Background Combined immunodeficiencies (CIDs) denote inborn errors of T-cell immunity with T cells present but quantitatively or functionally deficient. Impaired humoral immunity, either due to a primary B cell defect or secondary to the T-cell defect, is also frequent. Consequently, patients with CID display severe infections and/or autoimmunity. The specific molecular, cellular, and clinical features of many types of CID remain unknown. Methods We performed genetic and cellular immunological studies in five unrelated children who shared a history of early-onset invasive bacterial and viral infections, with lymphopenia and defective T-, B-, and NK-cell responses. Two patients died early in childhood, whereas the other three underwent allogeneic hematopoietic stem cell transplantation with normalization of T cell function and clinical improvement. Results We identified bi-allelic mutations in the Dedicator Of Cytokinesis 2 (DOCK2) gene in these five patients. RAC1 activation was impaired in T cells. Chemokine-induced migration and actin polymerization were defective in T, B, and NK cells. NK-cell degranulation was also affected. The production of interferon (IFN)-α and -λ by peripheral blood mononuclear cells (PBMCs) was diminished following virus infection. Moreover, in DOCK2-deficient fibroblasts, virus replication was increased and there was enhanced virus-induced cell death, which could be normalized by treatment with IFN-α2β or upon expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a Mendelian disorder with pleiotropic defects of hematopoietic and non-hematopoietic immunity. Children with clinical features of CID, especially in the presence of early-onset, invasive infections may have this condition.

Asthma risk is lower after wheezing associated with respiratory syncytial virus (RSV) than with non-RSV infection in infancy. RSV is the main wheezing-associated virus in infants aged ,6 months. We evaluated the outcome of children hospitalised for bronchiolitis at ,6 months of age, with special focus on viral aetiology and early risk factors.Out of 205 infants hospitalised for bronchiolitis at ,6 months of age, 127 (62%) attended a control visit at a mean age of 6.5 yrs and the parents of an additional 39 children were interviewed by telephone. Thus, follow-up data collected by identical structured questionnaires were available from 166 (81%) children. Viral aetiology of bronchiolitis, studied on admission by antigen detection or PCR, was demonstrable in 97% of cases.Current asthma was present in 21 (12.7%) children: 8.2% in the 110 former RSV patients versus 24% in non-RSV patients (p50.01). 45 (27%) children had ever had asthma. In adjusted analyses, atopic dermatitis, non-RSV bronchiolitis and maternal asthma were independently significant early-life risk factors for asthma.The risk of asthma was lower after RSV bronchiolitis than after bronchiolitis caused by other viruses in children hospitalised at ,6 months of age.

Summary:Purpose: Pro-and antiinflammatory cytokines regulate the febrile response during infection. Febrile seizures (FSs) conversely are associated with rapid onset of high fever. Activation of the cytokine network has been shown in previous studies of FSs and cytokines. In this study, the association between cytokines and FSs was further investigated.Methods: Interleukin-1␤ (IL-1␤), interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), interleukin-10, and tumor necrosis factor-␣ plasma levels were measured with enzyme-linked immunosorbent assay in 55 children with FSs and in 20 age-matched febrile controls immediately on arrival at the hospital. Cerebrospinal fluid cytokine levels also were measured in 16 FS children.Results: The plasma IL-1RA/IL-1␤ ratio (mean, 2,133 vs.119; median, 790 vs. 105; p < 0.0001) and plasma IL-6 (mean, 41.7 pg/ml vs. 16.1 pg/ml; median, 19.6 pg/ml vs. 10.5 pg/ml; p ‫ס‬ 0.005) were significantly higher in FS patients compared with control children. Logistic regression analysis was used to find the most significant predisposing factors for FSs. In this analysis, the high plasma IL-1RA/IL-1␤ ratio was the most significant factor connected to FSs (OR, 41.5; 95% CI, 4.9-352.8), but high plasma IL-6 also was significantly associated with FSs (OR, 5.3; 95% CI, 1.4-20.3).Conclusions: Present results support the hypothesis that the cytokine network is activated and could have a role in the pathogenesis of FS.

Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway.

We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.