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1.
J Clin Immunol ; 43(7): 1566-1580, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37273120

RESUMO

Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES.


Assuntos
Hipersensibilidade Imediata , Síndrome de Job , Humanos , Síndrome de Job/diagnóstico , Síndrome de Job/genética , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Fenótipo , Fator de Transcrição STAT3 , Hipersensibilidade Imediata/complicações , Mutação/genética
3.
Science ; 383(6686): eadh4059, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38422122

RESUMO

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.


Assuntos
Autoimunidade , Linfócitos Intraepiteliais , Glicoproteínas de Membrana , Receptores de Antígenos de Linfócitos T alfa-beta , Humanos , Autoimunidade/genética , Diferenciação Celular , Homozigoto , Linfócitos Intraepiteliais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Glicoproteínas de Membrana/genética , Mutação com Perda de Função , Contagem de Linfócitos , Alelos , Infecções/imunologia , Transtornos Linfoproliferativos/imunologia , Linhagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais
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