Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency

Abstract

in comparison with the intraparticipant variance of 15.3, as shown in sequential Bland-Altman plots in Fig E1 in this article's Online Repository at www.jacionline.org. This is consistent with low variability of periostin levels within subjects in a clinical sample representing a well-controlled adult asthmatic population. The 95% CI for individual predictions of periostin levels were plus or minus 7.7 ng/mL. The mean coefficient of variation for periostin for the 60 participants was 6.3% (95% CI, 5.7% to 7.0%). There was no evidence of monthly (P 5 .56, see Table E4 in this article's Online Repository at www.jacionline.org) or seasonal (P 5.90. see Table E5 in this article's Online Repository at www.jacionline.org) variation between participants. Five participants had a severe asthma exacerbation during the study and required systemic corticosteroids ( Fig 2) with a mean dose of 35 mg/d (range, 20-60 mg/d; courses lasting from 1-16 days; see Table E6 in this article's Online Repository at www.jacionline.org). The mixed linear model estimate of the difference in periostin levels between the first measurement after a severe exacerbation requiring systemic corticosteroids and the pre-exacerbation measurements for these 5 participants was 25.4 ng/mL (95% CI, 28.3 to 22.6 ng/mL; P 5 .002). The difference in periostin levels between the postexacerbation and pre-exacerbation levels was 24.5 ng/mL (95% CI, 27.0 to 21.9 ng/mL [P < .001]; which is smaller than the 95% CI for an individual prediction of periostin levels).In summary, we found little variability in periostin measurements within subjects over an 8-week period. The within-participant variance was 15.3, with a 95% CI for periostin levels of 67.7 ng/mL. These findings in adults receiving step 4 treatment according to Global Initiative for Asthma guidelines 9 are consistent with those of studies performed in populations with severe asthma over a period of 2 4 and 5 1 weeks, respectively. These studies reported a coefficient of variation rather than variance components, with point estimates of 5.0% and 5.3%, respectively. This is consistent with the low intraparticipant variability in periostin measurements observed in this study, in which the coefficient of variation was 6.3%. We found no evidence of a monthly or seasonal fluctuation in serum periostin levels between participants who were recruited over a 12-month period. Therefore it might not be necessary to consider seasonality when assessing periostin levels in candidates for treatment with the novel asthma biologic therapies. Periostin levels are modestly reduced by systemic corticosteroid treatment of a severe asthma exacerbation, but the effect lies within the level of variation expected in otherwise stable adults with asthma.In conclusion, we propose that the stability of periostin measurements supports its use as a biomarker in asthmatic patients, predicting responsiveness to biologic therapy directed against type 2 disease.We thank the study participants for their involvement in this study.

Clinical, Immunological, and Genetic Features in 49 Patients With ZAP-70 Deficiency: A Systematic Review

“…In these patients, the combination of the ZAP70 R192W allele with decreased ζ-chain binding plus the constitutively active R360P allele with decreased autoinhibition led to the development of autoimmunity. To analyze genotype-phenotype correlation, the patients were divided into three categories: 1) "classical" group of 36 patients with amorphic mutations that abolish protein expression and/or function, 2) "leaky" group consisting of 5 patients with hypomorphic mutations that result in residual ZAP70 protein expression (8,27,(36)(37)(38), 3) "atypical" group including 2 patients with both gain and loss-of-function mutations (5). For other patients we did not have enough information about protein expression…”

“…A decline in antibody response to polysaccharide and peptide vaccine was detected in 5 (55.6%) and 16 (80%) patients, respectively. Reduction in T-cell receptor excision circles (TREC) levels and phytohemagglutinin (PHA) response were observed in 5 (50%) and 38 (95%) of the cases with available data, respectively (5,7,8,27,(36)(37)(38). A supplementary file including each individual clinical, immunological, and genetic features is available as Supplementary File (Table 1_V1).…”

Novel ZAP-70-Related Immunodeficiency Presenting with Epstein–Barr Virus Lymphoproliferative Disorder and Hemophagocytic Lymphohistiocytosis

“…Zeta-chain-associated protein kinase 70 (ZAP-70) is a cytoplasmic kinase which plays an integral role in the T-cell antigenic receptor complex, leading to T-cell receptor activation, T-cell development, immunity, and tolerance [1][2][3][4][5][6][7]. ZAP-70 deficiency typically presents with recurrent infections in the first months of life, low or absent CD8 positive T cells, normal to increased nonfunctional CD4-positive Tcells, and defective B-cell antibody production-essentially severe combined immunodeficiency (SCID) [1][2][3][4][6][7][8]. More mild immunodeficiency phenotypes have been described with hypomorphic genetic mutations leading to decreased ZAP-70 expression or function, as opposed to the absence of ZAP-70 expression [3,7].…”

“…ZAP-70 deficiency typically presents with recurrent infections in the first months of life, low or absent CD8 positive T cells, normal to increased nonfunctional CD4-positive Tcells, and defective B-cell antibody production-essentially severe combined immunodeficiency (SCID) [1][2][3][4][6][7][8]. More mild immunodeficiency phenotypes have been described with hypomorphic genetic mutations leading to decreased ZAP-70 expression or function, as opposed to the absence of ZAP-70 expression [3,7].…”

A novel hypomorphic ζ-chain-associated protein tyrosine kinase 70 kDa mutation with normal CD8+ T cells count

“…[ 1 – 4 ] ZAP70 deficiency always results in recurrent bacterial, viral, and opportunistic infections, diarrhea, and autoimmune diseases. Distinctively, ZAP70 hypomorphic mutations appear to have observable clinical heterogeneity, such as Epstein-Barr virus-associated lymphoproliferative disorder/lymphoma, late-onset immunodeficiency, [ 3 ] and silent brain infarcts. [ 5 ] Hence, next-generation sequencing technology might be the predominant diagnostic approach.…”