Wednesday, February 22, 2017

Antigen-specific Tregs maintain immune privileges of male reproductive tract

This week Journal of Clinical Investigation published very good research article that shed light on how tolerance to sequestered self-antigens expressed by immune privileged  tissues are established

Some tissues such as brain, eye, testis or ovaries are thought to be "immune privileged" organs meaning that ordinarily immune system does not see their antigens. However, in this paper, the authors showed that in fact some testes antigens in male mice, for example lactate dehydrogenase 3 (LDH3), are actually secreted and detected by immune system.   

Series of experiments confirmed that WT male mice did not respond to LDH3 immunization, while female and LDH3-null male mice mount detectable immune response to it. This suggested that male mice were physiologically tolerant to LDH3. Notable, both male and female mice could be immunized against another testis antigen, zonadhesin (ZAN), implying absence of tolerance to ZAN in male mice. 



So, how male mice were tolerant to LDH3? To answer it, the authors temporally depleted Tregs and it led to immune response to LDH3 in immunized WT male mice. since no changes were seen in response to ZAN, the authors concluded that tolerance to LDH3 in WT male mice was dependent of presence of FOXP3+ Tregs.



Furthermore, depletion of Tregs even in absence of testes antigen immunization still led to autoimmune pathology in testes in ~40% of male mice ("autoimmune orchitis occurs in autoimmune polyendocrine syndrome 1 (APS1) patients due to mutations of AIRE, possibly associated with impaired thymic deletion of autoreactive T cells and deficient Treg function")




In summary, this study suggests that "immune privilege" is not absolute and self-antigens that naturally leak maintain tolerance by induction of antigen-specific Tregs.

David Usharauli



  

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