Dataset Information

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

ABSTRACT: We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ 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 αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.

SUBMITTER: Materna M

PROVIDER: S-EPMC10958617 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

Materna Marie M Delmonte Ottavia M OM Bosticardo Marita M Momenilandi Mana M Conrey Peyton E PE Charmeteau-De Muylder Bénédicte B Bravetti Clotilde C Bellworthy Rebecca R Cederholm Axel A Staels Frederik F Ganoza Christian A CA Darko Samuel S Sayed Samir S Le Floc'h Corentin C Ogishi Masato M Rinchai Darawan D Guenoun Andrea A Bolze Alexandre A Khan Taushif T Gervais Adrian A Krüger Renate R Völler Mirjam M Palterer Boaz B Sadeghi-Shabestari Mahnaz M Langlois de Septenville Anne A Schramm Chaim A CA Shah Sanjana S Tello-Cajiao John J JJ Pala Francesca F Amini Kayla K Campos Jose S JS Lima Noemia Santana NS Eriksson Daniel D Lévy Romain R Seeleuthner Yoann Y Jyonouchi Soma S Ata Manar M Al Ali Fatima F Stittrich Anna A Deswarte Caroline C Pereira Anaïs A Mégret Jérôme J Le Voyer Tom T Bastard Paul P Berteloot Laureline L Dussiot Michaël M Vladikine Natasha N Cardenas Paula P PP Jouanguy Emmanuelle E Alqahtani Mashael M Hasan Amal A Thanaraj Thangavel Alphonse TA Rosain Jérémie J Al Qureshah Fahd F Sabato Vito V Alyanakian Marie Alexandra MA Leruez-Ville Marianne M Rozenberg Flore F Haddad Elie E Regueiro Jose R JR Toribio Maria L ML Kelsen Judith R JR Salehi Mansoor M Nasiri Shahram S Torabizadeh Mehdi M Rokni-Zadeh Hassan H Changi-Ashtiani Majid M Vatandoost Nasimeh N Moravej Hossein H Akrami Seyed Mohammad SM Mazloomrezaei Mohsen M Cobat Aurélie A Meyts Isabelle I Toyofuku Etsushi E Nishimura Madoka M Moriya Kunihiko K Mizukami Tomoyuki T Imai Kohsuke K Abel Laurent L Malissen Bernard B Al-Mulla Fahd F Alkuraya Fowzan Sami FS Parvaneh Nima N von Bernuth Horst H Beetz Christian C Davi Frédéric F Douek Daniel C DC Cheynier Rémi R Langlais David D Landegren Nils N Marr Nico N Morio Tomohiro T Shahrooei Mohammad M Schrijvers Rik R Henrickson Sarah E SE Luche Hervé H Notarangelo Luigi D LD Casanova Jean-Laurent JL Béziat Vivien V

Science (New York, N.Y.) 20240301 6686

We describe humans with rare biallelic loss-of-function <i>PTCRA</i> variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also re ...[more]

PMID: 38422122

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Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.

Dataset Information

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

Publications

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

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