B cells can secrete IL-6 and drive Th17 response in autoimmunity

The main task of B cells is to release protective immunoglobulins. Yet it is not their only role since they are apparently capable to take on the diverse array of activities that do not directly form a part of effector humoral responses. Instead of just secreting antibodies B cells can influence the outcome of an immune response by dictating the behavior of other cell types. It appears that such mechanism may underlie the development of autoimmunity in the central nervous system. I have found the publication that by combining the work on a mouse experimental model and the analysis of human patients presents the compelling evidence pointing to how B cells stimulate CD4 T cells into the pathogenic phenotype through the antibody-independent action.

The link: http://jem.rupress.org/content/209/5/1001.abstract

The aim of the paper is to seek a clarification for the unexplained outcomes of various B cell depletion treatments during the course of multiple sclerosis or its mouse model – EAE. For example, the targeted reduction of antibody-secreting plasma cells results in the worsening of disease symptoms. Similarly, the broad B cell depletion leads to the improvement that precedes the drop in the level of autoantibodies. To understand whether B cells may have an additional antibody-independent role in the pathogenesis of multiple sclerosis or EAE investigators focus on IL-6 which is a pro-inflammatory cytokine and the essential factor in autoimmune conditions that afflict the central nervous system. They analyze how B cells can contribute to IL-6 secretion in the context of autoimmunity and assess if B cell-derived IL-6 may influence the conduct of CD4 T cells which are the main factor in multiple sclerosis/EAE development.

Authors show that B cells have the inherent ability to secrete IL-6 when they are stimulated with ligands engaging innate receptors (LPS or CpG plus anti-CD40 antibody) and attempt to prove that such B cells’ capacity may have the physiological importance.  To this end they demonstrate that B cells collected from mice that received EAE-driving immunizations are enriched for IL-6 mRNA compared to B cells from healthy mice. Additionally, the abrogation of IL-6 expression in B cells blunts the severity of neurological symptoms typical to EAE. The final proof indicating for the antibody-independent role of B cells in murine EAE pathogenesis comes from BCDT (B cell depletion therapy) experiments as such treatment is effective in alleviating the EAE-resulting damage only when B cells are competent to release IL-6. On the other hand, knocking out IL-6 expression in B cells does not influence their capacity to secrete antibodies. Investigators also pinpoint that marginal zone B cells are the subset which is most proficient in IL-6 release.

IL-6 is a cytokine involved in the formation of Th17 subset which is known for its participation in pathogenic responses pertinent to the autoimmunity driven by CD4 T cells. Because EAE stands as a representative such disorder, authors ask whether B cell-derived IL-6 could impact the development of Th17 population in the course of this disease. They demonstrate that it is indeed the case since the ablation of IL-6 expression in B cells is able to diminish the propagation of Th17 response during EAE. Remarkably, the B cell-derived IL-6/Th17 axis is operative regardless of antigen specificity as the Th17 population is also less numerous following immunizations with EAE-irrelevant OVA peptide. In the last part of paper devoted to human patients investigators show that the ability of B cells to control Th17 development through IL-6 release may be conserved across mammalian species.

The information that this report contains is obviously important because of its practical value but it also stimulates to ask broader questions. Why we are equipped with signaling pathways like the one described in the discussed report? To what end the apparently pathogenic (in the context of autoimmunity) B cell-derived IL-6/Th17 axis has evolved? Why B cells are so prone to act as autoimmunity mediators when stimulated with TLR ligands (especially nucleic acid-recognizing ligands)? The case of lupus and now that of multiple sclerosis have provided enough evidence for such ostensibly rebellious nature of B cells. Could potentially pathogenic pathways starting with the recognition of TLR ligands by B cells represent an evolutionary trade-off with the better control of gut commensal bacteria as an asset and the danger of autoimmunity as a liability? As a matter of fact MyD88 signaling in B cells has been shown to take part in accommodating the intestinal microbiota by preventing their systemic spread when colonic injury occurs (B Cell-Intrinsic MyD88 Signaling Prevents the Lethal Dissemination of Commensal Bacteria during Colonic Damage: Immunity. 2012; 36 (2): 228-38).

I have one more remark concerning the data that this paper presents. Authors show that CpG (TLR9 ligand) is more efficient that LPS (TLR4 ligand) in driving IL-6 secretion by B cells. Nucleic acid-recognizing TLRs are unusual because they are hidden from the cell surface to endolysosomal compartments. Apart from that, recent publications by Gregory Barton’s group reveal that TLR9, TLR7 and TLR3 (expressed by a macrophage cell line) require proteolytic processing prior to becoming functional detectors. Such feature is interpreted as an additional safety measure since ligands for these receptors are expressed both by host cells and pathogens. I am not really sure if it makes sense but nobody checked if the similar requirement for proteolytic cleavage exists in B cells.

Barr TA, Shen P, Brown S, Lampropoulou V, Roch T, Lawrie S, Fan B, O’Connor RA, Anderton SM, Bar-Or A, Fillatreau S, & Gray D (2012). B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. The Journal of experimental medicine, 209 (5), 1001-10 PMID: 22547654

Neutrophils and marginal zone B cells – a new partnership

Being interconnected – that’s one of cardinal features pertinent to the mammalian immune system. Cellular subsets involved in an immune response seldom act alone beyond the initial signal recognition stage. Instead, the converging and augmentation of warning signs, the induction, adjustments or limitations of effector branches and finally the maintenance of immunological memory – these steps are usually carried out by two or more interacting populations. It is always so interesting to learn about new connections between cells of immune system, therefore recent report describing the supportive role of neutrophils in the antibody secretion process has immediately caught my attention.

The link to the publication:


This article reminds me the other, now pretty notorious story about the partnership of germinal center B cells and follicular helper CD4 T cells – an interaction that’s been proven to be so important during the antibody maturation process. But we have quite other players this time around.  Marginal zone B cells form the population posed at the anatomical intersection between circulation and lymphoid areas in the spleen. They are considered to possess blood filtering functions and are critically important in sepsis. There also were reports describing their pre-activated phenotype, which means that they can be easily stimulated to make antibodies. Neutrophils are most numerous granulocytes; they are cells extremely proficient in phagocytosis – kind of the always-ready emergency crew generally thought to be the first line of defense.

The research is performed on human cells combining imaging and functional data. The paper starts with series of pictures showing that neutrophils can colonize the splenic marginal zone under homeostatic but not inflammatory conditions. As a control authors perform the identical staining procedure with secondary lymphoid organs that have no marginal zone like tonsils, Peyer’s patches and peripheral lymph nodes. Then, compelling and diverse evidences are presented on how neutrophils enhance repertoire diversification and antibody secretion by marginal zone B cells. Apart from that, authors provide an in-depth description of the novel neutrophil “B helper” phenotype that is attained on contact with splenic epithelial cells.

However, it is the last and shortest paragraph of result section that really draws my attention. According to authors the increase in splenic colonization by neutrophils correlates with postnatal microbial colonization and fluorescence microscopy has shown LPS presence in adult but not fetal spleens. LPS was also shown to boost reprogramming of neutrophils to the “B helper” phenotype by splenic epithelial cells. Additionally, germ-free mice displayed lower levels of “B helper” neutrophils. Authors state – “Thus, we propose that TLR signals from mucosal commensals enhanced the splenic recruitment and reprogramming of N BH cells to enhance innate MZ B cell responses to highly conserved microbial TI antigens”.

Postnatal microbial colonization is the process of inhabiting intestines by commensal bacteria known as microbiota. It occurs soon after birth and has the instructive as well as regulatory effect on our immune system. Obviously the innate arm of immunity has the ability to detect microbial products and convey signals to start the inflammation. However, under normal circumstances the presence of microbiota is accommodated, although how exactly it happens is not entirely clear. Before I’ve read this paper I thought that so called microbial translocation or in other words the leakage of bacterial material from intestines into the bloodstream could happen exclusively as a pathological process.  Our body needs to be kept sterile; otherwise fatal disaster like sepsis may develop. So how to explain LPS presence in the spleen detected under homeostatic, non-inflammatory conditions? The most intuitive answer would be that the low-level trickling of unwanted bacterial stuff from the gut is taking place on the normal basis. Hence neutrophils may be assigned the duty of “garbage workers”, especially around big lymphoid organs like spleen.

I wish that somebody confirmed the neutrophils/marginal zone B cells partnership in murine models that may allow manipulation with relevant genetic backgrounds and cellular populations. The obvious problem to be solved is what will happen when there are no “B helper” neutrophils around. Will that impair the ability of marginal zone B cells to mount the effective protection against blood-borne antigens? However, it is not the only question I would ask. Authors present data showing that “B helper” neutrophils are able to contain CD4 T cells’ proliferation, although they never really explore this feature. May their function be more inhibitory than stimulatory? Somehow, that unexpected LPS presence in spleen keeps on intriguing me.  But now I have no idea how to interpret that.