Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters

Database
Language
Publication year range
1.
J Clin Immunol ; 43(7): 1566-1580, 2023 10.
Article in English | MEDLINE | ID: mdl-37273120

ABSTRACT

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.


Subject(s)
Hypersensitivity, Immediate , Job Syndrome , Humans , Job Syndrome/diagnosis , Job Syndrome/genetics , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Phenotype , STAT3 Transcription Factor , Hypersensitivity, Immediate/complications , Mutation/genetics
3.
Science ; 383(6686): eadh4059, 2024 03.
Article in English | MEDLINE | ID: mdl-38422122

ABSTRACT

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.


Subject(s)
Autoimmunity , Intraepithelial Lymphocytes , Membrane Glycoproteins , Receptors, Antigen, T-Cell, alpha-beta , Humans , Autoimmunity/genetics , Cell Differentiation , Homozygote , Intraepithelial Lymphocytes/immunology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Membrane Glycoproteins/genetics , Loss of Function Mutation , Lymphocyte Count , Alleles , Infections/immunology , Lymphoproliferative Disorders/immunology , Pedigree , Male , Female , Middle Aged , Aged , Aged, 80 and over
SELECTION OF CITATIONS
SEARCH DETAIL