Coxsackievirus infection induces direct pancreatic ß cell killing but poor antiviral CD8+ T cell responses.

Coxsackievirus B (CVB) infection of pancreatic ß cells is associated with ß cell autoimmunity and type 1 diabetes. We investigated how CVB affects human ß cells and anti-CVB T cell responses. ß cells were efficiently infected by CVB in vitro, down-regulated human leukocyte antigen (HLA) class I, and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized a fraction of these peptides; only another subfraction was targeted by effector/memory T cells that expressed exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with ß cell antigen GAD. Infected ß cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Our in vitro and ex vivo data highlight limited CD8+ T cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and nonstructural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.

Coxsackievirus infection induces direct pancreatic ß-cell killing but poor anti-viral CD8+ T-cell responses.

Coxsackievirus B (CVB) infection of pancreatic ß cells is associated with ß-cell autoimmunity. We investigated how CVB impacts human ß cells and anti-CVB T-cell responses. ß cells were efficiently infected by CVB in vitro, downregulated HLA Class I and presented few, selected HLA-bound viral peptides. Circulating CD8+ T cells from CVB-seropositive individuals recognized only a fraction of these peptides, and only another sub-fraction was targeted by effector/memory T cells that expressed the exhaustion marker PD-1. T cells recognizing a CVB epitope cross-reacted with the ß-cell antigen GAD. Infected ß cells, which formed filopodia to propagate infection, were more efficiently killed by CVB than by CVB-reactive T cells. Thus, our in-vitro and ex-vivo data highlight limited T-cell responses to CVB, supporting the rationale for CVB vaccination trials for type 1 diabetes prevention. CD8+ T cells recognizing structural and non-structural CVB epitopes provide biomarkers to differentially follow response to infection and vaccination.

Impact of lockdown on children with type-1 diabetes: returning to the community was associated with a decrease in HbA1c.

Background: In March 2020, a 2-month lockdown of the entire population has been declared in France to limit the spread of COVID-19. Sudden changes in daily life can impact the glycemic control of patients with type 1 diabetes (T1D), especially children and adolescents. We aimed to assess the impact of the lockdown on glycemic control in children and adolescents with T1D. Methods: Children with T1D were prospectively recruited in two pediatric centers from May 11 to August 1, 2020. At inclusion, patients and/or parents were asked to fill in a form assessing the patient's lifestyle during the lockdown and a medical case report form was filled in by clinician. The mean of the three last glycated hemoglobin (HbA1c) values obtained before lockdown (HbA1c_mean; before March 17, 2020) was compared to the first HbA1c value measured after the lockdown (HbA1c_after; from May 11 to August 1, 2020). Univariable and multivariable analyses were performed, as appropriate, to identify factors associated with glycemic changes during lockdown. Results: One-hundred-and-eighteen children and adolescents (median age was 14.1 years, 50% males) with T1D (median time from diagnosis was 4.1 years) were enrolled in the study. No significant difference was observed between medians of HbA1c_mean and HbA1c_after values (8.37% [7.88; 9.32%] vs. 8.50% [7.70; 9.50%], respectively; p = 0.391). Returning to the community was a protective factor [OR 0.31 (0.09-0.94); p = 0.045]. Patients having increased HbA1c were more frequently in contact with a suspected case of COVID-19 [OR 9.07 (2.15-53.66); p = 0.006], whereas patients having decreased HbA1c had the feeling of increase number of hypoglycemia [OR 0.19 (0.05-0.57); p = 0.006]. Conclusion: In our patients, HbA1c before and after the lockdown was stable. In subgroup analysis, returning to the community was a protective factor. In addition, feeling of hypoglycemia was more frequent in the patients with decreased HbA1c.

Extending the clinical heterogeneity of iodide transport defect (ITD): a novel mutation R124H of the sodium/iodide symporter gene and review of genotype-phenotype correlations in ITD.

CONTEXT: Iodide transport defect (ITD) is an autosomal recessive disorder resulting in varying degrees of congenital hypothyroidism (CH) with goiter and low or absent radioiodide uptake (RIUT), as determined by thyroid scintigraphy, and low iodide saliva to plasma ratio. Defects of the sodium/iodide symporter gene (NIS) have been shown to cause ITD. OBJECTIVE: We describe molecular studies of NIS in a patient with ITD and genotype-phenotype correlation analysis in 31 patients with NIS defects reported worldwide. DESIGN: NIS sequencing and functional studies of the new NIS mutation in vitro were performed. RESULTS: In a newborn with symptomatic CH and a large goiter, thyroid scintigraphy showed no RIUT (0%). NIS sequencing identified the new homozygous mutation, R124H, in exon 2. This mutation was associated with abolition of iodide uptake in vitro when transfected in COS-7 cells. Immunocytochemical studies documented correct targeting of the mutated protein to the plasma membrane of transfected cells. Genotype-phenotype correlation analysis showed that the onset of hypothyroidism occurred during the neonatal period with four NIS mutations (neonatal onset of hypothyroidism genotype), during infancy with three NIS mutations (infancy onset of hypothyroidism genotype), and during childhood with three NIS mutations (childhood onset of hypothyroidism genotype). RIUT is a direct measure of residual NIS activity in vivo. Mean RIUT was lower in patients with the neonatal onset of hypothyroidism genotype (0.88 +/- 0.2%) than in the infancy onset of hypothyroidism (1.9 +/- 0.4%; P < 0.05) and childhood onset of hypothyroidism (2.6 +/- 0.7%; P < 0.05) genotypes. CONCLUSIONS: We identified a new NIS mutation, R124H, in a newborn with the complete clinical ITD phenotype. Genotype-phenotype correlations suggest that age at hypothyroidism onset may be genotype specific and may depend on genotype-specific residual NIS activity.

Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy.

OBJECTIVE: Decreased growth velocity and abnormal body composition including severe osteoporosis are common in glucocorticoid-treated patients with juvenile idiopathic arthritis (JIA). We evaluated the effects of recombinant human growth hormone (GH) given for 3 years on growth velocity, height standard deviation score (SDS), and body composition, together with potential adverse effects on glucose tolerance. METHODS: Thirteen patients received GH (0.46 mg/kg/week) for 3 years. Body composition was assessed by dual-energy x-ray absorptiometry and glucose tolerance by annual oral glucose tolerance tests. RESULTS: Median growth velocity increased from 2.1 to 6.0 cm/year (p = 0.002) in the first year and remained higher than baseline in the second year of treatment. Height SDS did not change significantly (-4.6 SDS at baseline vs -4.3 SDS at study completion), but the growth response varied markedly across patients. Compared with baseline, lean mass increased by 33%, fat mass remained stable, and lumbar bone mineral density increased by 36.6%. Transient glucose intolerance developed in 6 patients, but glycosylated hemoglobin concentrations did not change significantly and diabetes mellitus did not occur. CONCLUSION: Treatment with GH restored linear growth without inducing catch-up growth, significantly improved body composition, and prevented further bone loss. Prolonged followup is needed to assess the benefits of GH and longterm consequences of hyperinsulinism.

Long-term survival of renal graft complicated with Burkitt lymphoma.

A 10-year-old boy with steroid-resistant nephrotic syndrome developed disseminated Burkitt lymphoma 2 years after renal transplantation. Treatment consisting of reduction of immunosuppression and polychemotherapy was initiated, and induced complete tumor remission. A severe cerebellar syndrome attributed to high-dose cytarabine occurred during treatment. The patient recovered partially from this complication. Immunosuppression had to be resumed 2 years later because of a chronic rejection. Finally, at last follow-up, the patient was alive with a stable creatinine of 180 micromol/l.

Treatment of growth failure in juvenile chronic arthritis.

We retrospectively assessed linear growth and final height in a group of 24 patients suffering from juvenile idiopathic arthritis (JIA) during childhood, receiving steroid therapy. In these patients, a significant loss of height (-2.7 +/- 1.5 SDS) occurred in the first years of the disease which was positively correlated with prednisone therapy duration. After remission of the disease and prednisone discontinuation, most of the patients (70%) had catch-up growth but 30% had a persistent loss of height. Their mean final height was strongly correlated with their mean height at the end of steroid therapy and was significantly different between the group of patients with catch-up growth (-1.5 +/- 1.6 SDS) and the group without catch-up growth (-3.6 +/- 1.2 SDS). This pattern of growth observed in JIA patients should help us to define strategies of GH treatment in these patients in order to improve their final height. We have previously reported the beneficial effects on growth and body composition of a 1-year GH treatment in a group of 14 growth-retarded patients suffering from juvenile idiopathic arthritis, receiving glucocorticoid therapy. These patients (n = 13) were treated again with GH at the same dosage (0.46 mg/kg/week) for another 3-year period. GH treatment markedly increased growth velocity in these patients, but had a minor effect on SDS height suggesting that these children will remain short at adult age. Using GH earlier in these patients during the course of their disease may prevent growth deterioration and metabolic complications induced by chronic inflammation and long-term steroid therapy.