Defective tumor necrosis factor-α production in infants with cow’s milk allergy

As an aid to clarifying the role of immune mechanisms in the development of cow’s milk allergy (CMA) in suckling infants, we studied the capacity of peripheral blood mononuclear cells (PBMC) to produce tumor necrosis factor-α (TNF-α) in vitro. The study population consisted of 43 infants, aged 0.12–11.2 months; of these, 31 had challenge-proven cow’s milk allergy manifested with either skin or gastrointestinal symptoms or both. In addition, 12 healthy infants were studied as controls. The spontaneous, unstimulated and mitogen-induced production of TNF-α and interferon-γ (IFN-γ) by isolated peripheral blood leukocytes was evaluated. TNF-α and IFN-γ production of PBMC was significantly lower in infants with cow’s milk allergy than in healthy children. Our results indicate that, in infants with CMA, the function of TNF-α-producing cells is defective. This might disturb the development of oral tolerance and thereby lead to cow’s milk allergy. These results may help to clarify the etiopathology of CMA.     

Influence of smoking on human milk tumor necrosis factor‐α, interleukin‐1β, and soluble vascular cell adhesion molecule‐1 levels at postpartum seventh day

Background: The aim of this study was to investigate the effect of maternal smoking during pregnancy on human milk interleukin‐1β, tumor necrosis factor‐α (TNF‐α) and soluble vascular cell adhesion molecule‐1 levels at the postpartum seventh day. Methods: Forty‐four mothers (age range: 21–34 years) were enrolled in the study. Mothers were interviewed and classified according to their smoking status into one of two groups: the smoking mothers (n= 21) and the nonsmoking mothers (n= 23). Results: There were no significant differences between study groups with respect to human milk interleukin‐1β (P= 0.12) and soluble vascular cell adhesion molecule‐1 levels (P= 0.83). However, TNF‐α levels were found to be significantly lower in the smoking mothers compared with the controls (P= 0.002). Conclusion: This study shows that maternal smoking during pregnancy affects the levels of TNF‐α in milk. The protective effect of human milk against infections seems to be impaired in smoking mothers.     

The role of TNF‐α in eosinophilic inflammation associated with RSV bronchiolitis

Choi J, Callaway Z, Kim HB, Fujisawa T, Kim CK. The role of TNF‐α in eosinophilic inflammation associated with RSV bronchiolitis.
Pediatr Allergy Immunol 2010: 21: 474–479.
© 2009 John Wiley & Sons A/S The purpose of our study was to investigate whether tumor necrosis factor (TNF)‐α correlates with eosinophilic inflammation that occurs during a lower respiratory tract infection with the respiratory syncytial virus (RSV) in children. Sixty children with RSV bronchiolitis (RSV group) and 20 healthy children with no respiratory symptoms (Control group) were enrolled. We measured the nasal lavage fluid (NLF) Th2 cytokine (IL‐5), proinflammatory cytokine (TNF‐α, IL‐8), eosinophil‐active cytokine [granulocyte‐macrophage colony stimulating factor (GM‐CSF), IFN‐γ], and eosinophil‐active chemokine (eotaxin, regulated on activation normal T cell excreted and secreted) levels for both groups. We also measured serum eosinophil‐degranulation product (eosinophil‐derived neurotoxin; EDN, eosinophil cationic protein; ECP) levels from RSV group. TNF‐α, IL‐8, GM‐CSF, IFN‐γ, and eotaxin levels were significantly higher in the RSV group compared with the Control group. TNF‐α correlated with GM‐CSF (r = 0.87, p < 0.0001), IFN‐γ (r = 0.92, p < 0.0001), eotaxin (r = 0.64, p < 0.0001), and IL‐8 (r = 0.84, p < 0.0001). TNF‐α may have an important role in eosinophilic inflammation of airways in children with RSV bronchiolitis.     

β–HCG Elevation in Wilms Tumor: An Uncommon Presentation

Wilms tumor (nephroblastoma) is a readily diagnosed common abdominal tumor in children. Rarely, it may present with factors that may confound the diagnosis. We report a 6‐year‐old female child who presented with a rapidly growing and invasive abdominal mass with the histopathologic features of Wilms tumor associated with an elevated serum beta human chorionic gonadotropin, which has not been previously reported in this condition.     

Interferon-α potentiates priming-dependent FMLP-induced neutrophil superoxide generation in a patient with chronic myeloid leukemia

13 year old girl diagnosed as having chronic myeloid leukemia (CML) was treated with interferon-α (IFN-α) alone and 4 months later hematological remission was obtained. In the course of the IFN-α treatment there was neither infectious sign nor side effects. In this study we have examined the effect of IFN-α on superoxide O₂^? generation by polymorphonuclear neutrophils (PMN). The PMN of the patient generated less O₂^? than PMN from normal controls. When patient PMN were cultured in the presence of 1000 U/mL IFN-α, enhancement of the formyl-methionyl-leucyl-phenylalanine induced O₂^?generation following priming with tissue necrosis factor-α was observed. Over the course of the IFN-α therapy, such O₂^? generation was gradually restored. It is suggested that CML PMN are in the resting condition in terms of their ability to generate O₂^? and that IFN-α is effective in inducing O₂^? generation by CML PMN.     

Peripheral expansion of Vδ1-Jδ1/Jδ2+γδT cells and large granular lymphocytes in a patient with Wiskott-Aldrich syndrome

A 7 month old Japanese boy was diagnosed to have Wiskott-Aldrich syndrome (WAS) because of eczema, thrombocytopenia, progressive immune defect and CD43 (sialophorin) abnormality. He had developed repeated infections since 16 months of age. γδT cell-receptor positive T cells in the peripheral blood were gradually increased from 3.1% (7 months of age) to 5.6% (12 months), 19.6% (18 months) and 56.7% (25 months). The phenotypes of expanded γδT cells were δTCS1-positive (Vδ1-Jδ1/Jδ2) and CD8 dim-positive. The proportion of increased granular lymphocytes correlated well with that of γδT cells. The significance of peripheral expansion of γδT cells and granular lymphocytes in WAS is discussed.     

X-linked severe combined immunodeficiency with γδT cells

A patient with X-linked severe combined immunodeficiency (X-SCID) was found to have a deletion mutation of a four base pair in the transmembrane domain of the IL-2 receptor γ chain gene, a subunit shared by the receptors for IL-4, IL-7, IL-9, and IL-15 (common γ chain; γc). He had very few αβT cells but had a considerable number of γδT cells in his peripheral blood. Fluorescence in situ hybridization (FISH) analysis showed that the γδT cells in his peripheral blood were not of maternal origin. He had received a Bacillus Calmette-Guerin (BCG) vaccination before recognition of the disease, and the BCG infection remained quiescent with no reaction for 19 months. After successful bone marrow transplantation, the site of the BCG vaccination showed a reaction, and live BCG were detected. It is useful to consider the relationship between the existence of γδT cells and BCG in this case, and it is suggested that γδT cells may be, in a given situation, less dependent on the γc chain than are αβT cells.     

Low frequency of CD4+, but not CD8+, T cells expressing interferon‐γ is related to cow's milk allergy in infancy

Low interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNF‐α) production in peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis and food allergy have been reported previously. However, it remains unclear whether the weak cytokine production is caused by the imbalance of specific T‐cell subsets or by dysregulation of T‐cell function. In the present study we investigated the intracellular expression of these cytokines at a single‐cell level to clarify the background of the disruption. Twelve of 27 breast‐fed infants (0.1–8.8 months of age) had challenge‐proven cow's milk allergy (CMA), and 15 infants were studied as a healthy control group. PBMC were stimulated with phorbol 12‐myristate 13‐acetate (PMA) and ionomycin. The frequencies of the cells expressing intracellular IL‐4, IFN‐γ, and TNF‐α were assessed using flow cytometry. In addition, at this time‐point leucocyte subsets from the milk of mothers of these infants were evaluated using light microscopy. A lower number of CD8⁺ T cells and the defective capability of CD4⁺ T cells to express IFN‐γ in infant's peripheral blood co‐existed with a lower number of macrophages in their mother's milk.     

Cytokines in human milk and late‐onset breast milk jaundice

Background: Maternal milk plays an important role in the development of late‐onset breast milk jaundice (BMJ), possibly due to the unique characteristics of breast milk. The aim of this study was to investigate whether there is a relation between cytokine concentrations in the milk of nursing mothers and BMJ. Methods: Breast milk samples were collected from breast‐feeding mothers of healthy full‐term neonates, 40 with BMJ and 40 without jaundice. Milk samples were taken between the second and the fourth postpartum week. The concentrations of interleukin (IL)‐1 β, IL‐6, IL‐8, IL‐10, and tumor necrosis factor‐α were measured by flow cytometric bead array. Results: There were significant differences between the study groups in terms of IL‐1 β concentrations (P= 0.013). Not statistically significant but similar trends were also seen for IL‐10 (P= 0.067) and tumor necrosis factor‐α (P= 0.053) concentrations. However, no significant differences were noted in IL‐6 (P= 0.174) and IL‐8 (P= 0.285) concentrations. Conclusions: IL‐1 β concentration seems to be increased in milk of mothers whose infants had BMJ. Although the effect of these cytokines on BMJ is unknown, it may cause prolonged jaundice via hepatic uptake, hepatic excretion, conjugation and intestinal absorption.     

Evaluation of proximal tubular function in preterm infants by urinary α1-microglobulin

α₁-Microglobulin is a low molecular weight protein that is relatively stable in urine of low pH. There have been few reports on urinary α₁-microglobulin (U-A₁M) excretion in preterm infants. This study was designed to establish the ranges for U-A₁M in clinically stable preterm infants and to investigate changes observed in sick preterm infants. We measured U-A₁M and urinary β₂-microglobulin (U-B₂M) levels at 1, 4, 7, 14, 28 and 90 days after birth in stable preterm infants (Group 1) and sick preterm infants who were depressed at birth and required immediate resuscitation (Group 2). In Group 1 infants, both parameters were high during the first 28 days and appeared to decline thereafter. U-A₁M in Group 2 infants was only significantly increased compared with Group 1 on day 1, as was U-B₂M. On each day of the study, U-A₁M had significant positive correlations with U-B₂M for all the infants studied. The changes of the two parameters observed in Group 1 probably reflect postnatal evolution of proximal tubular function in stable preterm infants. A comparison of groups 1 and 2 shows a high prevalence of acute tubular injury at birth in sick infants and also suggests that U-A₁M as well as U-B₂M may be a sensitive index for detecting acute tubular damage and for following its course in preterm infants.     

TCR α+β+/CD19+ cell–depleted hematopoietic stem cell transplantation for pediatric patients

TCR α⁺β⁺/CD19⁺ cell depletion is an emerging technique for ex vivo graft manipulation in HSCT. We report 20 pediatric patients who underwent TCR α⁺β⁺/CD19⁺ cell–depleted HSCT in four Australian centers. Conditioning regimen was dependent on HSCT indication, which included immunodeficiency (n = 14), Fanconi anemia (n = 3), and acute leukemia (n = 3). Donor sources were haploidentical parent (n = 17), haploidentical sibling (n = 2), or matched unrelated donor (n = 1). Mean cell dose was 8.2 × 10⁸/kg TNC, 12.1 × 10⁶/kg CD34⁺ cells, and 0.4 × 10⁵/kg TCR α⁺β⁺ cells. All patients achieved primary neutrophil and platelet engraftment, with average time to neutrophil engraftment 11 days (range 8‐22) and platelet engraftment 24 days (range 12‐69). TRM at 1 year was 15%. Rate of grade II‐IV aGVHD at 1 year was 20% with no grade III‐IV aGVHD seen. CMV reactivation occurred in 81% of CMV‐positive recipients, with one patient developing CMV disease. Average time to CD4 recovery (>400 × 10⁶/L) was 258 days. Overall survival for the cohort at 5 years was 80%. This report highlights the initial experience of TCR α⁺β⁺/CD19⁺ cell–depleted HSCT in Australian centers, with high rates of engraftment, low rates of aGVHD, and acceptable TRM.     

α-Mannosidosis: The first Turkish case

We describe a 10 month old boy with α-mannosidosis who presented with recurrent bronchopneumonia and diarrhea. Facial coarsening, deafness, hepatosplenomegaly, umbilical hernia, pectus carinatum and widespread Mongolian spots were distinguishing features. He also had mild skeletal deformities grouped together as ‘dysostosis multiplex’, and vacuolated lymphocytes on peripheral blood smear. These findings coupled with an abnormal urinary oligosaccharide pattern led to the suspicion of a lysosomal storage disease in the patient which proved to be α-mannosidosis. An exceptionally low level of α-mannosidase activity was subsequently found in serum and cultured skin fibroblasts. The patient's brother, who had died at the age of 10 months, had similar features. To the best of our knowledge, this is the first case reported from Turkey.