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Relative immunity

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Science Translational Medicine  03 Feb 2016:
Vol. 8, Issue 324, pp. 324ec20
DOI: 10.1126/scitranslmed.aaf2007

The Hygiene Hypothesis has been proposed as a possible explanation for the rising prevalence of asthma and allergy. Several studies have demonstrated that siblings and larger household size reduce the risk of asthma development. However, potential mechanisms by which siblings exert this protective effect are not known. Now, Wolsk et al. describe a highly significant up-regulation of airway immune mediators in neonates with siblings, suggesting how siblings may exert an early immune modulatory effect.

Using filter paper strips inserted into the nasal cavity of 571 one-month-old neonates enrolled in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) birth cohort, mucosal lining fluid samples were analyzed for cytokines and chemokines grouped into Type 1 (TH1\CD8+/NKcell/ILC1), Type 2 (TH2/eosinophil/ILC2), Type 17 (TH17/neutrophil/ILC17) and regulatory (Treg) responses. The authors found that neonates with siblings had a significant up-regulation of 19 out of 20 mediators examined compared with neonates without siblings. The up-regulation persisted after adjustment for several confounding variables, suggesting that the presence of a sibling exerts an immune modulatory effect even when confounders are accounted. These findings were supported by a principal components analysis that demonstrated a high correlation between the 20 immune mediators but with a distinction between neonates with and without siblings. To investigate a possible in utero immune priming effect, the authors discovered an inverse association between time since last childbirth for the mother and the airway immune response in the neonate. Additionally, the ratio of cytokine/chemokine expression in neonates with siblings:neonates without siblings was highest for Type 1 and Type 17 mediators, although this up-regulation was not compared statistically with Type 2 or regulatory mediators. This supports the notion that presence of a sibling may help shift away from the Type 2 response of infants at birth. Further work clarifying the relative increase in Type 1 and Type 17 responses compared with Type 2 responses is required.

Importantly, the authors investigated whether the enhanced immune responsiveness might be explained by microbial exposure from the sibling. Nasopharyngeal samples to detect piconavirus by PCR and hypopharyngeal aspirates to assess bacterial culture of H. influenza, S. pneumonia, and M. catarrhalis were also collected at 1 month. Previous work by this group has found that infants with siblings had a higher detection rate of airway viruses and bacteria. Although adjustment for the presence of the limited pathogenic airway bacteria and piconavirus investigated decreased the overall levels of immune mediators, the overall affect of siblings persisted. This suggests that the effect of siblings on immune responses may be mediated by additional mechanisms besides carriage of airway pathogens. However, future studies with a more expansive examination of other bacterial and viral exposures are critical to verify these findings, as this study performed a limited examination of pathogens.

It is well established that the immune system continues to develop during early childhood and that environmental exposures at this time affect immune development. Although presence of siblings has been associated with lower asthma risk, the mechanisms by which siblings exert this protective effect are not well-defined. This work by Wolsk et al. demonstrates that the presence of siblings at birth associates with an up-regulation of neonatal nasal mucosal immune responses that is mediated both through carriage of airway pathogens and related to immune priming. It elucidates an important mechanistic link between sibship and asthma inception.

H. Wolsk et al., Siblings promote a Type 1/Type 17-orientaed immune response in the airways of asymptomatic neonates. Allergy 10.1111/all.12847 (2016). [Abstract]

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