Thursday, February 16, 2017

IL-33 → MyD88 pathway drives type II immunity in female genital mucosa

Type II immunity underlies several types of immune conditions such as asthma, allergy or response to parasitic helminths. It is not yet fully clear how type II immunity contributes to host's defenses. At this stage scientific inquiry is mostly focused on uncovering cellular and molecular mechanism behind type II immunity.

For these experiments the authors have used papain, a well established experimental type II inducer protease. As reported before, papain required enzymatic activity for its type II response.

Papain application to female vaginal mucosa induced IL-33, a member of IL-1 family implicated in type II immunity.

Indeed, IL-33 deficient mice showed reduced secretion of components of type II immunity (IL-4, IgE).

Interestingly, type II immunity in response to papain in female genital tract depended on IRF4+ CD11c+ dendritic cells but it was independent of basophils and eosinophils.

Furthermore, type II immunity in response to papain application to female vaginal tissue depended on MyD88 signaling.  

In summary, this study confirms the role of IL-33 in type II immunity.

David Usharauli

Thursday, February 9, 2017

Newborns' resistance to pneumonia is driven by acquired microbiota

This week Science Translational Medicine published new study that showed that in newborn mice resistance to pneumonia is driven by neonatally acquired microbiota. It revealed how antibiotic therapy given to mothers near time of delivery could alter and weaken baby's defenses against airway pathogens.

Newborn mice derived from germ-free or from antibiotic-exposed pregnant mice display increased susceptibility to Streptococcus pneumoniae serotype 19A-induced pneumonia that could be reversed by microflora.

Application of epithelial-focused cytokine IL-22 had similar effect on reversing newborn mice susceptibility to pneumonia.

In the lungs of newborn mice, majority of IL-22 is made by RORgt+ group 3 innate lymphoid cells (ILC3).

Antibiotic therapy of pregnant mice reduced IL-22+ ILC3 population in the newborn lungs that could be reversed by microflora.

Moreover, depletion of endogenous ILC3 increased host's susceptibility to pneumonia that could be reversed by adoptive transfer of WT ILC3.

In summary, this study showed that antibiotic therapy of pregnant females at the time of delivery could profoundly affect newborns' ability to mount proper defense against airway pathogens by depleting microflora and disrupting microflora → ILC3 → IL-22 axis.

David Usharauli

Tuesday, February 7, 2017

cGAS puts gas on anti-tumor effect of checkpoint inhibitor

This week PNAS published new article explaining mechanism of action of checkpoint inhibitors, such as anti-PDL1, in tumor immunity. It shows that cytoplasmic DNA sensor cGAS/STING pathway synergize with anti-PDL1 therapy in mouse model of melanoma.

While this study provides noteworthy observation, it is poorly done. For example, when comparing WT and KO mice (cGAS or STING KO mice), the authors did not mention if they used littermate control in these experiments.

In addition, when the authors used exogenous cGAMP (product of cGAS activity detected by STING), they did not use it on cGAS or STING KO mice as controls to verify relationship between cause and effect.   

In summary, the connection between DNA recognition system and checkpoint inhibitors is very interesting. Whether it is a simple generic augmentation of T cell priming or specific stimulation of tumor-specific T cells is to be seen.   

David Usharauli