Beyond their role in neutralization, antibodies mediate functions such as phagocytosis, cytotoxicity, and maintenance of immune homeostasis. Two modifications to the constant domain control antibody ...activity: theirreversible genomic selection of isotype/subclass and alterations in glycosylation. Because glycosylation alters the affinity of antibodies for Fc receptors, evidence suggests that glycosylation is a central mechanism for the immune system to tune a broad range of biological activities. While monoclonal therapeutics have exploited glycosylation to improve function, its in vivo control and whether it may be selectively harnessed to target pathogens and/or tumors isunknown. Here, we review the process of antibody glycosylation, how it changes with disease, how it impacts antibody functionality, and the potential for deliberately controlling this biological activity.
Emerging SARS-CoV-2 variants have raised concerns about resistance to neutralizing antibodies elicited by previous infection or vaccination. We examined whether sera from recovered and naïve donors ...collected prior to, and following immunizations with existing mRNA vaccines, could neutralize the Wuhan-Hu-1 and B.1.351 variants. Pre-vaccination sera from recovered donors neutralized Wuhan-Hu-1 and sporadically neutralized B.1.351, but a single immunization boosted neutralizing titers against all variants and SARS-CoV-1 by up to 1000-fold. Neutralization was due to antibodies targeting the receptor binding domain and was not boosted by a second immunization. Immunization of naïve donors also elicited cross-neutralizing responses, but at lower titers. Our study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.
As placental mammals, the pregnant women and the fetus have intense and prolonged interactions during gestation. There is increasing evidence that multiple molecular as well as cellular components ...originating in pregnant women are transferred to the fetus. The transfer of maternal antibodies has long been recognized as a central component of newborn immunity against pathogens. More recent studies indicate that inflammatory mediators, micronutrients, microbial products and maternal cells are transferred in utero and influence the fetal immune system. Together, these multiple signals are likely to form a complex network of interactions that program the neonatal immune system and tune its homeostatic regulation. Maternal disorders, in particular infectious diseases, modify these signals and may thereby alter immunity in early life. Understanding maternal programming of the newborn immune system could provide a basis for interventions promoting child health.
Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, ...particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo. .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, ...enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates.
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•NK cell-activating antibodies are selectively transferred across the placenta•Digalactosylated Fc glycans are preferentially transferred across the placenta•Digalactosylated antibodies bind more effectively to FcRn and FCGR3A•Although immature, neonatal NK cells are highly responsive to immune complexes
Antibodies with a specific glycan modification and with the ability to activate NK cells are selectively transferred across the placenta to the neonate.
Antibody responses develop following SARS-CoV-2 infection, but little is known about their epitope specificities, clonality, binding affinities, epitopes, and neutralizing activity. We isolated B ...cells specific for the SARS-CoV-2 envelope glycoprotein spike (S) from a COVID-19-infected subject 21 days after the onset of clinical disease. 45 S-specific monoclonal antibodies were generated. They had undergone minimal somatic mutation with limited clonal expansion, and three bound the receptor-binding domain (RBD). Two antibodies neutralized SARS-CoV-2. The most potent antibody bound the RBD and prevented binding to the ACE2 receptor, while the other bound outside the RBD. Thus, most anti-S antibodies that were generated in this patient during the first weeks of COVID-19 infection were non-neutralizing and target epitopes outside the RBD. Antibodies that disrupt the SARS-CoV-2 S-ACE2 interaction can potently neutralize the virus without undergoing extensive maturation. Such antibodies have potential preventive and/or therapeutic potential and can serve as templates for vaccine design.
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•Early B cell responses to SARS-CoV-2 spike protein are analyzed from a COVID-19 patient•Most antibodies target non-neutralizing epitopes outside the RBD•A potent neutralizing mAb blocks the interaction of the S protein with ACE2•Neutralizing antibodies are minimally mutated
Seydoux et al. analyze B cell responses in a COVID-19 patient and find that SARS-CoV-2 infection expands diverse B cell clones against the viral spike glycoprotein (S). Two neutralizing antibodies were identified that bind S with high affinity despite being minimally mutated. Thus, vaccine-induced neutralizing antibody responses may require activation of specific naive B cells without requiring extensive somatic mutation.
Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal ...model to optimize delivery of naturally-arising, autologous anti-SIV neutralizing antibodies expressed by Adeno-Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 10(12) AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. ...HIV-infected women have impaired placental IgG transfer, presenting a unique “disruption model” to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.
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•Maternal HIV progression factors are associated with poor placental IgG transfer•Binding to placental Fcγ receptors can predict placental IgG transfer efficiency•Fc region glycan profiles can predict the efficiency of placental transfer of IgG
The impaired transfer of maternal IgG from HIV-infected mothers to their infants is associated with altered binding to Fc receptors FcγRIIa and FcγRIIIa as well as glycan modifications in the Fc region.
Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by ...the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.
The study of neonatal immunology has been hampered by lack of access to infant samples. Novel sample sparing methods and systems-wide approaches have uniquely expanded this field, demonstrating that ...newborn immunity varies widely but converges over the first 3 months of life. During this important time window, environmental and genetic factors impact the infant immune system and can influence lifelong immunity.
The study of neonatal immunology has been hampered by lack of access to infant samples. Novel sample sparing methods and systems-wide approaches have uniquely expanded this field, demonstrating that newborn immunity varies widely but converges over the first 3 months of life. During this important time window, environmental and genetic factors impact the infant immune system and can influence lifelong immunity.
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