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1.
J Immunol ; 197(12): 4663-4673, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27849170

RESUMEN

The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cross-reactive with the HIV broadly neutralizing Ab (bnAb) 2F5. Molecular mimicry of host proteins by pathogens can lead to autoimmune disease. In this article, we demonstrate that neither the 2F5 bnAb nor HIV MPER-KYNU cross-reactive Abs elicited by immunization with an MPER peptide-liposome vaccine in 2F5 bnAb VHDJH and VLJL knock-in mice and rhesus macaques modified KYNU activity or disrupted tissue tryptophan metabolism. Thus, molecular mimicry by HIV-1 Env that promotes the evasion of host anti-HIV-1 Ab responses can be directed toward nonfunctional host protein epitopes that do not impair host protein function. Therefore, the 2F5 HIV Env gp41 region is a key and safe target for HIV-1 vaccine development.


Asunto(s)
Vacunas contra el SIDA/inmunología , Proteína gp41 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/inmunología , Hidrolasas/metabolismo , Péptidos/metabolismo , Triptófano/metabolismo , Animales , Anticuerpos Neutralizantes/metabolismo , Reacciones Cruzadas , Anticuerpos Anti-VIH/metabolismo , Proteína gp41 de Envoltorio del VIH/genética , Proteína gp41 de Envoltorio del VIH/inmunología , Interacciones Huésped-Patógeno , Humanos , Hidrolasas/genética , Hidrolasas/inmunología , Evasión Inmune , Macaca mulatta , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Imitación Molecular , Péptidos/genética , Péptidos/inmunología , Vacunación , Vacunas de Subunidad
2.
J Immunol ; 192(7): 3269-79, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24591365

RESUMEN

We have shown that the protective HIV-1 Ab, 2F5, avidly reacts with a conserved mammalian self-Ag, kynureninase, and that the development of B cells specific for the 2F5 epitope is constrained by immunological tolerance. These observations suggest that the capacity to mount Ab responses to the 2F5 epitope is mitigated by tolerance, but such capacity may be latent in the pretolerance and/or anergic B cell pools. In this study, we use B cell tetramer reagents to track the frequencies of B cells that recognize the HIV-1 2F5 epitope (SP62): in C57BL/6 mice, SP62-binding transitional B cells are readily identified in bone marrow but are lost during subsequent development. Unsurprisingly then, immunization with SP62 immunogen does not elicit significant humoral responses in normal C57BL/6 mice. Reconstitution of Rag1(null) mice with normal congenic B cells that have matured in vitro restores the capacity to mount significant serum Ab and germinal center responses to this HIV-1 epitope. These B cell cultures are permissive for the development of autoreactive B cells and support the development of SP62-specific B cell compartments normally lost in 2F5 Ab knockin mice. The recovery of humoral responses to the 2F5/SP62 epitope of HIV-1 by reconstitution with B cells containing forbidden, autoreactive clones provides direct evidence that normal C57BL/6 mice latently possess the capacity to generate humoral responses to a conserved, neutralizing HIV-1 epitope.


Asunto(s)
Formación de Anticuerpos/inmunología , Antígenos Virales/inmunología , VIH-1/inmunología , Linfocitos/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Epítopos/metabolismo , Citometría de Flujo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/inmunología , Proteína gp41 de Envoltorio del VIH/inmunología , Proteína gp41 de Envoltorio del VIH/metabolismo , Tolerancia Inmunológica/inmunología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica/inmunología , Bazo/inmunología , Bazo/metabolismo
3.
Proc Natl Acad Sci U S A ; 108(28): 11560-5, 2011 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-21700885

RESUMEN

The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch- or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda(-/-) mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM-induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging self-reactive immature and transitional B cells during their maturation in the bone marrow.


Asunto(s)
Linfocitos B/enzimología , Linfocitos B/inmunología , Citidina Desaminasa/inmunología , Autotolerancia/inmunología , Animales , Apoptosis , Autoanticuerpos/sangre , Linfocitos B/citología , Ligando de CD40/deficiencia , Ligando de CD40/genética , Ligando de CD40/inmunología , Diferenciación Celular , Citidina Desaminasa/deficiencia , Citidina Desaminasa/genética , Femenino , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Precursoras de Linfocitos B/citología , Células Precursoras de Linfocitos B/enzimología , Células Precursoras de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Autotolerancia/genética , Transducción de Señal/inmunología , Hipermutación Somática de Inmunoglobulina
4.
J Immunol ; 186(10): 5603-11, 2011 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-21464091

RESUMEN

Long-lived humoral immune responses depend upon the generation of memory B cells and long-lived plasma cells during the germinal center (GC) reaction. These memory compartments, characterized by class-switched IgG and high-affinity Abs, are the basis for successful vaccination. We report that a new member of the plexin family of molecules, plexin-D1, controls the GC reaction and is required for secondary humoral immune responses. Plexin-D1 was not required for B cell maturation, marginal zone precursor development, dark and light zone formation, Igλ(+) and Igκ(+) B cell skewing, B1/B2 development, and the initial extrafollicular response. Plexin-D1 expression was increased following B cell activation, and PlxnD1(-/-) mice exhibited defective GC reactions during T-dependent immune activation. PlxnD1(-/-) B cells showed a defect in migration toward the GC chemokines, CXCL12, CXCL13, and CCL19. Accordingly, PlxnD1(-/-) mice exhibited defective production of IgG1 and IgG2b, but not IgG3 serum Ab, accompanied by reductions in long-lived bone marrow plasmacytes and recall humoral memory responses. These data show a new role for immune plexins in the GC reaction and generation of immunologic memory.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Inmunidad Humoral , Inmunoglobulina G/biosíntesis , Glicoproteínas de Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Animales , Subgrupos de Linfocitos B/inmunología , Quimiocina CCL19/deficiencia , Quimiocina CCL19/metabolismo , Quimiocina CXCL12/deficiencia , Quimiocina CXCL12/metabolismo , Quimiocina CXCL13/deficiencia , Quimiocina CXCL13/metabolismo , Ensayo de Inmunoadsorción Enzimática , Centro Germinal/citología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Memoria Inmunológica , Péptidos y Proteínas de Señalización Intracelular , Activación de Linfocitos , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Células Plasmáticas/inmunología
5.
J Immunol ; 187(7): 3785-97, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21908739

RESUMEN

The HIV-1 broadly neutralizing Ab (bnAb) 2F5 has been shown to be poly-/self-reactive in vitro, and we previously demonstrated that targeted expression of its VDJ rearrangement alone was sufficient to trigger a profound B cell developmental blockade in 2F5 V(H) knockin (KI) mice, consistent with central deletion of 2F5 H chain-expressing B cells. In this study, we generate a strain expressing the entire 2F5 bnAb specificity, 2F5 V(H) × V(L) KI mice, and find an even higher degree of tolerance control than observed in the 2F5 V(H) KI strain. Although B cell development was severely impaired in 2F5 V(H) × V(L) KI animals, we demonstrate rescue of their B cells when cultured in IL-7/BAFF. Intriguingly, even under these conditions, most rescued B cell hybridomas produced mAbs that lacked HIV-1 Envelope (Env) reactivity due to editing of the 2F5 L chain, and the majority of rescued B cells retained an anergic phenotype. Thus, when clonal deletion is circumvented, κ editing and anergy are additional safeguards preventing 2F5 V(H)/V(L) expression by immature/transitional B cells. Importantly, 7% of rescued B cells retained 2F5 V(H)/V(L) expression and secreted Env-specific mAbs with HIV-1-neutralizing activity. This partial rescue was further corroborated in vivo, as reflected by the anergic phenotype of most rescued B cells in 2F5 V(H) × V(L) KI × Eµ-Bcl-2 transgenic mice and significant (yet modest) enrichment of Env-specific B cells and serum Igs. The rescued 2F5 mAb-producing B cell clones in this study are the first examples, to our knowledge, of in vivo-derived bone marrow precursors specifying HIV-1 bnAbs and provide a starting point for design of strategies aimed at rescuing such B cells.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Linfocitos B/inmunología , Infecciones por VIH/inmunología , Tolerancia Inmunológica/inmunología , Animales , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Técnicas de Sustitución del Gen , Genes de Inmunoglobulinas/genética , Genes de Inmunoglobulinas/inmunología , VIH-1/inmunología , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
6.
Proc Natl Acad Sci U S A ; 107(1): 181-6, 2010 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-20018688

RESUMEN

We previously reported that some of the rare broadly reactive, HIV-1 neutralizing antibodies are polyreactive, leading to the hypothesis that induction of these types of neutralizing antibody may be limited by immunologic tolerance. However, the notion that such antibodies are sufficiently autoreactive to trigger B cell tolerance is controversial. To test directly whether rare neutralizing HIV-1 antibodies can activate immunologic tolerance mechanisms, we generated a knock-in mouse in which the Ig heavy chain (HC) variable region rearrangement (V(H)DJ(H)) from the polyreactive and broadly neutralizing human monoclonal antibody 2F5 was targeted into the mouse Igh locus. In vitro, this insertion resulted in chimeric human/mouse 2F5 antibodies that were functionally similar to the human 2F5 antibody, including comparable reactivity to human and murine self-antigens. In vivo, the 2F5 V(H)DJ(H) insertion supported development of large- and small pre-B cells that expressed the chimeric human/mouse Igmu chain but not the production of immature B cells expressing membrane IgM. The developmental arrest exhibited in 2F5 V(H)DJ(H) knock-in mice is characteristic of other knock-in strains that express the Ig HC variable region of autoreactive antibodies and is consistent with the loss of immature B cells bearing 2F5 chimeric antibodies to central tolerance mechanisms. Moreover, homozygous 2F5 V(H)DJ(H) knock-in mice support reduced numbers of residual splenic B cells with low surface IgM density, severely diminished serum IgM levels, but normal to elevated quantities of serum IgGs that did not react with autoantigens. These features are consistent with elimination of 2F5 HC autoreactivity by additional negative selection mechanism(s) in the periphery.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Tolerancia Inmunológica/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/inmunología , Animales , Anticuerpos Neutralizantes/genética , Autoantígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/fisiología , Línea Celular , Femenino , Técnicas de Sustitución del Gen , Reordenamiento Génico , VIH-1/genética , Humanos , Tolerancia Inmunológica/genética , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Bazo/citología
7.
J Immunol ; 183(4): 2708-17, 2009 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-19625640

RESUMEN

Successful vaccines (i.e., tetanus and diphtheria) can induce long-lived Ab levels that are maintained by bone marrow plasma cells and plasma Ab levels do not correlate with numbers of blood memory B cells. Destruction of CD4(+) T cells early in HIV-1 acute infection may result in insufficient induction of neutralizing Ab responses; thus, an HIV-1 vaccine should elicit high levels of durable Abs by long-lived plasma cells to be protective. We asked if HIV-1 envelope-specific memory responses were sustained by memory B cells in the settings of HIV-1 gp120 envelope vaccination and chronic HIV-1 infection. Levels of anti-HIV-1 envelope plasma Abs and memory B cells were found to correlate in both settings. Moreover, whereas the expected half-life of plasma Ab levels to protein vaccines was >10 years when maintained by long-lived plasma cells, anti-envelope Ab level half-lives were approximately 33-81 wk in plasma from antiretroviral drug-treated HIV-1(+) subjects. In contrast, anti-p55 Gag Ab level half-life was 648 wk, and Ab titers against influenza did not decay in-between yearly or biennial influenza vaccine boosts in the same patients. These data demonstrated that HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma Abs in the settings of envelope vaccination and HIV-1 infection. The inability to generate high titers of long-lived anti-envelope Abs is a major hurdle to overcome for the development of a successful HIV-1 vaccine.


Asunto(s)
Vacunas contra el SIDA/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/virología , Anticuerpos Anti-VIH/sangre , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Memoria Inmunológica , Vacunas contra el SIDA/administración & dosificación , Adulto , Secuencia de Aminoácidos , Subgrupos de Linfocitos B/metabolismo , Células Cultivadas , Enfermedad Crónica , Femenino , Anticuerpos Anti-VIH/biosíntesis , Proteína gp120 de Envoltorio del VIH/administración & dosificación , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular
8.
Int J Exp Pathol ; 91(5): 472-83, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20804539

RESUMEN

Oil granuloma (OG) induced by intraperitoneal injection of pristane represents a non-infectious granuloma. Oil granuloma has been characterized, but the regulation of its formation still remains unknown. To address this, we injected pristane into various mice deficient for genes including, linker for activation of T cells (LAT), µMT, LTα, TNFα, IL-6. T cell deficient mice (LAT(-/-) ) responded to pristane by developing serosal granuloma and mesenteric granuloma (MG) as in wild type mice. The absence of B cells blocked serosal granuloma (SG) formation and diminished MG development in response to pristane. However, even when a comparable number of B cells were present in the mesentery, the absence of TNFα resulted in similar defects in OG formation after pristane treatment, demonstrating that both B cells and TNFα are very crucial for pristane-induced OG formation. Interestingly, IL-6(-/-) mice had intact MG formation; however, SG organization was impaired. These studies provide insight into granulomateous pathology induced by non-infectious substances for example, biomedical sutures.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Granuloma , Interleucina-6/genética , Linfotoxina-alfa/genética , Proteínas de la Membrana/genética , Fosfoproteínas/genética , Terpenos/toxicidad , Factor de Necrosis Tumoral alfa/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Linfocitos B/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Granuloma/inducido químicamente , Granuloma/genética , Granuloma/inmunología , Inmunosupresores/toxicidad , Interleucina-6/inmunología , Tejido Linfoide/inmunología , Linfotoxina-alfa/inmunología , Masculino , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Fosfoproteínas/inmunología , Factor de Necrosis Tumoral alfa/inmunología
9.
J Exp Med ; 210(2): 241-56, 2013 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-23359068

RESUMEN

Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance because mice expressing the V(H) and V(L) regions of 2F5 have a block in B cell development that is characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. We identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Autoantígenos/inmunología , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/inmunología , Autoantígenos/química , Autoantígenos/genética , Linfocitos B/inmunología , Línea Celular , Secuencia Conservada , Epítopos/química , Epítopos/genética , Epítopos/inmunología , Proteína gp41 de Envoltorio del VIH/química , Proteína gp41 de Envoltorio del VIH/inmunología , Humanos , Hidrolasas/química , Hidrolasas/genética , Hidrolasas/inmunología , Interacciones Hidrofóbicas e Hidrofílicas , Tolerancia Inmunológica , Inmunización , Ratones , Zarigüeyas/inmunología , Filogenia , Factores de Empalme de ARN , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
10.
J Immunol Methods ; 354(1-2): 53-67, 2010 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-20109461

RESUMEN

We describe and characterize a stromal cell independent culture system that efficiently supports pro-B cell to IgM+ B cell development with near normal levels of IgH and Igkappa diversity. Pro-B cells present in non-adherent bone marrow cells proliferate in the presence of IL-7 and subsequent to the removal of IL-7 and addition of BAFF, differentiate normally into IgM+ B cells. B cell development in vitro closely follows the patterns of development in vivo with culture-derived (CD) B cells demonstrating characteristic patterns of surface antigen expression and gene activation. IgM+ CD B cells respond to TLR stimulation by proliferation and differentiation into antibody-secreting cells. Self-reactive IgM+ B cell development is blocked in 3H9 IgH knockin mice; however, cultures of 3H9 IgH knockin pro-B cells yields high frequencies of "forbidden", autoreactive IgM+ B cells. Furthermore, serum IgG autoantibody exceeded that present in autoimmune, C4(-/-) animals following the reconstitution of RAG1(-/-) mice with IgM+ CD cells derived from BL/6 mice.


Asunto(s)
Autoinmunidad , Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Diferenciación Celular , Proliferación Celular , Isotipos de Inmunoglobulinas/metabolismo , Células Precursoras de Linfocitos B/inmunología , Células del Estroma/inmunología , Animales , Formación de Anticuerpos , Antígenos de Superficie/metabolismo , Autoanticuerpos/sangre , Autoinmunidad/genética , Factor Activador de Células B/metabolismo , Técnicas de Cultivo de Célula , Diferenciación Celular/genética , Supervivencia Celular , Células Cultivadas , Complemento C4/deficiencia , Complemento C4/genética , Citometría de Flujo , Perfilación de la Expresión Génica , Reordenamiento Génico de Linfocito B , Genotipo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Inmunoglobulina D/metabolismo , Isotipos de Inmunoglobulinas/genética , Inmunoglobulina M/metabolismo , Inmunofenotipificación , Interleucina-7/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fenotipo , Factores de Tiempo , Receptores Toll-Like/agonistas
11.
PLoS One ; 4(10): e7215, 2009 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-19806186

RESUMEN

The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi) subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a) (BALB/c) and Igh(b) (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a) locus. Mapping of MPER gp41 interactions with IgM(a) identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H) regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a) determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses.


Asunto(s)
Receptor del Factor Activador de Células B/metabolismo , Linfocitos B/virología , Antígenos CD79/metabolismo , Membrana Celular/metabolismo , Proteína gp41 de Envoltorio del VIH/metabolismo , VIH-1/metabolismo , Animales , Epítopos/química , Femenino , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Unión Proteica , Transducción de Señal , Bazo/metabolismo
12.
Immunity ; 24(6): 667-669, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16782021

RESUMEN

Toll-like receptors (TLRs) modulate immune responses indirectly by promoting the efficacy of antigen presentation. In this issue of Immunity, Nagai et al. (2006) demonstrate that TLR signals also bias hematopoietic progenitor cells toward myelopoiesis directly by replacing cytokine and differentiative cues.


Asunto(s)
Células Madre Hematopoyéticas/citología , Mielopoyesis , Receptores Toll-Like/metabolismo , Animales , Células Madre Hematopoyéticas/metabolismo , Ratones
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