While the Authors indicate that their results are consistent with the (antibody-mediated) autoimmune pathogenesis of CFS, an alternative explanation of their findings may be that the depletion of B cells helped to improve CFS symptoms by enhancing cell-mediated (type-1) immunity that can be adversely affected by activated B cells.
(Moderators: Perhaps it might be helpful to move this thread to the rituximab forum?)
Yes, the comment by Pawel Kalinski:
is effectively another way of saying that the rituximab may be relieving some aberrant form of immune suppression, which I tend to think is a bit more likely than autoimmunity as a major cause of ME/CFS.
I've seen several papers now showing how that B cells may be behaving badly (and potentially contributing to immune suppression) without seemingly invoking an autoimmune aspect. For example, this one:
Resident bacteria-stimulated IL-10-secreting B cells ameliorate T cell-mediated colitis by inducing Tr-1 cells that require IL-27-signaling
(I also replied about that particular study on another thread here:
ETA: The authors in that study are viewing the effect they've found as being a good thing in the case of colitis, but obviously it may be a bad thing in another context where immune suppression is not desired.
That is a study on genetically engineered mice, Nandixon. For sure you can make B cells do funny things if you make them do funny things but I cannot see what it has to do with people. People are supposed to have NORMAL IL-10 secreting B cells that suppress T cell responses. So taking those away might increase certain T cell responses but in that case the B cells would not be the cause of any immunosuppression because they were normal - if you see the point I am making. Something else must be the reason for the T cells being lazy.
The problem with the idea of IL-10 secreting B cells causing anything is that this is just a phase B cells go through early in development. They are not an abnormal or special sort of cell. Somebody in our department actually started calling them Breg cells until it became clear that nobody could actually work out which cells these were.
I am afraid this is what I call immunobabble!
[From the Discussion section of the full text.]
The transitional immature B-cell subset (CD24highCD38high) has been proposed as the main producer of IL-10 by the B-cell population . [Prof. @Jonathan Edwards may have been referring to that work when he said, "this is just a phase B cells go through early in development."] However, in another study, the IL-10-secreting cells were predominantly found in the CD24highCD27+ B-cell population . [And that is the study @Jon_Tradicionali cited.] Considering that a consensus about CD24 expression seemed to emerge as a hallmark for IL-10-secreting human B cells, we monitored expression of this surface marker upon incubation of human B cells with L. infantum amastigotes. We report herein that the parasite leads to a significant reduction in the expression of CD24 (Fig. 4B), indicative of B-cell activation [102,103], with no effect on CD38 (Fig. 4C). Altogether, these results suggest that the phenotype of IL-10-secreting B cells following incubation with L. infantum is different from those that were described previously. In a related set of experiments, we studied different purified B-cell subsets (i.e. CD24+, CD27+ and CD38+) and surprisingly, only the CD27-negative B-cell subpopulation responded to the parasite by producing IL-10 (Fig. 5A). Furthermore, we were able to reveal the importance of CD24+cells, but not CD38+, for the secretion of IL-10 by B cells in response to L. infantum amastigotes (Fig. 5B). This suggests a quite different IL-10-secreting B-cell subset from those that were previously described both in human in vitro and murine in vivo models [41,43,46,48]. While it is assumed that phenotypic characteristics of IL-10-producer cells might differ according to the stimuli to which they are exposed, this CD24+CD27- human B-cell subpopulation seems to respond to L. infantum amastigotes by secreting high levels of IL-10.
What about the people exhibiting ABNORMAL iL10 secreting B cells?
Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells.
CD1dhiCD5+ B cells are the iL10 producing B cells in question. They have been referred to as B10 cells and are strongly related to inflammatory/autoimmune diseases.
Now on to Rituximab being effective in only 66% of patients in recent studies.
"While rituximab is effective in depleting the vast majority of circulating B cells, these only represent approximately 2% of all B cells."
"Even among patients exhibiting some blood B cell depletion, there can be considerable heterogeneity. Similar results have been obtained in lupus patients, highlighting the potential variability of B cell depletion by rituximab in the treatment of autoimmune disease "
The study above also states that B10 Cells severely limit aCD20 ability of Rituximab. Interestingly, the sheer presence of these cells deemed immunotherapy ineffective.
Therefore, Dr Edwards, iL10 doesn't necessarily have to be "normal" in us, just because it behaves normally in healthy controls. The last two decades of inconsistent iL10 findings in PWC have not disproved nor proved this.
This study provides an additional example as well (bracketed italics are mine):
Leishmania infantum Amastigotes Trigger a Subpopulation of Human B Cells with an Immunoregulatory Phenotype
Current therapies for non-Hodgkin lymphoma commonly include CD20 mAb to deplete tumor cells. However, the response is not durable in a substantial proportion of patients. Herein, we report our studies in mice testing the hypothesis that heterogeneity in endogenous tissue CD20+ B cell depletion influences in vivo lymphoma therapy. Using highly effective CD20 mAbs that efficiently deplete endogenous mature B cells and homologous CD20+ primary lymphoma cells through monocyte- and antibody-dependent mechanisms, we found that lymphoma depletion and survival were reduced when endogenous host B cells were not depleted, particularly a rare IL-10–producing B cell subset (B10 cells) known to regulate inflammation and autoimmunity. Even small numbers of adoptively transferred B10 cells dramatically suppressed CD20 mAb–mediated lymphoma depletion by inhibiting mAb-mediated monocyte activation and effector function through IL-10–dependent mechanisms. However, the activation of innate effector cells using a TLR3 agonist that did not activate B10 cells overcame the negative regulatory effects of endogenous B10 cells and enhanced lymphoma depletion during CD20 immunotherapy in vivo. Thus, we conclude that endogenous B10 cells are potent negative regulators of innate immunity, with even small numbers of residual B10 cells able to inhibit lymphoma depletion by CD20 mAbs. Consequently, B10 cell removal could provide a way to optimize CD20 mAb–mediated clearance of malignant B cells in patients with non-Hodgkin lymphoma.
I just had a chance to read the second study you cited, which is titled:
Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice
I wonder if this might be helpful in the potential rituximab treatment of ME/CFS as well? The authors suggest using Ampligen in combination with rituximab as a way to overcome the B10 problem and augment the rituximab.
If I understand correctly, I think they were using an especially potent anti-mouse CD20 mAb for the mice that is significantly more efficient (in mice) at depleting the B cells than rituximab is in humans.Note that they say that anti-CD20 kills lymphoma cells perfectly well in ordinary mice. It is only mice that have cells without CD20 that have a problem that can be improved by adding the TLR3 agonist. This seems an extraordinary bit of genticogymnastics from which one cannot draw any conclusions at al about human beings.
It has been discussed before in a thread I started:I'm not sure if anyone has discussed this before, but I haven't heard anyone mention it recently anyway: http://www.plosone.org/annotation/listThread.action?root=20999