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1.
Immunity ; 47(1): 159-170.e10, 2017 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-28723548

RESUMEN

Clearance of pathogens or tumor cells by antibodies traditionally requires both Fab and Fc domains of IgG. Here, we show the Fc domain of IgG alone mediates recognition and clearance of herpes simplex virus (HSV1)-infected cells. The human natural killer (NK) cell surface is naturally coated with IgG bound by its Fc domain to the Fcγ receptor CD16a. NK cells utilize the Fc domain of bound IgG to recognize gE, an HSV1-encoded glycoprotein that also binds the Fc domain of IgG but at a site distinct from CD16a. The bridge formed by the Fc domain between the HSV1-infected cell and the NK cell results in NK cell activation and lysis of the HSV1-infected cell in the absence of HSV1-specific antibody in vitro and prevents fatal HSV1 infection in vivo. This mechanism also explains how bacterial IgG-binding proteins regulate NK cell function and may be broadly applicable to Fcγ-receptor-bearing cells.


Asunto(s)
Anticuerpos Antivirales/metabolismo , Herpes Simple/inmunología , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/metabolismo , Células Asesinas Naturales/inmunología , Simplexvirus/inmunología , Animales , Anticuerpos Antivirales/inmunología , Células Cultivadas , Citotoxicidad Inmunológica , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Unión Proteica , Agregación de Receptores , Receptores de IgG/metabolismo , Transducción de Señal , Proteínas Virales/inmunología
3.
Biochem Biophys Res Commun ; 644: 25-33, 2023 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-36621149

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein.


Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Estudio de Asociación del Genoma Completo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Cuerpos de Lewy/metabolismo , Antígenos HLA
4.
Cell ; 132(6): 935-44, 2008 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-18358807

RESUMEN

Glycoprotein B (gB) is one of the essential components for infection by herpes simplex virus-1 (HSV-1). Although several cellular receptors that associate with glycoprotein D (gD), such as herpes virus entry mediator (HVEM) and Nectin-1, have been identified, specific molecules that mediate HSV-1 infection by associating with gB have not been elucidated. Here, we found that paired immunoglobulin-like type 2 receptor (PILR) alpha associates with gB, and cells transduced with PILRalpha become susceptible to HSV-1 infection. Furthermore, HSV-1 infection of human primary cells expressing both HVEM and PILRalpha was blocked by either anti-PILRalpha or anti-HVEM antibody. Our results demonstrate that cellular receptors for both gB and gD are required for HSV-1 infection and that PILRalpha plays an important role in HSV-1 infection as a coreceptor that associates with gB. These findings uncover a crucial aspect of the mechanism underlying HSV-1 infection.


Asunto(s)
Herpes Simple/metabolismo , Herpesvirus Humano 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Virales/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Células CHO , Línea Celular , Células Cultivadas , Cricetinae , Cricetulus , Herpes Simple/virología , Humanos , Transfección
5.
Nature ; 552(7683): 101-105, 2017 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-29186116

RESUMEN

Malaria is among the most serious infectious diseases affecting humans, accounting for approximately half a million deaths each year. Plasmodium falciparum causes most life-threatening cases of malaria. Acquired immunity to malaria is inefficient, even after repeated exposure to P. falciparum, but the immune regulatory mechanisms used by P. falciparum remain largely unknown. Here we show that P. falciparum uses immune inhibitory receptors to achieve immune evasion. RIFIN proteins are products of a polymorphic multigene family comprising approximately 150-200 genes per parasite genome that are expressed on the surface of infected erythrocytes. We found that a subset of RIFINs binds to either leucocyte immunoglobulin-like receptor B1 (LILRB1) or leucocyte-associated immunoglobulin-like receptor 1 (LAIR1). LILRB1-binding RIFINs inhibit activation of LILRB1-expressing B cells and natural killer (NK) cells. Furthermore, P. falciparum-infected erythrocytes isolated from patients with severe malaria were more likely to interact with LILRB1 than erythrocytes from patients with non-severe malaria, although an extended study with larger sample sizes is required to confirm this finding. Our results suggest that P. falciparum has acquired multiple RIFINs to evade the host immune system by targeting immune inhibitory receptors.


Asunto(s)
Evasión Inmune/inmunología , Receptor Leucocitario Tipo Inmunoglobulina B1/inmunología , Proteínas de la Membrana/inmunología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Receptores Inmunológicos/inmunología , Secuencia de Aminoácidos , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células CHO , Cricetulus , Eritrocitos/inmunología , Eritrocitos/parasitología , Células HEK293 , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Receptor Leucocitario Tipo Inmunoglobulina B1/química , Ligandos , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Malaria Falciparum/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Receptores Inmunológicos/química , Tamaño de la Muestra
6.
Biochem Biophys Res Commun ; 613: 41-46, 2022 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-35526487

RESUMEN

Varicella-zoster virus (VZV) first infects hematopoietic cells, with the infected cells then acting to distribute the virus throughout the body. Sialic acid-binding immunoglobulin-like lectin (Siglec) family molecules recognize sialic acid-containing molecules on the same cell surface, called cis-ligands, or molecules on other cells or soluble agents, called trans-ligands. Among the Siglec family molecules, Siglec-4 and Siglec-7 mediate VZV infection through association with glycoprotein B (gB). As Siglec-7, but not Siglec-4, is expressed on hematopoietic cells such as monocytes, the regulatory mechanism by which Siglec-7 associates with gB is important to our understanding of VZV infection of blood cells. Here, we found that Siglec-7 is required for VZV to infect human primary monocytes. Furthermore, treatment of primary monocytes with sialidase enhanced both VZV gB binding to monocytes and VZV infectivity. Calcium influx in primary monocytes decreased the expression of Siglec-7 cis-ligands and increased VZV infectivity. These results demonstrate that the Siglec-7 cis-ligands present on primary monocytes play an important role in VZV infection through regulation of the interaction between gB and Siglec-7.


Asunto(s)
Antígenos de Diferenciación Mielomonocítica , Herpesvirus Humano 3 , Lectinas , Monocitos , Antígenos de Diferenciación Mielomonocítica/metabolismo , Herpesvirus Humano 3/fisiología , Humanos , Lectinas/metabolismo , Ligandos , Monocitos/virología , Ácido N-Acetilneuramínico , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Infección por el Virus de la Varicela-Zóster/metabolismo , Infección por el Virus de la Varicela-Zóster/virología
7.
Biochem Biophys Res Commun ; 607: 67-72, 2022 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-35367830

RESUMEN

Sialic acid immunoglobulin-like lectin (Siglec) family molecules are immune regulatory receptors that bind to specific molecules containing sialic acids. Varicella-zoster virus (VZV), a member of the herpesvirus family, infects hematopoietic cells and spreads throughout the body, causing chickenpox, shingles, and, sometimes fatal encephalomyelitis. However, the cellular entry receptors that are required for VZV to infect hematopoietic cells have remained unclear. Here, we found that Siglec-7, mainly expressed on hematopoietic cells, binds to VZV envelope glycoprotein B in a sialic acid-dependent manner. Furthermore, Siglec-7 mediated VZV infection by inducing membrane fusion. Our findings provide the first evidence for a molecular mechanism by which VZV infects hematopoietic cells.


Asunto(s)
Antígenos de Diferenciación Mielomonocítica , Varicela , Herpes Zóster , Lectinas , Antígenos de Diferenciación Mielomonocítica/metabolismo , Herpesvirus Humano 3 , Humanos , Lectinas/metabolismo , Ácido N-Acetilneuramínico , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Proteínas del Envoltorio Viral
8.
Antimicrob Agents Chemother ; 65(10): e0049421, 2021 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-34228537

RESUMEN

The antiherpetic drug amenamevir (AMNV) inhibits the helicase-primase complex of herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus directly as well as inhibiting the replication of these viruses. Although several mutated HSV viruses resistant to helicase-primase inhibitors have been reported, the mutations contributing to the resistance remain unclear, as recombinant viruses containing a single mutation have not been analyzed. We obtained AMNV-resistant viruses with amino acid substitutions by several passages under AMNV treatment. Twenty HSV-1 and 19 HSV-2 mutants with mutation(s) in UL5 helicase and/or UL52 primase, but not in cofactor UL8, were isolated. The mutations in UL5 were located downstream of motif IV, with UL5 K356N in HSV-1 and K355N in HSV-2, in particular, identified as having the highest frequency, which was 9/20 and 9/19, respectively. We generated recombinant AMNV-resistant HSV-1 with a single amino acid substitution using bacterial artificial chromosome (BAC) mutagenesis. As a result, G352C in UL5 helicase and F360C/V and N902T in UL52 primase were identified as novel mutations. The virus with K356N in UL5 showed 10-fold higher AMNV resistance than did other mutants and showed equivalent viral growth in vitro and virulence in vivo as the parent HSV-1, although other mutants showed attenuated virulence. All recombinant viruses were susceptible to the other antiherpetic drugs, acyclovir and foscarnet. In conclusion, based on BAC mutagenesis, this study identified, for the first time, mutations in UL5 and UL52 that contributed to AMNV resistance and found that a mutant with the most frequent K356N mutation in HSV-1 maintained viral growth and virulence equivalent to the parent virus.


Asunto(s)
ADN Primasa , Herpesvirus Humano 1 , ADN Helicasas/genética , ADN Primasa/genética , Herpesvirus Humano 1/genética , Oxadiazoles , Proteínas Virales/genética
9.
Biochem Biophys Res Commun ; 534: 680-686, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33208230

RESUMEN

Type 1 diabetes (T1D) is an autoimmune disease caused by destruction of insulin-producing ß cells. The response of autoreactive T cells to ß cell antigens plays a central role in the development of T1D. Recently, fusion peptides composed by insulin C-peptide fragments and other proteins were reported as ß cell target antigens for diabetogenic CD4+ T cells in non-obese diabetic (NOD) mice. In this study, we generated a T cell-receptor (TCR)-like monoclonal antibody (mAb) against a fusion peptide bound to major histocompatibility complex (MHC) class II component to elucidate the function of the fusion peptides in T1D. In addition, we developed a novel NFAT-GFP TCR reporter system to evaluate the TCR-like mAb. The NFAT-GFP reporter T cells expressing the diabetogenic TCR were specifically activated by the fusion peptide presented on the MHC class II molecules. By using the NFAT-GFP reporter T cells, we showed that the TCR-like mAb blocks the diabetogenic T cell response against the fusion peptide presented on the MHC class II molecules. Furthermore, the development of T1D was ameliorated when pre-diabetic NOD mice were treated with this mAb. These findings suggest that NFAT-GFP reporter T cells are useful to assess the function of specific TCR and the recognition of fusion peptides by T cells is crucial for the pathogenesis of T1D.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Diabetes Mellitus Tipo 1/prevención & control , Proinsulina/antagonistas & inhibidores , Proinsulina/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Péptido C/antagonistas & inhibidores , Péptido C/genética , Péptido C/inmunología , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/inmunología , Progresión de la Enfermedad , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Ratones , Ratones Endogámicos NOD , Proinsulina/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Linfocitos T/inmunología
10.
Biochem Biophys Res Commun ; 548: 167-173, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33647792

RESUMEN

Plasmodium falciparum causes the most severe form of malaria. Acquired immunity against P. falciparum provides insufficient protection even after repeated infections. Therefore, P. falciparum parasites might exploit inhibitory receptors for immune evasion. P. falciparum RIFINs are products of a multigene family consisting of 150-200 genes. Previously, we demonstrated that some RIFINs downregulate the immune response through the leukocyte immunoglobulin-like receptor (LILR) family inhibitory receptor, LILRB1, and leukocyte-associated immunoglobulin-like receptor 1, LAIR1. In this study, we further analyzed the expression of inhibitory receptor ligands on P. falciparum-infected erythrocytes and found that P. falciparum-infected erythrocytes expressed ligands for another LILR family inhibitory receptor, LILRB2, that recognizes HLA class I molecules as a host ligand. Furthermore, we identified that a specific RIFIN was a ligand for LILRB2 by using a newly developed RIFIN expression library. In addition, the domain 3 of LILRB2 was involved in RIFIN binding, whereas the domains 1 and 2 of LILRB2 were involved in the binding to HLA class I molecules. These results suggest that inhibitory receptor LILRB2 is also targeted by RIFIN for immune evasion of P. falciparum similar to LILRB1 and LAIR1.


Asunto(s)
Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Eritrocitos/parasitología , Femenino , Células HEK293 , Humanos , Ligandos , Malaria Falciparum/parasitología , Glicoproteínas de Membrana/química , Ratones Endogámicos BALB C , Unión Proteica , Dominios Proteicos , Receptores Inmunológicos/química
11.
Int Immunol ; 31(5): 303-314, 2019 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-30721990

RESUMEN

Natural killer (NK) cells are a major FcγRIIIA-expressing lymphocyte population that mediate antibody-dependent cellular cytotoxicity. Although NK cells are critical for immunity against viruses and tumors, they are also activated in the joints of patients with rheumatoid arthritis (RA) and may be involved in disease progression. We previously found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins, such as IgG heavy chain (IgGH), to the cell surface via association with their peptide-binding grooves. Furthermore, we found that IgGHs bound to HLA class II molecules encoded by RA susceptibility alleles are specific targets for rheumatoid factor, an auto-antibody involved in RA. Here, we report that IgGHs bound to HLA class II molecules preferentially stimulate FcγRIIIA-expressing but not FcγRI-expressing cells. A significant correlation was observed between the reactivity of FcγRIIIA-expressing cells to IgGH complexed with a specific HLA-DR allele and the odds ratio for HLA-DR allele's association with RA. Moreover, primary human NK cells expressing FcγRIIIA demonstrated IFN-γ production and cytotoxicity against cells expressing IgGH complexed with HLA class II molecules. Our findings suggest that IgGH complexed with HLA class II molecules are involved in the activation of FcγRIIIA-expressing NK cells observed within arthritic joints.


Asunto(s)
Antígenos de Histocompatibilidad Clase II/inmunología , Inmunoglobulina G/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Células Asesinas Naturales/inmunología , Receptores de IgG/inmunología , Células HEK293 , Humanos
12.
Biochem Biophys Res Commun ; 511(4): 862-868, 2019 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-30850159

RESUMEN

HLA class I molecules play a central role in the immune system by presenting peptide antigens to cytotoxic T cells. Although most HLA class I molecules are associated with ß2-microglobulin, HLA class I heavy chain that is not associated with ß2-microglobulin is also expressed on certain cells. We recently found that cellular misfolded proteins are transported to the cell surface by HLA class II molecules via association with their peptide-binding grooves. Furthermore, misfolded self-antigens bound to autoimmune disease-susceptible HLA class II molecules are the targets for autoantibodies produced in certain autoimmune diseases. In the present study, we found that misfolded proteins were also transported to the cell surface by specific HLA class I molecules including HLA-B27, which is strongly associated with ankylosing spondylitis. In addition, the efficiency with which HLA class I molecules encoded by each allele transport misfolded proteins to the cell surface was significantly correlated with HLA class I free heavy chain expression on that surface. Moreover, misfolded proteins were coprecipitated with HLA class I free heavy chain but not with correctly folded HLA class I molecules. These findings reveal a novel function of HLA class I molecules to transport misfolded proteins to the cell surface, which might help us to understand the pathogenesis of HLA class I-associated diseases.


Asunto(s)
Antígeno HLA-B27/metabolismo , Deficiencias en la Proteostasis/metabolismo , Espondilitis Anquilosante/metabolismo , Animales , Pollos , Células HEK293 , Humanos , Muramidasa/metabolismo , Pliegue de Proteína , Transporte de Proteínas , Proteostasis , Microglobulina beta-2/metabolismo
13.
Biochem Biophys Res Commun ; 509(1): 216-221, 2019 01 29.
Artículo en Inglés | MEDLINE | ID: mdl-30587340

RESUMEN

Major histocompatibility complex class II (MHC II) molecules are mainly expressed on antigen presentation cells and play an important role in immune response. It has been reported that MHC II molecules are also detected in serum as a soluble form (sMHC II molecules), and they are considered to be involved in the maintenance of self-tolerance. However, the mechanism by which sMHC II molecules are produced remains unclear. Invariant chain (Ii), also called CD74, plays an important role in antigen presentation of MHC II molecules. In the present study, we analyzed the role of Ii on the production of sMHC II molecules. We found that the amount of sMHC II molecules in serum was decreased in Ii-deficient mice compared to wild-type mice. sMHC II molecules were secreted from cells transfected with MHC II molecules and Ii but not from cells transfected with MHC II molecules alone. Moreover, isoform p41 of Ii-transfected cells induced more sMHC II molecules compared to isoform p31-transfected cells. The molecular weight of sMHC II molecules from MHC II and Ii p41-transfected cells was approximately 60 kDa, indicating that sMHC II molecules are a single heterodimer of α and ß chains that is not associated with micro-vesicles. From the analysis of Ii-deletion mutants, we found that the luminal domain of Ii p41 is crucial for the production of sMHC II molecules. These results suggested that Ii has an important role in production of sMHC II molecules.


Asunto(s)
Antígenos de Diferenciación de Linfocitos B/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Animales , Antígenos de Diferenciación de Linfocitos B/sangre , Antígenos de Diferenciación de Linfocitos B/genética , Eliminación de Gen , Células HEK293 , Antígenos de Histocompatibilidad Clase II/sangre , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Isoformas de Proteínas/sangre , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Solubilidad , Transfección
14.
Blood ; 125(18): 2835-44, 2015 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-25733579

RESUMEN

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. ß2-glycoprotein I (ß2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact ß2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize ß2GPI/HLA class II complexes in the absence of phospholipids. In situ association between ß2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against ß2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that ß2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis.


Asunto(s)
Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido , Antígenos de Histocompatibilidad Clase II/inmunología , Complejos Multiproteicos/inmunología , beta 2 Glicoproteína I/inmunología , Adulto , Anciano , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/sangre , Síndrome Antifosfolípido/inmunología , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Células Cultivadas , Femenino , Células HEK293 , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/inmunología , beta 2 Glicoproteína I/metabolismo
15.
Proc Natl Acad Sci U S A ; 111(10): 3787-92, 2014 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-24567378

RESUMEN

Specific HLA class II alleles are strongly associated with susceptibility to rheumatoid arthritis (RA); however, how HLA class II regulates susceptibility to RA has remained unclear. Recently, we found a unique function of HLA class II molecules: their ability to aberrantly transport cellular misfolded proteins to the cell surface without processing to peptides. Rheumatoid factor (RF) is an autoantibody that binds to denatured IgG or Fc fragments of IgG and is detected in 70-80% of RA patients but also in patients with other diseases. Here, we report that intact IgG heavy chain (IgGH) is transported to the cell surface by HLA class II via association with the peptide-binding groove and that IgGH/HLA class II complexes are specifically recognized by autoantibodies in RF-positive sera from RA patients. In contrast, autoantibodies in RF-positive sera from non-RA individuals did not bind to IgGH/HLA class II complexes. Of note, a strong correlation between autoantibody binding to IgG complexed with certain HLA-DR alleles and the odds ratio for that allele's association with RA was observed (r = 0.81; P = 4.6 × 10(-5)). Our findings suggest that IgGH complexed with certain HLA class II alleles is a target for autoantibodies in RA, which might explain why these HLA class II alleles confer susceptibility to RA.


Asunto(s)
Artritis Reumatoide/inmunología , Autoanticuerpos/inmunología , Susceptibilidad a Enfermedades/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunoglobulina G/inmunología , Artritis Reumatoide/etiología , Cartilla de ADN/genética , ADN Complementario/genética , Citometría de Flujo , Células HEK293 , Humanos , Immunoblotting , Inmunoprecipitación , Oportunidad Relativa , Plásmidos/genética , Pliegue de Proteína
16.
J Biol Chem ; 290(32): 19833-43, 2015 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-26105052

RESUMEN

Varicella-zoster virus (VZV) is a member of the human Herpesvirus family that causes varicella (chicken pox) and zoster (shingles). VZV latently infects sensory ganglia and is also responsible for encephalomyelitis. Myelin-associated glycoprotein (MAG), a member of the sialic acid (SA)-binding immunoglobulin-like lectin family, is mainly expressed in neural tissues. VZV glycoprotein B (gB) associates with MAG and mediates membrane fusion during VZV entry into host cells. The SA requirements of MAG when associating with its ligands vary depending on the specific ligand, but it is unclear whether the SAs on gB are involved in the association with MAG. In this study, we found that SAs on gB are essential for the association with MAG as well as for membrane fusion during VZV infection. MAG with a point mutation in the SA-binding site did not bind to gB and did not mediate cell-cell fusion or VZV entry. Cell-cell fusion and VZV entry mediated by the gB-MAG interaction were blocked by sialidase treatment. N-glycosylation or O-glycosylation inhibitors also inhibited the fusion and entry mediated by gB-MAG interaction. Furthermore, gB with mutations in N-glycosylation sites, i.e. asparagine residues 557 and 686, did not associate with MAG, and the cell-cell fusion efficiency was low. Fusion between the viral envelope and cellular membrane is essential for host cell entry by herpesviruses. Therefore, these results suggest that SAs on gB play important roles in MAG-mediated VZV infection.


Asunto(s)
Células Epiteliales/metabolismo , Herpesvirus Humano 3/metabolismo , Glicoproteína Asociada a Mielina/metabolismo , Neuroglía/metabolismo , Polisacáridos/química , Ácidos Siálicos/química , Proteínas del Envoltorio Viral/química , Línea Celular Tumoral , Células Epiteliales/patología , Células Epiteliales/virología , Glicosilación , Células HEK293 , Herpesvirus Humano 3/química , Herpesvirus Humano 3/genética , Interacciones Huésped-Patógeno , Humanos , Fusión de Membrana , Glicoproteína Asociada a Mielina/química , Glicoproteína Asociada a Mielina/genética , Neuraminidasa/química , Neuraminidasa/genética , Neuraminidasa/metabolismo , Neuroglía/patología , Neuroglía/virología , Mutación Puntual , Polisacáridos/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ácidos Siálicos/metabolismo , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus
17.
Int Immunol ; 27(6): 307-14, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25710489

RESUMEN

Inflammatory bowel disease is thought to be a complex multifactorial disease, in which an increased inflammatory response plays an important role. Paired immunoglobulin-like type 2 receptor α (PILRα), well conserved in almost all mammals, is an inhibitory receptor containing immunoreceptor tyrosine-based inhibitory motifs in the cytoplasmic domain. PILRα is mainly expressed on myeloid cells and plays an important role in the regulation of inflammation. In the present study, we investigated the function of PILRα in inflammatory bowel disease using PILRα-deficient mice. When mice were orally administered dextran sulfate sodium (DSS), colonic mucosal injury and inflammation were significantly exacerbated in DSS-treated PILRα-deficient mice compared with wild-type (WT) mice. Flow cytometric analysis revealed that neutrophil and macrophage cell numbers were higher in the colons of DSS-treated PILRα-deficient mice than in those of WT mice. Blockade of CXCR2 expressed on neutrophils using a CXCR2 inhibitor decreased the severity of colitis observed in PILRα-deficient mice. These results suggest that PILRα negatively regulates inflammatory colitis by regulating the infiltration of inflammatory cells such as neutrophils and macrophages.


Asunto(s)
Colitis/inmunología , Colon/fisiología , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Macrófagos/fisiología , Neutrófilos/fisiología , Receptores Inmunológicos/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Colitis/inducido químicamente , Colon/patología , Sulfato de Dextran/administración & dosificación , Progresión de la Enfermedad , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Modelos Animales , Receptores Inmunológicos/genética , Receptores de Interleucina-8B/antagonistas & inhibidores
18.
Nature ; 467(7317): 859-62, 2010 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-20944748

RESUMEN

Herpes simplex virus-1 (HSV-1), the prototype of the α-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis. HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD). However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo remain unknown. Here we show that non-muscle myosin heavy chain IIA (NMHC-IIA), a subunit of non-muscle myosin IIA (NM-IIA), functions as an HSV-1 entry receptor by interacting with gB. A cell line that is relatively resistant to HSV-1 infection became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell-cell fusion when gB, gD, gH and gL were coexpressed. Cell-surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. A specific inhibitor of myosin light chain kinase, which regulates NM-IIA by phosphorylation, reduced the redistribution of NMHC-IIA as well as HSV-1 infection in cell culture and in a murine model for herpes stromal keratitis. NMHC-IIA is ubiquitously expressed in various human tissues and cell types and, therefore, is implicated as a functional gB receptor that mediates broad HSV-1 infectivity both in vitro and in vivo. The identification of NMHC-IIA as an HSV-1 entry receptor and the involvement of NM-IIA regulation in HSV-1 infection provide an insight into HSV-1 entry and identify new targets for antiviral drug development.


Asunto(s)
Herpesvirus Humano 1/fisiología , Miosina Tipo IIA no Muscular/metabolismo , Receptores Virales/metabolismo , Adsorción , Animales , Azepinas/farmacología , Células CHO , Fusión Celular , Chlorocebus aethiops , Cricetinae , Cricetulus , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HL-60 , Herpes Simple/virología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/metabolismo , Humanos , Ratones , Quinasa de Cadena Ligera de Miosina/antagonistas & inhibidores , Naftalenos/farmacología , Miosina Tipo IIA no Muscular/deficiencia , Miosina Tipo IIA no Muscular/genética , Temperatura , Regulación hacia Arriba , Células Vero , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus/efectos de los fármacos
19.
J Virol ; 87(19): 10900-3, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23885076

RESUMEN

The human herpesvirus 6 (HHV-6) envelope glycoprotein gH/gL/gQ1/gQ2 complex associates with host cell CD46 as its cellular receptor. Although gB has been suggested to be involved in HHV-6 infection, its function in membrane fusion has remained unclear. Here, we have developed an HHV-6A (strain GS)and HHV-6B (strain Z29) virus-free cell-to-cell fusion assay and demonstrate that gB and the gH/gL/gQ1/gQ2 complex are the minimum components required for membrane fusion by HHV-6.


Asunto(s)
Fusión Celular , Glicoproteínas/metabolismo , Infecciones por Herpesviridae/metabolismo , Herpesvirus Humano 6/fisiología , Proteína Cofactora de Membrana/metabolismo , Fusión de Membrana , Células Cultivadas , ADN Viral/genética , Citometría de Flujo , Glicoproteínas/clasificación , Glicoproteínas/genética , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/virología , Humanos , Riñón/citología , Riñón/metabolismo , Riñón/virología , Luciferasas/metabolismo , Proteína Cofactora de Membrana/genética , Reacción en Cadena de la Polimerasa
20.
Int Immunol ; 25(4): 235-46, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23334921

RESUMEN

Nascent MHC class II molecules are associated with the invariant chain and are transported to the endolysosomal pathway, where MHC class II molecules acquire peptide antigens. On the other hand, misfolded endoplasmic reticulum (ER) proteins are generally degraded in the cells and are neither expressed on the cell surface nor secreted. Here, we found that MHC class II molecules associate with some misfolded ER proteins via the peptide-binding groove in competition with invariant chain. The misfolded proteins associated with MHC class II molecules are transported intact to the cell surface without processing to peptides. Furthermore, these complexes efficiently stimulate antigen-specific B cells. These findings reveal that MHC class II molecules function as a chaperone for the cell surface expression of misfolded ER proteins. In addition, we suggest that MHC class II molecules present not only peptides but also intact host-cell-derived proteins on the cell surface. These findings provide new insights into the function of MHC class II molecules.


Asunto(s)
Autoantígenos/metabolismo , Linfocitos B/inmunología , Membrana Celular/metabolismo , Retículo Endoplásmico/metabolismo , Antígenos HLA-C/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Animales , Presentación de Antígeno , Antígenos de Diferenciación de Linfocitos B/metabolismo , Autoantígenos/inmunología , Células CHO , Cricetinae , Células HEK293 , Antígenos HLA-C/inmunología , Humanos , Activación de Linfocitos , Ratones , Unión Proteica , Pliegue de Proteína , Transporte de Proteínas
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