Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 129
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34019795

RESUMEN

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Fragmentos Fab de Inmunoglobulinas/inmunología , Polisacáridos/inmunología , SARS-CoV-2/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/inmunología , Dimerización , Epítopos/inmunología , Glicosilación , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Macaca mulatta , Polisacáridos/química , Receptores de Antígenos de Linfocitos B/química , Virus de la Inmunodeficiencia de los Simios/genética , Vacunas/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética
2.
Cell ; 177(5): 1124-1135.e16, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-31100267

RESUMEN

Vaccines to generate durable humoral immunity against antigenically evolving pathogens such as the influenza virus must elicit antibodies that recognize conserved epitopes. Analysis of single memory B cells from immunized human donors has led us to characterize a previously unrecognized epitope of influenza hemagglutinin (HA) that is immunogenic in humans and conserved among influenza subtypes. Structures show that an unrelated antibody from a participant in an experimental infection protocol recognized the epitope as well. IgGs specific for this antigenic determinant do not block viral infection in vitro, but passive administration to mice affords robust IgG subtype-dependent protection against influenza infection. The epitope, occluded in the pre-fusion form of HA, is at the contact surface between HA head domains; reversible molecular "breathing" of the HA trimer can expose the interface to antibody and B cells. Antigens that present this broadly immunogenic HA epitope may be good candidates for inclusion in "universal" flu vaccines.


Asunto(s)
Anticuerpos Antivirales/inmunología , Epítopos/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Inmunoglobulina G/inmunología , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae , Adulto , Animales , Perros , Femenino , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Persona de Mediana Edad , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/prevención & control
3.
Immunity ; 55(2): 272-289.e7, 2022 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-35081372

RESUMEN

T follicular helper (Tfh) cells are defined by a Bcl6+CXCR5hiPD-1hi phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether GC-resident and -nonresident Tfh cells share a common physiology and function. Fluorescently labeled, GC-resident Tfh cells in different mouse models were distinguished by low expression of CD90. CD90neg/lo GCTfh cells required antigen-specific, MHCII+ B cells to develop and stopped proliferating soon after differentiation. In contrast, nonresident, CD90hi Tfh (GCTfh-like) cells developed normally in the absence of MHCII+ B cells and proliferated continuously during primary responses. The TCR repertoires of both Tfh subsets overlapped initially but later diverged in association with dendritic cell-dependent proliferation of CD90hi GCTfh-like cells, suggestive of TCR-dependency seen also in TCR-transgenic adoptive transfer experiments. Furthermore, the transcriptomes of CD90neg/lo and CD90hi GCTfh-like cells were enriched in different functional pathways. Thus, GC-resident and nonresident Tfh cells have distinct developmental requirements and activities, implying distinct functions.


Asunto(s)
Centro Germinal/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/metabolismo , Subgrupos de Linfocitos T/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Comunicación Celular/inmunología , Diferenciación Celular , Proliferación Celular , Células Dendríticas/inmunología , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/metabolismo , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Células T Auxiliares Foliculares/inmunología , Subgrupos de Linfocitos T/inmunología , Antígenos Thy-1/metabolismo
4.
Cell ; 165(2): 449-63, 2016 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-26949186

RESUMEN

Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/química , Linfocitos B/inmunología , Anticuerpos Anti-VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Alineación de Secuencia
5.
Immunity ; 53(3): 473-475, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32937146

RESUMEN

In this issue of Immunity, Kato et al. show that high-affinity vaccines targeting rare B cells capable of broadly protective antibody responses are not hindered by promotion of terminal plasmacytic differentiation. These findings provide new understanding into vaccine design and offer important insight into B cell fate decisions.


Asunto(s)
Linfocitos B , Vacunas , Formación de Anticuerpos , Linfocitos B/inmunología , Diferenciación Celular
6.
Cell ; 158(3): 481-91, 2014 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-25065977

RESUMEN

Development of strategies for induction of HIV-1 broadly neutralizing antibodies (bnAbs) by vaccines is a priority. Determining the steps of bnAb induction in HIV-1-infected individuals who make bnAbs is a key strategy for immunogen design. Here, we study the B cell response in a bnAb-producing individual and report cooperation between two B cell lineages to drive bnAb development. We isolated a virus-neutralizing antibody lineage that targeted an envelope region (loop D) and selected virus escape mutants that resulted in both enhanced bnAb lineage envelope binding and escape mutant neutralization-traits associated with increased B cell antigen drive. Thus, in this individual, two B cell lineages cooperated to induce the development of bnAbs. Design of vaccine immunogens that simultaneously drive both helper and broadly neutralizing B cell lineages may be important for vaccine-induced recapitulation of events that transpire during the maturation of neutralizing antibodies in HIV-1-infected individuals.


Asunto(s)
Vacunas contra el SIDA/química , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , VIH-1/fisiología , Secuencia de Aminoácidos , Linfocitos B/inmunología , Evasión Inmune , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Alineación de Secuencia , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
7.
Immunity ; 48(1): 174-184.e9, 2018 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-29343437

RESUMEN

Human B cell antigen-receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross-reacting antibodies (Abs) are uncommon. We analyzed Bmem compartments in three unrelated, adult donors and found frequent cross-group BCRs, both HA-head directed and non-head directed. Members of a clonal lineage from one donor had a BCR structure similar to that of a previously described Ab, encoded by different gene segments. Comparison showed that both Abs contacted the HA receptor-binding site through long heavy-chain third complementarity determining regions. Affinities of the clonal-lineage BCRs for historical influenza-virus HAs from both group 1 and group 2 viruses suggested that serial responses to seasonal influenza exposures had elicited the lineage and driven affinity maturation. We propose that appropriate immunization regimens might elicit a comparably broad response.


Asunto(s)
Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Virus de la Influenza A/inmunología , Adulto , Técnicas de Cultivo de Célula , Reacciones Cruzadas/inmunología , Femenino , Citometría de Flujo , Hemaglutininas Virales/inmunología , Humanos , Interferometría , Masculino
8.
Immunity ; 49(6): 1162-1174.e8, 2018 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-30552024

RESUMEN

Elicitation of VRC01-class broadly neutralizing antibodies (bnAbs) is an appealing approach for a preventative HIV-1 vaccine. Despite extensive investigations, strategies to induce VRC01-class bnAbs and overcome the barrier posed by the envelope N276 glycan have not been successful. Here, we inferred a high-probability unmutated common ancestor (UCA) of the VRC01 lineage and reconstructed the stages of lineage maturation. Env immunogens designed on reverted VRC01-class bnAbs bound to VRC01 UCA with affinity sufficient to activate naive B cells. Early mutations defined maturation pathways toward limited or broad neutralization, suggesting that focusing the immune response is likely required to steer B cell maturation toward the development of neutralization breadth. Finally, VRC01 lineage bnAbs with long CDR H3s overcame the HIV-1 N276 glycan barrier without shortening their CDR L1, revealing a solution for broad neutralization in which the heavy chain, not CDR L1, is the determinant to accommodate the N276 glycan.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Polisacáridos/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Secuencia de Aminoácidos , Anticuerpos Monoclonales/clasificación , Anticuerpos Monoclonales/genética , Anticuerpos Neutralizantes/clasificación , Anticuerpos Neutralizantes/genética , Linfocitos B/inmunología , Linfocitos B/metabolismo , Sitios de Unión/genética , Anticuerpos ampliamente neutralizantes , Antígenos CD4/genética , Antígenos CD4/inmunología , Antígenos CD4/metabolismo , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Filogenia , Polisacáridos/metabolismo , Homología de Secuencia de Aminoácido
9.
Proc Natl Acad Sci U S A ; 121(1): e2316964120, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38147556

RESUMEN

Phylogenetically and antigenically distinct influenza A and B viruses (IAV and IBV) circulate in human populations, causing widespread morbidity. Antibodies (Abs) that bind epitopes conserved in both IAV and IBV hemagglutinins (HAs) could protect against disease by diverse virus subtypes. Only one reported HA Ab, isolated from a combinatorial display library, protects against both IAV and IBV. Thus, there has been so far no information on the likelihood of finding naturally occurring human Abs that bind HAs of diverse IAV subtypes and IBV lineages. We have now recovered from several unrelated human donors five clonal Abs that bind a conserved epitope preferentially exposed in the postfusion conformation of IAV and IVB HA2. These Abs lack neutralizing activity in vitro but in mice provide strong, IgG subtype-dependent protection against lethal IAV and IBV infections. Strategies to elicit similar Abs routinely might contribute to more effective influenza vaccines.


Asunto(s)
Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Infecciones por Orthomyxoviridae , Humanos , Ratones , Animales , Hemaglutininas , Epítopos , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Virus de la Influenza B
10.
PLoS Biol ; 21(12): e3002415, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38127922

RESUMEN

Antibody titers that inhibit the influenza virus hemagglutinin (HA) from engaging its receptor are the accepted correlate of protection from infection. Many potent antibodies with broad, intra-subtype specificity bind HA at the receptor binding site (RBS). One barrier to broad H1-H3 cross-subtype neutralization is an insertion (133a) between positions 133 and 134 on the rim of the H1 HA RBS. We describe here a class of antibodies that overcomes this barrier. These genetically unrestricted antibodies are abundant in the human B cell memory compartment. Analysis of the affinities of selected members of this class for historical H1 and H3 isolates suggest that they were elicited by H3 exposure and broadened or diverted by later exposure(s) to H1 HA. RBS mutations in egg-adapted vaccine strains cause the new H1 specificity of these antibodies to depend on the egg adaptation. The results suggest that suitable immunogens might elicit 133a-independent, H1-H3 cross neutralization by RBS-directed antibodies.


Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Humanos , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Subtipo H3N2 del Virus de la Influenza A , Sitios de Unión
11.
Immunity ; 44(3): 542-552, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26948373

RESUMEN

Germinal center (GC) B cells evolve toward increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten-specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens-Bacillus anthracis protective antigen and influenza hemagglutinin-in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naive B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early "winners" were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection.


Asunto(s)
Linfocitos B/fisiología , Selección Clonal Mediada por Antígenos , Centro Germinal/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Afinidad de Anticuerpos/genética , Diversidad de Anticuerpos , Antígenos Bacterianos/inmunología , Toxinas Bacterianas/inmunología , Células Cultivadas , Femenino , Hemaglutininas Virales/inmunología , Humanos , Inmunidad Humoral , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Orthomyxoviridae/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Anticuerpos de Dominio Único/genética
12.
Immunity ; 45(5): 1108-1121, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27851912

RESUMEN

Detailed studies of the broadly neutralizing antibodies (bNAbs) that underlie the best available examples of the humoral immune response to HIV are providing important information for the development of therapies and prophylaxis for HIV-1 infection. Here, we report a CD4-binding site (CD4bs) antibody, named N6, that potently neutralized 98% of HIV-1 isolates, including 16 of 20 that were resistant to other members of its class. N6 evolved a mode of recognition such that its binding was not impacted by the loss of individual contacts across the immunoglobulin heavy chain. In addition, structural analysis revealed that the orientation of N6 permitted it to avoid steric clashes with glycans, which is a common mechanism of resistance. Thus, an HIV-1-specific bNAb can achieve potent, near-pan neutralization of HIV-1, making it an attractive candidate for use in therapy and prophylaxis.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Sitios de Unión de Anticuerpos/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Especificidad de Anticuerpos , Linfocitos T CD4-Positivos/inmunología , Separación Celular , Proteína gp120 de Envoltorio del VIH/inmunología , Humanos
13.
Immunity ; 41(6): 909-18, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25526306

RESUMEN

In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid-aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169-recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos Antivirales/metabolismo , Linfocitos B/inmunología , Epítopos de Linfocito B/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/inmunología , Cadenas Ligeras de Inmunoglobulina/metabolismo , Secuencia de Aminoácidos , Animales , Afinidad de Anticuerpos/genética , Células Cultivadas , Ensayos Clínicos como Asunto , Secuencia Conservada/genética , Mapeo Epitopo , Epítopos de Linfocito B/genética , Epítopos de Linfocito B/inmunología , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/prevención & control , Humanos , Macaca mulatta , Datos de Secuencia Molecular , Mutación/genética , Filogenia , Unión Proteica/genética , Ingeniería de Proteínas
14.
J Immunol ; 207(5): 1478-1492, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34389622

RESUMEN

Stable, long-term culture of primary B lymphocytes has many potential scientific and medical applications, but remains an elusive feat. A major obstacle to long-term culture is that in vitro mitogens quickly drive B cells to differentiate into short-lived plasma cells (PCs). PC differentiation is governed by opposing teams of transcription factors: Pax5, Bach2, and Bcl6 suppress PC commitment, whereas IFN regulatory factor 4 and Blimp1 promote it. To determine whether transcriptional programming could prolong B cell culture by blocking PC commitment, we generated mouse primary B cells harboring gain- or loss-of-function in the key transcription factors, continuously stimulated these cells with CD154 and IL-21, and determined growth potential and phenotypes in vitro. We found that transgenic expression of Bach2 prohibits PC commitment and endows B cells with extraordinary growth potential in response to external proliferation and survival cues. Long-term Bach2-transgenic B cell lines have genetically stable BCRs [i.e., do not acquire V(D)J mutations], express high levels of MHC class II and molecules for costimulation of T cells, and transduce intracellular signals when incubated with BCR ligands. Silencing the Bach2 transgene in an established transgenic cell line causes the cells to secrete large quantities of Ig. This system has potential applications in mAb production, BCR signaling studies, Ag presentation to T cells, and ex vivo clonal expansion for adoptive cell transfer. Additionally, our results provide insight into molecular control over activated B cell fate and suggest that forced Bach2 expression in vivo may augment germinal center B cell or memory B cell differentiation at the expense of PC commitment.


Asunto(s)
Linfocitos B/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Centro Germinal/inmunología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Regulación de la Expresión Génica , Memoria Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo
15.
Immunol Rev ; 292(1): 24-36, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31559648

RESUMEN

B lymphocytes must respond to vast numbers of foreign antigens, including those of microbial pathogens. To do so, developing B cells use combinatorial joining of V-, D-, and J-gene segments to generate an extraordinarily diverse repertoire of B-cell antigen receptors (BCRs). Unsurprisingly, a large fraction of this initial BCR repertoire reacts to self-antigens, and these "forbidden" B cells are culled by immunological tolerance from mature B-cell populations. While culling of autoreactive BCRs mitigates the risk of autoimmunity, it also opens gaps in the BCR repertoire, which are exploited by pathogens that mimic the forbidden self-epitopes. Consequently, immunological tolerance, necessary for averting autoimmune disease, also acts to limit effective microbial immunity. In this brief review, we recount the evidence for the linkage of tolerance and impaired microbial immunity, consider the implications of this linkage for vaccine development, and discuss modulating tolerance as a potential strategy for strengthening humoral immune responses.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Anticuerpos Antifúngicos/inmunología , Linfocitos B/inmunología , Tolerancia Inmunológica/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Animales , Linfocitos B/metabolismo , Linfocitos B/microbiología , Humanos , Inmunidad Humoral/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal/inmunología
16.
J Immunol ; 205(1): 90-101, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32414809

RESUMEN

BCR transgenic mice dominate studies of B cell tolerance; consequently, tolerance in normal mice expressing diverse sets of autoreactive B cells is poorly characterized. We have used single B cell cultures to trace self-reactivity in BCR repertoires across the first and second tolerance checkpoints and in tolerized B cell compartments of normal mice. This approach reveals affinity "setpoints" that define each checkpoint and a subset of tolerized, autoreactive B cells that is long-lived. In normal mice, the numbers of B cells avidly specific for DNA fall significantly as small pre-B become immature and transitional-1 B cells, revealing the first tolerance checkpoint. By contrast, DNA reactivity does not significantly change when immature and transitional-1 B cells become mature follicular B cells, showing that the second checkpoint does not reduce DNA reactivity. In the spleen, autoreactivity was high in transitional-3 (T3) B cells, CD93+IgM-/loIgDhi anergic B cells, and a CD93- anergic subset. Whereas splenic T3 and CD93+ anergic B cells are short-lived, CD93-IgM-/loIgDhi B cells have half-lives comparable to mature follicular B cells. B cell-specific deletion of proapoptotic genes, Bak and Bax, resulted in increased CD93-IgM-/loIgDhi B cell numbers but not T3 B cell numbers, suggesting that apoptosis regulates differently persistent and ephemeral autoreactive B cells. The self-reactivity and longevity of CD93-IgM-/loIgDhi B cells and their capacity to proliferate and differentiate into plasmacytes in response to CD40 activation in vitro lead us to propose that this persistent, self-reactive compartment may be the origin of systemic autoimmunity and a potential target for vaccines to elicit protective Abs cross-reactive with self-antigens.


Asunto(s)
Autoantígenos/inmunología , Autoinmunidad , Linfocitos B/inmunología , Células Precursoras de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Autoantígenos/metabolismo , Linfocitos B/metabolismo , Células Cultivadas , Anergia Clonal , Reacciones Cruzadas , Semivida , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Modelos Animales , Células Precursoras de Linfocitos B/metabolismo , Cultivo Primario de Células , Análisis de la Célula Individual , Bazo/citología , Bazo/inmunología
17.
Immunol Rev ; 284(1): 42-50, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29944756

RESUMEN

Germinal centers (GCs) are the primary sites of antibody affinity maturation, sites where B-cell antigen-receptor (BCR) genes rapidly acquire mutations and are selected for increasing affinity for antigen. This process of hypermutation and affinity-driven selection results in the clonal expansion of B cells expressing mutated BCRs and acts to hone the antibody repertoire for greater avidity and specificity. Remarkably, whereas the process of affinity maturation has been confirmed in a number of laboratories, models for how affinity maturation in GCs operates are largely from studies of genetically restricted B-cell populations competing for a single hapten epitope. Much less is known about GC responses to complex antigens, which involve both inter- and intraclonal competition for many epitopes. In this review, we (i) compare current methods for analysis of the GC B-cell repertoire, (ii) describe recent studies of GC population dynamics in response to complex antigens, discussing how the observed repertoire changes support or depart from the standard model of clonal selection, and (iii) speculate on the nature and potential importance of the large fraction of GC B cells that do not appear to interact with native antigen.


Asunto(s)
Antígenos/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Selección Clonal Mediada por Antígenos/genética , Selección Clonal Mediada por Antígenos/inmunología , Centro Germinal/citología , Humanos , Receptores de Antígenos de Linfocitos B/genética , Linfocitos T Colaboradores-Inductores/inmunología
18.
J Immunol ; 203(12): 3268-3281, 2019 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-31732530

RESUMEN

2F5 is an HIV-1 broadly neutralizing Ab that also binds the autoantigens kynureninase (KYNU) and anionic lipids. Generation of 2F5-like Abs is proscribed by immune tolerance, but it is unclear which autospecificity is responsible. We sampled the BCR repertoire of 2F5 knock-in mice before and after the first and second tolerance checkpoints. Nearly all small pre-B (precheckpoint) and 35-70% of anergic peripheral B cells (postcheckpoint) expressed the 2F5 BCR and maintained KYNU, lipid, and HIV-1 gp41 reactivity. In contrast, all postcheckpoint mature follicular (MF) B cells had undergone L chain editing that purged KYNU and gp41 binding but left lipid reactivity largely intact. We conclude that specificity for KYNU is the primary driver of tolerization of 2F5-expressing B cells. The MF and anergic B cell populations favored distinct collections of editor L chains; surprisingly, however, MF and anergic B cells also frequently expressed identical BCRs. These results imply that BCR autoreactivity is the primary determinant of whether a developing B cell enters the MF or anergic compartments, with a secondary role for stochastic factors that slightly mix the two pools. Our study provides mechanistic insights into how immunological tolerance impairs humoral responses to HIV-1 and supports activation of anergic B cells as a potential method for HIV-1 vaccination.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Hidrolasas/inmunología , Tolerancia Inmunológica/inmunología , Vacunas contra el SIDA/inmunología , Animales , Anticuerpos Monoclonales/genética , Anticuerpos ampliamente neutralizantes/genética , Reacciones Cruzadas , Femenino , Técnicas de Sustitución del Gen , Células HEK293 , Anticuerpos Anti-VIH/genética , Humanos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos B/inmunología
19.
J Immunol ; 203(12): 3282-3292, 2019 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-31704880

RESUMEN

Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the disruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines.


Asunto(s)
Anticuerpos Antivirales/inmunología , Inmunoglobulina A/inmunología , Vacunas de Partículas Similares a Virus/inmunología , Animales , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Infecciones por Caliciviridae/prevención & control , Humanos , Inmunidad Mucosa , Cambio de Clase de Inmunoglobulina/genética , Cambio de Clase de Inmunoglobulina/inmunología , Inmunoglobulina G/inmunología , Memoria Inmunológica , Ratones , Ratones Transgénicos , Norovirus/inmunología
20.
Immunol Rev ; 275(1): 79-88, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28133807

RESUMEN

Induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccine development. BNAbs are made during HIV infection by a subset of individuals but currently cannot be induced in the setting of vaccination. Considerable progress has been made recently in understanding host immunologic controls of bNAb induction and maturation in the setting of HIV infection, and point to key roles for both central and peripheral immunologic tolerance mechanisms in limiting bnAb development. Immune tolerance checkpoint inhibition has been transformative in promotion of anti-tumor CD8 T-cell responses in the treatment of certain malignancies. Here, we review the evidence for host controls of bNAb responses, and discuss strategies for the transient modulation of immune responses with vaccines toward the goal of enhancing germinal center B-cell responses to favor bNAb B-cell lineages and to foster their maturation to full neutralization potency.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/metabolismo , Linfocitos B/inmunología , Anticuerpos Anti-VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/inmunología , Animales , Linfocitos B/virología , Diferenciación Celular , Interacciones Huésped-Patógeno , Humanos , Tolerancia Inmunológica , Inmunidad Humoral
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA