Observations on the B cell repertoire in young and elderly people

Since I have not written for a while I decided to choose for my comeback something that could be summarized in couple of shorts paragraph, something that I am not very familiar with, so I am not grounded in endless divagations yet something that is of enough interest to whet my appetite for more posts to come soon. I selected an article that compares the overall B cell repertoires between humans that are respectively young or elderly as well as brings an additional variable to the age parameter, that is the seropositivity for either CMV or EBV.

The link: http://www.jimmunol.org/content/192/2/603

This is a study in which authors analyze the rearanged heavy chain gene sequences from PMBC cells isolated from peripheral blood of study participants that are assigned to three different age group. Additionally all collected samples were assessed for the presence of anti-CMV or EBV antibodies. The conclusions could be put in a nutshell in few sentences. There seems to be no difference in V, D and J usage between young and elderly age groups. However, the older age appears to correlate with lengthening of the CDR3 region. People advanced in years also harbor more highly mutated IgM and IgG Ig genes and some of them display a trend towards the accumulation of expanded and persistent B cell clones. Last but not least, either the chronic infection with CMV or EBV appears to imprint its own discreet mark on the overall B cell repertoire.

Krishna M. Roskin, Tho D. Pham, Jonathan Laserson, Chen Wang, Yi Liu, Lan T. Xu, Katherine J. L. Jackson, Eleanor L. Marshall, Katie Seo, Ji-Yeun Lee, David Furman, Daphne Koller, Cornelia L. Dekker, Mark M. Davis, Andrew Z. Fire and Scott D. Boyd (2014). Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires. Journal of Immunology DOI: 10.4049/jimmunol.1301384

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On the wild mice and autoimmunity

Only the relatively small part of mammalian genome is formed by protein-coding sequences. The long stretches between these protein-bearing fragments contain other components which could be either non-transcribed regulatory elements or the variety of non-translated RNAs many of which are also taking part in the regulation of gene expression. This intricate network influences the decision whether a given protein is present in the particular physiological situation and how much of it is available. Therefore the issue how proteins are regulated may in fact be equally or more important than the structural differences in coding parts of the protein in question. The problem of transcriptional regulation that affects the autoimmunity development composes the leading theme of the publication I am discussing today. Like the majority of experimental studies this work uses the cornerstone model organism – the mouse Mus musculus. However, unlike the most it provides also some glimpse into the natural populations of rodents.

The link: http://jem.rupress.org/content/209/12/2307.abstract

The particular problem analyzed by this publication comprises the association between FcγRIIb receptor and the aptitude to develop autoimmune reactions. Authors analyze the populations of wild mice from various part of the globe and find out that the vast majority of them are in the possession of FcγRIIb haplotype that is also present in several laboratory mice known for their propensity to develop the autoimmunity. Such arrangement is of interest because it suggests that in the wild populations such autoimmunity-correlated variant of FcγRIIb may actually be positively selected.

FcγRIIb is the receptor that recognizes the constant portion of an antibody that has switched to the IgG isotype and unlike other receptors that also bind to IgG its ligation on B cells causes the modulation of immune responses. To gain an insight of how FcγRIIb haplotype which is predominantly present in the wild mice may influence the immune response of the classic laboratory strain C57BL/6 (which itself has FcγRIIb haplotype not associated with the autoimmunity) investigators exchange the copies of that receptor by the knock-in approach and study the immune parameters of the resulting strain.

It turns out that the alterations between two haplotypes lie in their transcriptional regulation. In the non-autoimmune setting (as demonstrated by C57B/6 strain) FcγRIIb is upregulated on germinal center B cells whereas the knocked-in variant of this receptor cancels this up-regulation. Additionally, when compared to to C57BL/6 line the novel knock-in strain displays the reduced amount of FcγRIIb on activated B cells, splenic transitional B cells and bone marrow residing pre-B cells. Authors pin down the difference in the DNA sequence that underlies the disparate regulation of two variants and propose the transcription factor which may be responsible for the up-regulation seen when the non-autoimmune haplotype is present. Finally, investigators also show that the two haplotypes in questions differ in qualitative terms that comprise the number of germinal center B cells, affinity maturation and autoimmunity development.

Why do I think that this report is interesting? When you look at the paper conclusions from the broader perspective they seem to confirm the notion that in the natural circumstances the autoimmunity is not a problem. The widespread presence of that particular FcγRIIb haplotype among the wild mice suggests that at least for germinal center B cells the natural selection may have favored the situation where the efficiency of immune reaction is maximized even at the cost of potential collateral damage. Maybe it looks like the obvious notion but it is good to have some hard data that confirm it.

Espeli, M., Clatworthy, M., Bokers, S., Lawlor, K., Cutler, A., Kontgen, F., Lyons, P., & Smith, K. (2012). Analysis of a wild mouse promoter variant reveals a novel role for Fc RIIb in the control of the germinal center and autoimmunity Journal of Experimental Medicine, 209 (12), 2307-2319 DOI: 10.1084/jem.20121752