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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 Host & Microbe Nov 2023Epstein-Barr virus (EBV) is a global public health concern, as it is known to cause multiple diseases while also being etiologically associated with a wide range of...
Epstein-Barr virus (EBV) is a global public health concern, as it is known to cause multiple diseases while also being etiologically associated with a wide range of epithelial and lymphoid malignancies. Currently, there is no available prophylactic vaccine against EBV. gB is the EBV fusion protein that mediates viral membrane fusion and participates in host recognition, making it critical for EBV infection in both B cells and epithelial cells. Here, we present a gB nanoparticle, gB-I53-50 NP, that displays multiple copies of gB. Compared with the gB trimer, gB-I53-50 NP shows improved structural integrity and stability, as well as enhanced immunogenicity in mice and non-human primate (NHP) preclinical models. Immunization and passive transfer demonstrate a robust and durable protective antibody response that protects humanized mice against lethal EBV challenge. This vaccine candidate demonstrates significant potential in preventing EBV infection, providing a possible platform for developing prophylactic vaccines for EBV.
Topics: Cricetinae; Animals; Mice; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Antibody Formation; CHO Cells; Vaccines; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37848029
DOI: 10.1016/j.chom.2023.09.011 -
Cell Dec 2023Germinal centers (GCs) form in lymph nodes after immunization or infection to facilitate antibody affinity maturation and memory and plasma cell (PC) development. PC...
Germinal centers (GCs) form in lymph nodes after immunization or infection to facilitate antibody affinity maturation and memory and plasma cell (PC) development. PC differentiation is thought to involve stringent selection for GC B cells expressing the highest-affinity antigen receptors, but how this plays out during complex polyclonal responses is unclear. We combine temporal lineage tracing with antibody characterization to gain a snapshot of PCs developing during influenza infection. GCs co-mature B cell clones with antibody affinities spanning multiple orders of magnitude; however, each generates PCs with similar efficiencies, including weak binders. Within lineages, PC selection is not restricted to variants with the highest-affinity antibodies. Differentiation is commonly associated with proliferative expansion to produce "nodes" of identical PCs. Immunization-induced GCs generate fewer PCs but still of low- and high-antibody affinities. We propose that generating low-affinity antibody PCs reflects an evolutionary compromise to facilitate diverse serum antibody responses.
Topics: Antibody Formation; B-Lymphocytes; Germinal Center; Lymph Nodes; Plasma Cells; Cell Line; Humans; Animals; Mice; Cricetinae; Antibody Affinity; Influenza A virus; Cell Differentiation
PubMed: 37951212
DOI: 10.1016/j.cell.2023.10.022 -
The Journal of Clinical Investigation Jan 2024BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute...
BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.
Topics: Humans; Dependovirus; Thrombotic Microangiopathies; Immunoglobulin M; Immunoglobulin G
PubMed: 37988172
DOI: 10.1172/JCI173510 -
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 -
Frontiers in Immunology 2023Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a serious autoimmune disease that is characterized by vascular necrosis. The pathogenesis... (Review)
Review
Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a serious autoimmune disease that is characterized by vascular necrosis. The pathogenesis of AAV includes ANCA-mediated neutrophil activation, subsequent release of inflammatory cytokines and reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs). Excessive NETs could participate not only in ANCA-mediated vascular injury but also in the production of ANCAs per se as autoantigens. Thus, a vicious cycle of NET formation and ANCA production is critical for AAV pathogenesis. Elucidating the molecular signaling pathways in aberrant neutrophil activation and NETs clearance systems will allow specific therapeutics to regulate these pathways. Currently, standard therapy with high doses of glucocorticoids and immunosuppressants has improved outcomes in patients with AAV. However, AAV frequently develops in elderly people, and adverse effects such as severe infections in the standard regimens might contribute to the mortality. Mechanistically, cytokines or complement factors activate and prime neutrophils for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential replacement for glucocorticoids in clinical settings. Recent studies have demonstrated that receptor-interacting protein kinases (RIPK3) and cyclophilin D (CypD), which regulate cell necrosis, may be involved in ANCA-induced NETs formation. Meanwhile, targeting NETs clearance, including the addition of deoxyribonuclease I (DNase I) and macrophage engulfment, may improve vasculitis. In this review, we focus on the pathogenesis of NETs and discuss potential targeted therapies for AAV based on recent experimental evidence.
Topics: Humans; Aged; Extracellular Traps; Antibodies, Antineutrophil Cytoplasmic; Neutrophils; Necrosis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
PubMed: 37781373
DOI: 10.3389/fimmu.2023.1261151 -
Science (New York, N.Y.) Feb 2024Influenza viruses escape immunity owing to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. We...
Influenza viruses escape immunity owing to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. We found that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 bound and disengaged CD19 from its chaperone CD81, permitting CD19 to translocate to the B cell receptor complex to trigger signaling. Moreover, Gb3 regulated major histocompatibility complex class II expression to increase diversity of T follicular helper and GC B cells reactive with subdominant epitopes. In influenza infection, elevating Gb3, either endogenously or exogenously, promoted broadly reactive antibody responses and cross-protection. These data demonstrate that Gb3 determines the affinity and breadth of B cell immunity and has potential as a vaccine adjuvant.
Topics: Antibody Formation; B-Lymphocytes; Germinal Center; Trihexosylceramides; Animals; Mice; Mice, Knockout; Humans; Orthomyxoviridae; Orthomyxoviridae Infections; Antibodies, Viral
PubMed: 38359115
DOI: 10.1126/science.adg0564 -
Cellular & Molecular Immunology Feb 2024The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 prompted scientific, medical, and biotech communities to investigate infection- and... (Review)
Review
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 prompted scientific, medical, and biotech communities to investigate infection- and vaccine-induced immune responses in the context of this pathogen. B-cell and antibody responses are at the center of these investigations, as neutralizing antibodies (nAbs) are an important correlate of protection (COP) from infection and the primary target of SARS-CoV-2 vaccine modalities. In addition to absolute levels, nAb longevity, neutralization breadth, immunoglobulin isotype and subtype composition, and presence at mucosal sites have become important topics for scientists and health policy makers. The recent pandemic was and still is a unique setting in which to study de novo and memory B-cell (MBC) and antibody responses in the dynamic interplay of infection- and vaccine-induced immunity. It also provided an opportunity to explore new vaccine platforms, such as mRNA or adenoviral vector vaccines, in unprecedented cohort sizes. Combined with the technological advances of recent years, this situation has provided detailed mechanistic insights into the development of B-cell and antibody responses but also revealed some unexpected findings. In this review, we summarize the key findings of the last 2.5 years regarding infection- and vaccine-induced B-cell immunity, which we believe are of significant value not only in the context of SARS-CoV-2 but also for future vaccination approaches in endemic and pandemic settings.
Topics: Humans; SARS-CoV-2; Antibody Formation; COVID-19 Vaccines; COVID-19; Vaccination; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37945737
DOI: 10.1038/s41423-023-01095-w