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

Yung-Feng Lin; Wen-I Lee; Ching-Huang Ho; Shih-Hsiang Chen; Mei-Hsin Hsu; Ren-Chin Wu; Wan-Fang Lee; Tang-Her Jaing; Jing-Long Huang; Shih-Feng Tsai

doi:10.1016/j.clim.2023.109236

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

Clin Immunol. 2023 Feb:247:109236. doi: 10.1016/j.clim.2023.109236. Epub 2023 Jan 17.

Authors

Affiliations

¹ Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
² Department of Pediatrics, Division of Allergy, Asthma and Rheumatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: wen2707@gmail.com.
³ Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan; VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
⁴ Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department Pediatrics, Division of Hematology/Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁵ Department of Pediatric Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁶ Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Pediatrics, Division of Allergy, Asthma and Rheumatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁸ Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Pediatrics, New Taipei Municipal TuChen Hospital, New Taipei, Taiwan.

PMID: 36669607
DOI: 10.1016/j.clim.2023.109236

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.

Keywords: Autoimmune; Combined T and B immunodeficiency; Hematopoietic stem cell transplantation; Immune dysregulation; Omenn syndrome; ZAP70.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Male
Mutation
Phosphorylation
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / metabolism
Receptors, Antigen, T-Cell, alpha-beta* / genetics
Signal Transduction*
T-Lymphocytes, Regulatory / metabolism
ZAP-70 Protein-Tyrosine Kinase / genetics

Substances

ZAP-70 Protein-Tyrosine Kinase
Receptors, Antigen, T-Cell, alpha-beta
Receptors, Antigen, T-Cell