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


MyD88 signaling in B cells prevents commensals from turning into pathogens

Several years ago Ruslan Medzhitov’s group has published the paper revealing that TLR signaling in response to commensal bacteria is important for the maintenance of intestinal homeostasis. In the model that uses chemical injury (DSS) to compromise the gut integrity such protectiveness provided by recognition of microbiota was completely counter-intuitive result. Why the massive inflammation did not occur when scores of bacterial derivatives have traversed from intestinal lumen to lamina propria and got exposed to the immune system? The recent paper analyses what cellular population is responsible for this unexpected phenomenon and delivers the equally unexpected result – they are B cells. Without MyD88 signaling in B cells commensals that inhabit the gastrointestinal tract show their bad face and turn into pathogens.

The link:

Authors demonstrate that MyD88-deficient mice have compromised survival during DSS treatment and their increased mortality is dependent on the bacterial presence in the gut. The selective inactivation of MyD88 in various cell lineages (epithelial cells, dendritic cells, macrophages, T cells and B cells) shows that the observed mortality effect is due to MyD88 lack in B cells only. The B cell-specific MyD88 signaling seems to regulate IgM response to commensal bacteria. B cells do not need intrinsic MyD88 expression to secrete IgA, although when MyD88 is systemically deleted there is the significant reduction in IgA titers. Finally, the publication points out that IgM-driven complement deposition on microbiota could be accountable for MyD88-dependent homeostasis balance in the gut.

The adaptive response switched on innate-type signals that are received directly by B cells and in which absence commensal microbiota turn to pathogens – such data may have significance that extends beyond strictly practical implications (like new therapies). The intricate relationship between vertebrates and their bacterial symbionts and the impact of microbiota on host physiology are widely accepted facts. But how this association between members of different life domains did originate? I don’t have the answer, nobody probably has and most likely getting such answer is not possible without time machine. However, there are some interesting correlations to be made. Among animals vertebrates and agnathans stand apart as having both the adaptive immune system and the intestinal microflora (at least vertebrates, since I don’t remember reading any paper describing lamprey’s gut bacteria). And despite what an average immunologist trained on mouse models can think of invertebrates – they are highly successful and diverse animals, too. Consider just arthropods or mollusks – they can efficiently defend themselves without the adaptive immunity and spent much more time on this planet than we did. So, what was the evolutionary force behind the formation of adaptive immunity? Maybe it wasn’t protection against infectious organisms?

Kirkland D, Benson A, Mirpuri J, Pifer R, Hou B, Defranco AL, & Yarovinsky F (2012). B Cell-Intrinsic MyD88 Signaling Prevents the Lethal Dissemination of Commensal Bacteria during Colonic Damage. Immunity, 36 (2), 228-38 PMID: 22306056