RESUMO
Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in the humoral response is not well defined. Here, we study the effect of Ngfr loss on lymph node organization and function, demonstrating that Ngfr depletion leads to spontaneous germinal center (GC) formation and an expansion of the GC B cell compartment. In accordance with this effect, stromal cells are altered in Ngfr-/- mice with a higher frequency of FDCs, characterized by CD21/35, MAdCAM-1, and VCAM-1 overexpression. GCs are located ectopically in Ngfr-/- mice, with lost polarization together with impaired high-affinity antibody production and an increase in circulating autoantibodies. We observe higher levels of autoantibodies in Bcl2 Tg/Ngfr-/- mice, concomitant with a higher incidence of autoimmunity and lower overall survival. Our work shows that NGFR is involved in maintaining GC structure and function, participating in GC activation, antibody production, and immune tolerance.
Assuntos
Receptor de Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural , Animais , Camundongos , Autoanticorpos , Células Dendríticas Foliculares , Centro GerminativoRESUMO
To understand the fine differential elements that can lead to or prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients, it is crucial to investigate the immune response architecture. We herein dissected the multiple layers of B cell responses by flow cytometry and Ig repertoire analysis from acute phase to recovery. Flow cytometry with FlowSOM analysis showed major changes associated with COVID-19 inflammation such as an increase of double-negative B-cells and ongoing plasma cell differentiation. This paralleled COVID-19-driven expansion of two disconnected B-cell repertoires. Demultiplexing successive DNA and RNA Ig repertoire patterns characterized an early expansion of IgG1 clonotypes with atypically long and uncharged CDR3, the abundance of this inflammatory repertoire being correlated with ARDS and likely pejorative. A superimposed convergent response included convergent anti-SARS-CoV-2 clonotypes. It featured progressively increasing somatic hypermutation together with normal-length or short CDR3 and it persisted until a quiescent memory B-cell stage after recovery.
RESUMO
CAR-T cells have recently made a stunning entry on the arena of immunotherapy of B-cell lymphomas. This new treatment approach represents the culmination of 30 years of efforts to understand the role of T cells in the antitumor response. However, this technology is still in its infancy and suffers from a number of limitations. Many areas for improvement, based in particular on the possibilities of additional genetic manipulations of CAR-T cells, aim at reducing their toxicity, increasing their persistence in vivo, preventing the risk of tumor escape, recruiting other immune effectors, or extending their application to other cancers. Further studies of the dynamic interaction between the patient and these live drugs will allow elucidating the mechanisms determining the antitumor response in this context and thus developing more efficiently the future CAR-T cells.
Assuntos
Imunoterapia Adotiva/tendências , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Engenharia Celular , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Injeções Intravenosas , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/administração & dosagem , Linfócitos T/imunologia , Evasão Tumoral/imunologiaRESUMO
DQA1*05:18 differs from DQA1*05:01:01:03 by one nucleotide substitution at position 94 in exon 2.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
HLA-B*08:67:02N differs from B*08:01:01:01 by one nucleotide substitution at position 224 in exon 2.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Éxons/genética , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
DQA1*03:11 differs from DQA1*03:03:01:01 by one nucleotide substitution at position 664 in exon 4.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
DQA1*05:13 differs from DQA1*05:05:01:04 by one nucleotide substitution at position 37 in exon 1.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Cadeias alfa de HLA-DQ/genética , Humanos , Análise de Sequência de DNARESUMO
DQB1*02:162N differs from DQB1*02:02:01:01 by one nucleotide substitution at position 276 in exon 2.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Cadeias beta de HLA-DQ/genética , HumanosRESUMO
B*51:296 differs from B*51:01:01:01 by one nucleotide substitution at position 1030 in exon 6.
Assuntos
Antígenos HLA-B , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Antígenos HLA-B/genética , Humanos , Mutação de Sentido IncorretoRESUMO
B*40:450 differs from B*40:01:02:01 by one nucleotide substitution at position 5 in exon 1.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Éxons/genética , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
B*18:181 differs from B*18:01:01:02 by one nucleotide substitution at position 1043 in exon 6.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Éxons/genética , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
DRB1*11:260 differs from DRB1*11:03:01 by one nucleotide substitution at position 484 in exon 3.
Assuntos
Cadeias HLA-DRB1 , Alelos , Éxons/genética , Cadeias HLA-DRB1/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
DQB1*03:417 differs from DQB1*03:01:01:01 by one nucleotide substitution at position 179 in exon 2.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Cadeias beta de HLA-DQ/genética , HumanosRESUMO
B*44:476 differs from B*44:03:01:01 by one nucleotide substitution at position 934 in exon 5.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Éxons/genética , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
DRB1*01:107 differs from DRB1*01:01:01:01 by one nucleotide substitution at position 484 in exon 3.
Assuntos
Cadeias HLA-DRB1 , Alelos , Éxons/genética , Cadeias HLA-DRB1/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
DRB1*08:97 differs from DRB1*08:03:02:01 by one nucleotide substitution at position 485 in exon 3.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Éxons/genética , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade , HumanosRESUMO
B*44:452 differs from B*44:02:01:01 by one nucleotide substitution at position 527 in exon 3.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Éxons/genética , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
B*35:460Q differs from B*35:03:01:01 by one nucleotide substitution at position 406 in exon 3.
Assuntos
Genes MHC Classe I , Antígenos HLA-B , Alelos , Éxons/genética , Antígenos HLA-B/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
HLA-C*14:114 differs from C*14:02:01:01 by one nucleotide substitution at position 1077 in exon 7.