RESUMEN
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.
Asunto(s)
Receptor de Factor de Crecimiento Nervioso , Receptores de Factor de Crecimiento Nervioso , Animales , Ratones , Autoanticuerpos , Células Dendríticas Foliculares , Centro GerminalRESUMEN
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.
RESUMEN
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.
Asunto(s)
Inmunoterapia Adoptiva/tendencias , Neoplasias/terapia , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/trasplante , Ingeniería Celular , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Inyecciones Intravenosas , Neoplasias/inmunología , Receptores Quiméricos de Antígenos/administración & dosificación , Linfocitos T/inmunología , Escape del Tumor/inmunologíaRESUMEN
DQA1*01:19 differs from DQA1*01:02:01:04 by one nucleotide substitution at position 731 in exon 4.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Cadenas alfa de HLA-DQ/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
DRB1*11:260 differs from DRB1*11:03:01 by one nucleotide substitution at position 484 in exon 3.
Asunto(s)
Cadenas HLA-DRB1 , Alelos , Exones/genética , Cadenas HLA-DRB1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
DQB1*02:162N differs from DQB1*02:02:01:01 by one nucleotide substitution at position 276 in exon 2.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Cadenas beta de HLA-DQ/genética , HumanosRESUMEN
DQB1*03:417 differs from DQB1*03:01:01:01 by one nucleotide substitution at position 179 in exon 2.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Cadenas beta de HLA-DQ/genética , HumanosRESUMEN
B*44:476 differs from B*44:03:01:01 by one nucleotide substitution at position 934 in exon 5.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Alelos , Exones/genética , Antígenos HLA-B/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
DRB1*01:107 differs from DRB1*01:01:01:01 by one nucleotide substitution at position 484 in exon 3.
Asunto(s)
Cadenas HLA-DRB1 , Alelos , Exones/genética , Cadenas HLA-DRB1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
DRB1*08:97 differs from DRB1*08:03:02:01 by one nucleotide substitution at position 485 in exon 3.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Cadenas HLA-DRB1/genética , Prueba de Histocompatibilidad , HumanosRESUMEN
B*44:452 differs from B*44:02:01:01 by one nucleotide substitution at position 527 in exon 3.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Alelos , Exones/genética , Antígenos HLA-B/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
B*07:384 differs from B*07:02:01:01 by one nucleotide substitution at position 472 in exon 3.
Asunto(s)
Antígeno HLA-B7 , Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , HumanosRESUMEN
B*35:460Q differs from B*35:03:01:01 by one nucleotide substitution at position 406 in exon 3.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Alelos , Exones/genética , Antígenos HLA-B/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
DQB1*05:235N differs from DQB1*05:03:01:01 by one nucleotide substitution at position 123 in exon 2, resulting in a premature stop codon.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Cadenas beta de HLA-DQ/genética , HumanosRESUMEN
B*18:181 differs from B*18:01:01:02 by one nucleotide substitution at position 1043 in exon 6.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-B , Alelos , Exones/genética , Antígenos HLA-B/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
DQA1*01:38:01:01 differs from DQA1*01:02:01:01 by one nucleotide substitution at position 554 in exon 3.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Cadenas alfa de HLA-DQ/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
HLA-C*14:114 differs from C*14:02:01:01 by one nucleotide substitution at position 1077 in exon 7.
Asunto(s)
Genes MHC Clase I , Antígenos HLA-C , Alelos , Exones/genética , Antígenos HLA-C/genética , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
B*51:296 differs from B*51:01:01:01 by one nucleotide substitution at position 1030 in exon 6.
Asunto(s)
Antígenos HLA-B , Secuenciación de Nucleótidos de Alto Rendimiento , Alelos , Exones/genética , Antígenos HLA-B/genética , Humanos , Mutación MissenseRESUMEN
B*40:450 differs from B*40:01:02:01 by one nucleotide substitution at position 5 in exon 1.