity Aug 2023Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the...
Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract.
Topics: Humans; Influenza Vaccines; Antibody Formation; Antibodies, Viral; T-Lymphocytes; Antigens; Organoids; Influenza, Human
PubMed: 37478854
DOI: 10.1016/j.immuni.2023.06.019 -
Cell Jan 2020Repeated exposure to pathogens or their antigens triggers anamnestic antibody responses that are higher in magnitude and affinity than the primary response. These...
Repeated exposure to pathogens or their antigens triggers anamnestic antibody responses that are higher in magnitude and affinity than the primary response. These involve reengagement of memory B cell (MBC) clones, the diversity and specificity of which determine the breadth and effectiveness of the ensuing antibody response. Using prime-boost models in mice, we find that secondary responses are characterized by a clonality bottleneck that restricts the engagement of the large diversity of MBC clones generated by priming. Rediversification of mutated MBCs is infrequent within secondary germinal centers (GCs), which instead consist predominantly of B cells without prior GC experience or detectable clonal expansion. Few MBC clones, generally derived from higher-affinity germline precursors, account for the majority of secondary antibody responses, while most primary-derived clonal diversity is not reengaged detectably by boosting. Understanding how to counter this bottleneck may improve our ability to elicit antibodies to non-immunodominant epitopes by vaccination.
Topics: Adaptive Immunity; Animals; Antibody Formation; Antigens; B-Lymphocytes; CHO Cells; Cell Line; Cricetulus; Female; Germinal Center; Humans; Immunologic Memory; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal
PubMed: 31866068
DOI: 10.1016/j.cell.2019.11.032 -
Nature Immunology Dec 2022Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccination. However, the generalizability and mechanisms...
Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccination. However, the generalizability and mechanisms that underlie this association remain poorly defined. Here, we sought to identify a common pre-vaccination signature and mechanisms that could predict the immune response across 13 different vaccines. Analysis of blood transcriptional profiles across studies revealed three distinct pre-vaccination endotypes, characterized by the differential expression of genes associated with a pro-inflammatory response, cell proliferation, and metabolism alterations. Importantly, individuals whose pre-vaccination endotype was enriched in pro-inflammatory response genes known to be downstream of nuclear factor-kappa B showed significantly higher serum antibody responses 1 month after vaccination. This pro-inflammatory pre-vaccination endotype showed gene expression characteristic of the innate activation state triggered by Toll-like receptor ligands or adjuvants. These results demonstrate that wide variations in the transcriptional state of the immune system in humans can be a key determinant of responsiveness to vaccination.
Topics: Humans; Antibody Formation; Vaccination; Vaccines; Adjuvants, Immunologic; Immunity, Innate
PubMed: 36316476
DOI: 10.1038/s41590-022-01329-5 -
Science (New York, N.Y.) Jan 2024Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon...
Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling. Antibody-secreting cells had increased I34 levels and were more reliant on I34 for protein production than naïve B cells. Furthermore, antibody I34-dependent codon usage may influence B cell passage through regulatory checkpoints. Our work elucidates the interface between the tRNA pool and protein production in the immune system and has implications for the design and selection of antibodies for vaccines and therapeutics.
Topics: Antibody Formation; Codon; Codon Usage; Inosine; RNA, Transfer; Antibodies; Humans; B-Lymphocytes; Immunoglobulin Heavy Chains
PubMed: 38207021
DOI: 10.1126/science.adi1763 -
Immunological Reviews Sep 2021Antibody-secreting plasma cells are a central component of short- and long-term adaptive immunity. Yet, many fundamental questions about how activated B cells decide to... (Review)
Review
Antibody-secreting plasma cells are a central component of short- and long-term adaptive immunity. Yet, many fundamental questions about how activated B cells decide to yield functional plasma cells have yet to be answered. Likewise, the biochemical processes underpinning the ability of plasma cells to generate and secrete large numbers of antibodies, the capacity of some plasma cell to sustain antibody secretion, presumably without interruption, for decades, and the capacity of long-lived plasma cells to avoid apoptosis despite the high-energy demands associated with sustained robust antibody synthesis and secretion each remain mysterious processes. Our objective here is to review what is currently known about these processes with an emphasis on the earliest phases of plasma cell genesis. Along the way, we will work toward developing a model that ties the biochemistry of plasma cell function and survival. The chief idea imbedded in this model is that progress toward understanding plasma cell survival mechanisms may require increased focus on the unique cell autonomous processes inherent in plasma cell differentiation and function.
Topics: Antibody Formation; Antibody-Producing Cells; B-Lymphocytes; Cell Differentiation; Lymphocyte Activation; Plasma Cells
PubMed: 34313339
DOI: 10.1111/imr.12992 -
Frontiers in Immunology 2020
Topics: Antibody Formation; B-Lymphocytes; Drug Discovery; High-Throughput Nucleotide Sequencing; Humans; Vaccines
PubMed: 32714328
DOI: 10.3389/fimmu.2020.01344 -
Human Vaccines & Immunotherapeutics Oct 2021Neutralizing antibodies are the basis of almost all approved prophylactic vaccines and the foundation of effective protection from pathogens, including the recently...
Neutralizing antibodies are the basis of almost all approved prophylactic vaccines and the foundation of effective protection from pathogens, including the recently emerging SARS Coronavirus 2 (SARS-CoV-2). However, the contribution of antibodies to protection and to the course of the disease during first-time exposure to a pathogen is unknown. We analyzed the antibodies and B cell responses in severe and mild COVID-19 patients. Despite our primary assumption that high antibody titers contribute to a mild disease, we found that severe COVID-19 illness, and not mild infection, correlates with strong anti-viral antibody and memory B cell responses. This phenomenon was also demonstrated for anti-Mycobacterium inhibiting antibodies that we recently isolated from an actively infected Tuberculosis-sick donor. This correlation between disease severity and antibody responses can be explained by the fact that high viral loads drive B cell stimulation and generation of high-affinity antibodies that will be protective upon future encounter with the particular pathogen.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Antibody Formation; COVID-19; Humans; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 34032550
DOI: 10.1080/21645515.2021.1929034 -
Trends in Immunology Mar 2021'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While... (Review)
Review
'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While observations of antibody convergence across individuals support the assumption that responses may be replicated, the diversity of humoral immunity and the process of antibody selection are rooted in stochasticity. Drawing from experience with in vitro antibody engineering by directed evolution, we consider how antibody selection may be driven, as in germline-targeting vaccine approaches to elicit broadly neutralizing antibodies and illustrate the potential consequences of over-defining a template antibody response. We posit that the prospective definition of template antibody responses and the odds of replicating them must be considered within the randomness of humoral immunity.
Topics: Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV-1; Humans; Prospective Studies
PubMed: 33514459
DOI: 10.1016/j.it.2021.01.001