Saturday, April 14, 2018

Access to self antigens during germinal center reaction improves self/nonself discrimination against mimicry antigens

This week journal Science published short paper from Chis Goodnow's lab that raises very interesting question about biological significance for existence of anergic self-reactive B cells. Ordinarily, developing B cells when encountering self-antigens undergo deletion, receptor editing or physiological receptor signaling down-regulation that makes such 'anergic' B cells refractory to presence of normal level of self antigens. However, anergic B cells could be re-energized if challenged with high density self antigens or antigens sharing epitope similarity with self antigen.

Now, new study indicates that rather than developing into full blown auto-reactive immune response, anergic B cells when challenged with mimicry antigens mutates its receptors in a such a way, during process of hypermutation, as to achieve a high degree of discrimination between mimicry antigen and actual self antigen.   

The experimental set up itself is quite simple, only complex aspect was to analyze single cell B cell receptor mutation and their binding affinity recovered after antigen challenge. Two type of hosts were used here. Both groups harbor small numbers of self-reactive B cells (CD45.1+ SWHEL B cells)  but only one group also harbored a specific antigen detected by these transgenic SWHEL B cells and expressed "as as an integral membrane protein, mHEL3X, encoded by a transgene with a ubiquitin promoter".

As expected SWHEL B cells in double transgenic hosts were anergic with decreased surface immunoglobulin M (IgM) expression. However, these anergic B cells could be re-activated in germinal centers when challenged with Sheep red blood cells (SRBCs) covalently coupled with self antigen, HEL3X, at high density.

Next set of experiments however showed very unusual results. When challenged with mimicry antigen DEL which slightly differs from self HEL antigen anergic B cell receptors in double transgenic hosts rapidly accumulated mutations that decreased binding affinity to self HEL antigen.

In fact, single cell BCR receptor analysis clearly showed that presence of self antigens dramatically enhanced anergic B cell receptor mutations that allowed up to 5,000-fold better discrimination capacity between self and mimicry antigen (pre vs. post comparison). This is based on assumption that starting affinity to self are the same for both normal and anergic SWHEL B cells population. 

In summary, this study suggests that during germinal center reaction where B cell receptors undergo hypermutation, anergic B cell repertoire, in presence of self antigen, could be salvaged (redeemed) by accelerated accumulation of mutations that modifies their original specificity away from self antigens and allowing more fine discrimination between self and mimicry, cross-reactive nonself antigen. In this scenario, self antigens serve as negative-feedback templates that hypermutating receptors interacts repeatedly in real time to achieve minimal level of binding.

In my view such negative-feedback loop to B cells can only delivered by specialized cell type in germinal center that maintains, keeps memory of host's unadulterated "self antigen collection'' visible to B cells, a task somewhat similar to Foxp3+ Tregs. So, it is possible that new cell type need to be discovered that does it or it is also possible that the same Foxp3+ Tregs localized in germinal centers, referred as follicular Foxp3+ T regs, do it too. 

What are the global implication for such mechanism: It could explain why anergic B cells hang around and how their repertoire could be salvaged without compromising tolerance. The authors also puts forward another intriguing idea that commensal mcrobes and their antigens could serve as negative-feedback loop 'self' templates for anergic B cells that allows them to discriminate between self and mimicking nonself during immune response. 

posted by David Usharauli       

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