Lymphocyte Disturbance in The [Asp521Asn] ZAP70 Mutation and An Overview of All Phenotype/Genotype

Abstract Background. Activated Zeta (ζ)-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαβ:CD3:ζ-complex to diversify the initial TCR signal. Patients with the ZAP70 mutations could present with the phenotype of immune dysregulation. Methods. We identified the first Taiwanese boy with the ZAP70 mutation, assessed downstream signaling, investigated lymphocyte disturbance and analyzed all available phenotype/genotype for optimal treatment.Results. With the [Asp521Asn]ZAP70 mutation, the infant who had hypogammaglobulinemia, eosinophilia, isolated CD8 lymphopenia, and impaired lymphocyte proliferation experienced recurrent pneumonia, refractory diarrhea, transient hematuria and autoimmune hepatitis. Decreased CD3/CD28 downstream phosphorylation of AKT, ZAP70 and Ca2+ influx related to the Th2-skewing T follicular helper cells, expanded transitional B, increased CD21-low B cells and lower Treg cells. To speculate clinical course for effective treatment, we overviewed 45 available published patients. Except for two asymptomatic post-transplant infants, common pathogens were oral candida (n=9), PJP (n=7), CMV (n=5), varicella (n=4), parainfluenza (n=3) and disseminated BCG (n=3). Their phenotypes of immune dysregulation mainly included IBD-like diarrhea (n=12), dermatitis (n=7), hepatosplenomegaly (n=3) and nephritic syndrome (n=3). Founder-effect or hot-spot mutations (32/90 alleles) involving the kinase domain clustered on intron 12 [1624-11G>A] (in 24) and exon 12[1520C>T] (in 8). Eleven died of sepsis (n=3), CMV pneumonitis (n=2), viral encephalitis, disseminated measles-vaccine infection, ARDS, HLH-like, EBV-lymphoproliferative disorder, and lymphoma each. Whatever developing opportunistic infections (p=0.2240), immune dysregulation (p=0.5268), or failure to thrive (p=0.5215), those who receiving HSCT had significantly better prognosis (p=0.0003). Conclusions. The Asp521Asn-ZAP70 hinders TCR-CD3 downstream phosphorylation and disturbs lymphocyte subgroup “profiles” leading to autoimmune/autoinlfmmation. The lymphocyte disturbance should be validated in large-scale studies. Receiving HSCT is a significantly better survival factor, rather than mutation types, opportunistic infections, or immune dysregulation.