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Background Characterization of regulatory immune pathways is a research priority for both the pathogenesis of allergic disease and potential therapeutic strategies. Objective The thymus is a rich source of regulatory T (Treg) cells, which offers a novel opportunity to document the maturation of these pathways beyond limited studies on small volumes of peripheral blood available from young children. Methods Thymus tissue was collected from children undergoing cardiac surgery (age, 1 week to 14 years), and skin prick testing was performed from 12 months of age. The ontogeny of Treg cell maturation and function was examined in atopic (n = 20) and nonatopic (n = 20) children by assessing their phenotype, enumeration, proliferation, and suppressive ability. Results Age-related changes in the thymic cytokine milieu paralleled the changes seen in peripheral immune function. Specifically, the thymic microenvironment is similarly T H 2 skewed during the early postnatal period, and this undergoes age-related suppression as the T H 1 (IFN-γ) response increased. We detected CD4 + CD25 + CD127 lo/− forkhead box protein 3 (FOXP3)–positive Treg cells in the neonatal thymus. These cells suppressed the proliferative response to allogeneic stimulation of CD4 + CD25 − T cells dose dependently. In nonatopic children Treg cell turnover and suppressive function increased with age and paralleled the increase in global thymic FOXP3 mRNA expression, whereas in atopic children Treg cell maturation was significantly delayed compared with that seen in age-matched nonatopic children. Conclusion These data suggest that the developmental changes in the thymus parallel the recognized changes in peripheral blood responses. There is also a developmental delay in the function of thymic regulatory cells in atopic compared with nonatopic children. These differences are fundamental to understanding early events that lead to immune dysregulation and might predispose to allergic disease.

Background Environmental changes influencing the interaction between the maturing immune system and pathogen exposure are implicated in the rising rates of allergic disease. There is emerging evidence that differences in innate immune function contribute to the development of allergy. Consequently, associated genetic factors may be critical for the difference in immune ontogeny, seen in allergic children. Aims We examined if genetic variation associated with the IL28B gene, encoding for the potent immune modulator IFN lambda 3, contributes to the divergent immune response in selected children who were followed from birth to 5 years of age (35 allergic and 35 non-allergic children). Results We found that carriage of the T allele of the SNP rs12979860, tagging the IL28B gene, is significantly associated with allergy ( p = 0.004; OR 4.56). This association increases with age and is particularly evident in girls (OR 16). In addition, variation at rs12979860 correlates with differences in the pro-inflammatory profile (IL1B production) at birth after TLR stimulation of cord blood cells. Conclusion In the context of rising rates of disease, the genetic variation described may contribute to key differences in innate immune development of allergic children and points towards a role of IFN lambda III in allergic disease pathogenesis.

Background The protective effect of Mycobacterium bovis BCG vaccination against infection and atopy varies between populations. Objective To identify differences in neonatal responses to BCG between diverse populations and study longitudinal associations with memory T-cell responses. Methods Cord blood mononuclear cells were collected from Papua New Guinean (PNG) and Western Australian (WA) newborns. Toll-like receptor (TLR)-2, TLR4, and TLR9 mRNA expression and in vitro BCG-stimulated (±IFN-γ priming) innate cytokine responses were compared. When PNG infants were 3 months old, PBMCs were stimulated in vitro with Mycobacterium -purified protein derivative (PPD) to determine memory T-cell responses. Results BCG-induced IL-10 and IFN-γ responses were significantly higher in cord blood mononuclear cells of PNG newborns, and TLR2 and TLR9 expression was significantly higher and TLR4 expression lower compared with WA newborns. High neonatal IL-10 and low IFN-γ responses to BCG were found to promote the development of PPD-memory T H 2 responses in infancy, whereas neonatal BCG-TNFα responses inhibited the development of PPD-IL 10 responses. When primed with IFN-γ, BCG-induced TNF-α, IL-12p70, and in particular IFN-γ responses were enhanced to a significantly higher extent in WA than in PNG newborns. In response to IFN-γ priming and BCG stimulation, natural killer cells of WA newborns produced IFN-γ, whereas natural killer cells of PNG newborns contributed only indirectly to this response. Conclusion Neonatal BCG-related innate immune responses control the differentiation of T H memory responses and vary between populations. This may explain differences in the effects of BCG vaccination between populations.

BACKGROUND Although endoscopic sinus surgery has been widely used for the treatment of chronic rhinosinusitis, some patients fail to derive clinical benefit from this procedure. We evaluated the efficacy of a treatment regimen consisting of selective irrigation of diseased sinus mucosa with topical antibiotics and steroids in conjunction with oral antibiotics and steroids. METHODS Twenty patients suffering from chronic rhinosinusitis and resistant to medical treatment (mean duration 3.4 years) underwent intubations of the affected maxillary and/or ethmoid sinuses for irrigation for a duration of 21 to 30 days. A computed tomographic (CT) scan of the paranasal sinus was taken both pre- and post-treatment and staged according to the Lund-MacKay system. Clinical symptoms were scored for rhinorrhea, facial pain, nasal congestion, and smell at least 2 months prior to treatment and approximately 18 months after the follow-up. RESULTS The clinical experience with the technique of intubation and irrigation was well tolerated by all patients. We found an improvement in all symptom scores, including rhinorrhea, nasal congestion, smell (n = 20; p < .001), and facial pain (n = 20; p < .01). Similar improvements were seen on the CT scans, with reduced staging from 14.6 +/- 1.1 to 5.6 +/- 1.1 (p < .001). Only three patients did not respond to selective irrigation of the sinuses and needed further surgery. CONCLUSION These results suggest that sinus irrigation could provide a reasonable and effective alternative to ethmoidectomy with drainage procedures and offer promise for the treatment of patients with chronic rhinosinusitis who are resistant to medical treatment.

Asthma was originally described as an inflammatory disease that predominantly involves the central airways. Pathological and physiological evidence reported during the past few years suggests that the inflammatory process extends beyond the central airways to the peripheral airways and the lung parenchyma. The small airways are capable of producing T-helper-2 cytokines, as well as chemokines, and they have recently been recognized as a predominant site of airflow obstruction in asthmatic persons. The inflammation at this distal site has been described as more severe than large airway inflammation. These findings are of great clinical significance, and highlight the need to consider the peripheral airways as a target in any therapeutic strategy for treatment of asthma.

Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the 299Gly and 399Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence (299Asp/399Thr), or the 299Gly or 399Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing 299Gly or 399Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-κB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-α. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus.

Methods In a double-blind randomized controlled trial (ACTR N12606000281594), 420 infants of high atopic risk received fish oil (containing 280mg docosahexaenoic acid (DHA) and 110mg eicosapentanoic acid (EPA)) or control oil daily from birth to six months. Fatty acid levels, induced cytokine responses, were assessed at 6 months of age in 150 infants. Eczema, food allergy, asthma and sensitization were assessed in 323 infants who completed clinical follow up at 12 months of age.

Results Der p 1 was present in 58% Brazilian, 70% French, and 78% Australian colostrum. Median [Der p 1] was similar between countries (96 pg/mL). In mature milk, Der p1 was found in 55% of samples, median [Der p 1] was 65·9 pg/mL and was significantly lower than in colostrum (p=0·0001). Der p 1-containing milks were able to induce basophils degranulation. Mice breastfed by Der p-exposed mothers had 5-fold increased levels of Der p specific IgE and IgG1 compared to mice breastfed by naive mothers. Their allergic airway inflammation was not affected.