Saturday, May 7, 2016

Maternal IgG fully compensates IgA to influence newborn's immune system maturation

The mammalian babies are born with immature immune system. It is not clear why it is the case, though in my view, most likely explanation would be that it has something to do with initial encounter with and adaptation to endogenous commensal gut [and other tissue] microbiota. 

Since babies are born more or less sterile [devoid of microorganisms], their immune system has to learn to set a "baseline" for what is a "normal" microbial community [i.e. microbiota]. Babies immune system needs to tolerate this local microbial community. Once such "baseline" and tolerance threshold are set, only then baby's immune system can recognize to respond to "foreign" microbe and reject it. 

One way for a mammalian babies to set normal tolerance threshold and "baseline" is via instructions from their mom's [experienced] immune system. Maternally derived IgA and IgG accumulate in newborns [from milk or during gestation] and transfer initial instructions for proper immune maturation in babies.

In this regard new study in Cell is interesting. By utilizing several of genetically-modified mouse strains, the authors were able to show that maternal milk-derived IgG3 and IgG2b (subclasses of IgG), could fully compensate IgA in "educating" newborn's immune system.

First, the authors showed that normal WT mouse serum detects gut microbiota. As expected, microbiota-bound IgA was detected even in absence of added serum. As expected, serum from µMT- /- mice that lack most of B cells did not stain gut flora.

Presence of microbiota-specific IgG in the serum was unexpected [unlike IgA or IgM]. Further analysis revealed that these IgG was made mostly of IgG3 and IgG2b subclasses.

And, these IgG3 and IgG2b were indeed microbiota-specific because no staining was observed with serum from germ-free mice that lack microbiota.

Presence of microbiota-specific IgG3 and IgG2b were independent of adaptive T cells and dependent on TLR signaling.

Microbiota staining dynamic revealed that serum IgG in pups before age of 4 weeks were maternally derived [between weeks 4-8, pups were starting to make their own microbiota-specific IgG antibodies].

Next big question that the authors answered was to show what was the immunological consequences of failure to transfer maternal antibodies to offspring. First, they showed that specific absence of milk-derived antibodies (pups born to µMT- /- parents or WT pups cross-fostered by µMT- /- moms) increased both microbiota translocation and effector CD4 T cells differentiation in pups.

Second, pups born to IgA-KO parents showed no such changes indicating something else compensated IgA in "educating" newborn's immune system.

Indeed, if mom's milk did not contain both IgA and IgG (in pups born to IgA/FcRn double KO parents), then pup's immune system showed over-activation. This indicates that microbiota-specific IgG could fully compensate microbiota-specific IgA deficiency with regard of immune system education [however, "cleaner" model would be to use IgG-KO mouse here, if available].

Finally, at cellular level, absence of milk derived IgG was associated with over-expansion of antibody-inducing follicular T helper cells (Tfh cells) and germinal-center B cells in 3-4 weeks old pups.

In summary, this fundamental study showed that in mice milk-derived antibodies, both IgG and IgA subtypes, play important role in setting normal threshold of immune maturation [activation] in newborns, thus contributing to proper education of developing immune system.

David Usharauli

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