Wednesday, March 2, 2016

Microbiota-specific serum IgG protects against systemic bacterial dissemination

This week journal Immunity published a study from Gabriel Núñez lab describing the role of serum IgG in protecting the body against systemic dissemination of gut commensal bacteria.

Initially, the authors showed that WT mouse serum contained IgG specific for fecal bacteria and its production depended on (a) gut microflora and (b) T cells.

These data indicated that gut bacteria [or its parts] "circulate systemically in spite of intact intestinal barriers." Indeed, the presence of bacterial 16S rRNA gene was confirmed in the spleens, for example.

However, the authors showed that such "access" was not a "random" translocation. Only certain gut bacteria (for example, Enterobacteriaceae and Moraxellaceae, but not Porphyromonadaceae and Prevotellaceae) were able to disseminate internally.

Correspondingly, immunoblotting analysis of serum IgG against fecal bacterial antigens confirmed "selective" IgG response to gut flora gram-negative Escherichia coli (EC) or Klebsiella pneumoniae (KP), but not to gram-positive Enterococcus faecalis (EF) or Clostridium bifermentans (CB).

In parallel experiments, the authors showed that serum IgG from WT mice, but not from quasi-monoclonal (QM) mice which have limited B cell repertoire, could protect B cell deficient mice from gram-negative E.coli infection.

Since gram-negative bacteria are recognized by TLR4 the authors tested mice deficient TLR4 signaling pathway. Indeed, absence of TLR4 specifically on B cells selectively reduced serum IgG against fecal bacteria (single TLR4-KO mice showed the same effect, while single TLR2-KO had no effect).

Similar to B cell-deficient mice, mice with TLR4-deficient B cells were highly susceptible to E.coli infection and could be rescued only by IgG from WT mice, but not by IgG from quasi-monoclonal (QM) mice.  

Analysis of gram-negative WT or mutant bacteria showed that serum IgG was mostly directed against murein lipoprotein (MLP), a highly conserved outer membrane protein of ~7 kD expressed abundantly in gram-negative enterobacteria.

Finally, the authors showed that monoclonal anti-MLP IgG injection could protect B cell deficient mice from E.coli infection almost as efficiently as total WT IgG injection.

In summary, this study suggests that normal serum IgG protects the body in situations when gram-negative bacteria from gut gains access to systemic circulation (for example, in "leaky gut" or during a sepsis). Generation of such protective IgG requires presence of T cells and normal B cell receptor diversity.

It is not clear what role IgA plays in this process. The authors have not tested IgA-KO mice to determine its exact contribution in preventing gut flora translocation. No data are provided regarding presence and [amount] of gut bacteria in systemic circulation in different KO mice shown in this study either. This would have given some valuable information.

David Usharauli

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