Lymphocyte disturbance and functional assessment of the [Asp521Asn] ZAP70 mutation.

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  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 100883537 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-7035 (Electronic) Linking ISSN: 15216616 NLM ISO Abbreviation: Clin Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Orlando, FL : Academic Press, c1999-
    • Subject Terms:
      Signal Transduction* ; Receptors, Antigen, T-Cell, alpha-beta*/genetics; Male ; Animals ; ZAP-70 Protein-Tyrosine Kinase/genetics ; Mutation ; Phosphorylation ; T-Lymphocytes, Regulatory/metabolism ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism
    • Abstract:
      Activated zeta-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαβ:CD3:zeta complex to diversify and amplify TCR signaling. Patients with ZAP70 mutations can present with phenotypes of immune dysregulation as well as infection. We identified the first Taiwanese boy with the [Asp521Asn] ZAP70 mutation who presented with recurrent pneumonia, inflammatory bowel disease-like diarrhea, transient hematuria and autoimmune hepatitis. He had isolated CD8 lymphopenia, eosinophilia, hypogammaglobulinemia, and impaired lymphocyte proliferation. Downstream CD3/CD28 signaling, phosphorylation of AKT, ZAP70 and Ca2+ influx were decreased in [Asp521Asn] ZAP70 lymphocytes. Immunophenotyping analysis revealed expansion of transitional B and CD21-low B cells, Th2-skewing T follicular helper cells, but lower Treg cells. The Asp521Asn-ZAP70 hindered TCR-CD3 downstream phosphorylation and disturbed lymphocyte subgroup "profiles" leading to autoimmunity/autoinflammation. Further large-scale studies are warranted to clarify this lymphocyte disturbance. The prognosis significantly depends on hematopoietic stem cell transplantation, but not the genotype, the presence of opportunistic infections or immune dysregulation.
      Competing Interests: Declaration of Competing Interest The authors declared that they have no conflict of interest.
      (Copyright © 2023 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Autoimmune; Combined T and B immunodeficiency; Hematopoietic stem cell transplantation; Immune dysregulation; Omenn syndrome; ZAP70
    • Accession Number:
      EC 2.7.10.2 (ZAP-70 Protein-Tyrosine Kinase)
      0 (Receptors, Antigen, T-Cell, alpha-beta)
      0 (Receptors, Antigen, T-Cell)
    • Publication Date:
      Date Created: 20230120 Date Completed: 20230214 Latest Revision: 20230318
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.clim.2023.109236
    • Accession Number:
      36669607