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

Activated zeta-chain-associated protein kinase 70 (ZAP70) phosphorylates the TCRαß: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.

Early-life weight gain is associated with non-atopic asthma in childhood.

Background: Previous studies suggest the association between early-life weight gain and asthma. It remains unclear whether early-life weight gain is associated with atopic or non-atopic asthma. This study aimed to investigate whether early-life weight gain is associated with atopic or non-atopic asthma. Methods: Included in this study were 1343 singleton-birth children (761 boys, 57%) born between January 2010 and December 2011 participating in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort were evaluated by a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and interviewed by pediatricians between July 1, 2016 and May 31, 2018 at the mean age of 6.4 years. Weight gain z-scores during the first 6, 12, and 18 months of life were classified into 4 groups: slow (below -0.67), on track (-0.67 to 0.67), rapid (0.67 to 1.28), and extremely rapid (above 1.28). The main outcomes were atopic and non-atopic asthma. Asthma was defined as having physician-diagnosed asthma and the presence of wheeze or asthma exacerbations in the last 12 months. Atopy was determined by Phadiatop Infant. Results: The extremely rapid weight gain group of children during the first 6, 12, and 18 months of life was significantly associated with an increased risk of non-atopic asthma (adjusted odd ratio [AOR], 2.14, 95% confidence interval [CI], 1.01-4.53 for the first 6 months; AOR, 2.86, 95% CI, 1.34-6.14 for the first 12 months; AOR, 3.26, 95% CI 1.49-7.15 for the first 18 months) compared with the on track group. No significant association was found in atopic asthma. A sex-stratified analysis revealed the association of early-life weight gain with non-atopic asthma was statistically significant only in boys (AOR, 4.24, 95% CI, 1.44-12.50). Conclusion: Extremely rapid weight gain during the first 6-18 months of life was significantly associated with 2.1- to 3.3-fold increased risk of non-atopic asthma, with a more pronounced risk found in boys.

Characteristics and genetic analysis of patients suspected with early-onset systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is rarely diagnosed before 5-years-old. Those with disease onset at a very young age are predicted by a higher genetic risk and a more severe phenotype. We performed whole-exome sequencing to survey the genetic etiologies and clinical manifestations in patients fulfilling 2012 SLICC SLE classification criteria before the age of 5. CASE PRESENTATION: Among the 184 childhood-onset SLE patients regularly followed in a tertiary medical center in Taiwan, 7 cases (3.8%) of which onset ≦ 5 years of age were identified for characteristic review and genetic analysis. Compared to those onset at elder age, cases onset before the age of 5 are more likely to suffer from proliferative glomerulonephritis, renal thrombotic microangiopathy, neuropsychiatric disorder and failure to thrive. Causative genetic etiologies were identified in 3. In addition to the abundance of autoantibodies, patient with homozygous TREX1 (c.292_293 ins A) mutation presented with chilblain-like skin lesions, peripheral spasticity, endocrinopathy and experienced multiple invasive infections. Patient with SLC7A7 (c.625 + 1 G > A) mutation suffered from profound glomerulonephritis with full-house glomerular deposits as well as hyperammonemia, metabolic acidosis and episodic conscious disturbance. Two other cases harbored variants in lupus associating genes C1s, C2, DNASE1 and DNASE1L3 and another with CFHR4. Despite fulfilling the classification criteria for lupus, many of the patients required treatments beyond conventional therapy. CONCLUSIONS: Genetic etiologies and lupus mimickers were found among a substantial proportion of patients suspected with early-onset SLE. Detail clinical evaluation and genetic testing are important for tailored care and personalized treatment.

Comparison of [3H]-Thymidine, Carboxyfluorescein Diacetate Succinimidyl Ester and Ki-67 in Lymphocyte Proliferation.

Background: Patients with T cell deficiency <10% of normal proliferation are indicated to receive immune reconstruction by hematopoietic stem cell transplantation (HSCT). This study aimed to investigate whether non-radioactive assays can be used to quantitatively detect the lymphocyte proliferation <10% of normal as radioactive [3H]-thymidine." Methods: Radioactive [3H]-thymidine, non-radioactive carboxyfluorescein diacetate succinimidyl ester (CFSE), and Ki-67 protein expressions were used to measure the lymphocyte proliferation as calculated using the stimulation index (SI), subtraction percentage, and proliferation index (FlowJo software). Normal references were established for comparison in the absence of parallel healthy controls. Results: Normal ranges of mitogen-stimulated lymphocyte proliferation were established as a SI of 15-267 (CSFE 47-92%, Ki-67 42-79%) with phytohemagglutinin (PHA) 5 µg/ml stimulation; 19-139 (CFSE 62-83%, 45-74% Ki-67) with concanavalin-A (ConA) 5 µg/ml stimulation; 7-53 (CFSE 6-23%, Ki-67 10-24%) with pokeweed mitogen (PWM) 0.1 ug/ml stimulation; 3-28 (CFSE 4-10%, Ki-67 5-14%) with candida 10 ug/ml stimulation; and 2-27 (CFSE 6-41%, Ki-67 6-30%) with bacille Calmette-Guerin (BCG) 0.02 ng/ml stimulation. The normalized CFSE-proliferation index was between 2.1 and 3.0. Although there was no significant correlation between these three assays in the healthy controls, the SI value for <10% [3H]-thymidine proliferation in those with T cell deficiency was compatible with CFSE- and Ki-67-stained lymphocyte percentages, and validated in patients with IL2RG, RAG1, and ZAP70 mutations. When calculating [3H]-thymidine <10% of normal lymphocyte proliferation, the threshold of parallel controls was more reliable than previously established normal references. Conclusion: The large quantitative value of radioactive [3H]-thymidine was more easily recognizable than that for non-radioactive CFSE and Ki-67. Even though the correlation was not significant, those identified to have <10% of normal proliferation by [3H]-thymidine could be consistently detected by CFSE and Ki-67, and consequently indicated for HSCT.

Association between maternal age at delivery and allergic rhinitis in schoolchildren: A population-based study.

BACKGROUND: Some studies have shown associations of maternal age at delivery with asthma and food allergy in offspring. However, the relationship between maternal age at delivery and allergic rhinitis is largely unclear. This study aimed to investigate the association between maternal age at delivery and allergic rhinitis in a population sample of Asian children, and to explore potential effect modifiers. METHODS: A total of 1344 singleton-birth children (763 boys, 56.8%; mean age, 6.4 years) participating in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort were evaluated by a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and interviewed by pediatricians. Allergic sensitization was determined by using Phadiatop Infant. Multiple logistic regression models with covariates adjustment were performed to investigate the association of maternal age at delivery with allergic rhinitis and allergic sensitization in offspring. RESULTS: Among 1344 study children, 793 (59%) had physician-diagnosed allergic rhinitis. Advanced maternal age at delivery (≥40 years) was significantly associated with increased odds of allergic rhinitis (adjusted odds ratio [AOR] = 4.58, 95% confidence interval [CI]: 1.90-11.03) and allergic sensitization (AOR = 2.86, 95% CI: 1.13-7.22) in offspring. A sex-stratified analysis revealed that the association of advanced maternal age with allergic rhinitis was statistically significant only in female offspring (AOR = 7.02, 95% CI: 1.89-26.14). Stratified analyses by birth order or environmental tobacco smoke exposure during pregnancy did not reveal any significant differences. CONCLUSION: Advanced maternal age at delivery was associated with increased risk of allergic rhinitis in Asian children, probably more pronounced among girls.

Correction to: Biomarkers associating endothelial dysregulation in pediatric-onset systemic lupus erythematous.

Following publication of the original article [1], we have been notified that the colour representation of the graph is not correct in Figure 6 legend.

Biomarkers associating endothelial Dysregulation in pediatric-onset systemic lupus erythematous.

BACKGROUND/PURPOSE: Endothelium is a key element in the regulation of vascular homeostasis and its alteration can lead to the development of vascular diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with potential extensive vascular lesions, involving skin vessels, renal glomeruli, cardiovascular system, brain, lung alveoli, gastrointestinal tract vessels and more. We aimed to assess endothelial dysregulation related biomarkers in pediatric-onset SLE (pSLE) patient serum and elucidate its correlation with their clinical features, laboratory parameters, and the overall disease activity. METHODS: Disease activities were evaluated by SLE disease activity index (SLEDAI). Patient characteristics were obtained by retrospective chart review. Six biomarkers associated with endothelial dysregulation, including Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, Vascular endothelial growth factor (VEGF), thrombomodulin, and a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) were tested through enzyme-linked immunosorbent assay (ELISA) measurement. RESULTS: This study comprised 118 pSLE patients. Data from 40 age-matched healthy controls were also obtained. The mean diagnostic age was 13 ± 4.12 years-old and 90.7% are females. Serum levels of VEGF, Tie2, thrombomodulin were significantly higher while serum ADAMTS13 was lower in active pSLE patients when compared to those with inactive diseases (all p < 0.05). In organ specific association, serum thrombomodulin level was higher in pSLE patient with renal involvement, and serum ADAMTS13 levels was negatively associated with neurological involvement (p < 0.05). A cutoff of thrombomodulin at 3333.6 pg/ml best correlated renal involvement. (AUC = 0.752, p < 0.01). CONCLUSION: Endothelial dysregulation associating proteins seems to be potent biomarkers for pSLE activity as well as organ involvement in pSLE patients. These biomarkers may be beneficial in understanding of the vascular pathogenesis and disease monitoring.