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1.
Nat Commun ; 12(1): 3789, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145279

RESUMO

Influenza viruses are a major public health problem. Vaccines are the best available countermeasure to induce effective immunity against infection with seasonal influenza viruses; however, the breadth of antibody responses in infection versus vaccination is quite different. Here, we show that nasal infection controls two sequential processes to induce neutralizing IgG antibodies recognizing the hemagglutinin (HA) of heterotypic strains. The first is viral replication in the lung, which facilitates exposure of shared epitopes that are otherwise hidden from the immune system. The second process is the germinal center (GC) response, in particular, IL-4 derived from follicular helper T cells has an essential role in the expansion of rare GC-B cells recognizing the shared epitopes. Therefore, the combination of exposure of the shared epitopes and efficient proliferation of GC-B cells is critical for generating broadly-protective antibodies. These observations provide insight into mechanisms promoting broad protection from virus infection.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Hemaglutininas Virais/imunologia , Interleucina-4/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Amplamente Neutralizantes/sangue , Epitopos/imunologia , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H2N2/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Células T Auxiliares Foliculares/imunologia , Vacinação
2.
Int Immunol ; 32(3): 163-174, 2020 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-31713611

RESUMO

IgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.


Assuntos
Doença Relacionada a Imunoglobulina G4/imunologia , Imunoglobulina G/imunologia , Inflamação/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Recombinantes/imunologia
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