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Rituximab-driven Improvement of CFS Symptoms: Suppression of
Autoantibody-mediated Autoimmunity or Enhanced Cell-mediated Immunity
Following B Cell Depletion?
Posted by Pawel on 25 Oct 2011 at 14:04 GMT
In this interesting and important study, Fluge and colleagues report
on the improvement of self-reported Fatigue score in 10/15 (67%)
patients with Chronic Fatigue Syndrome who received treatment with (B
cell-depleting) Rituximab . 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.
The phenomenon of enhanced Th1 immunity following B cell depletion has
been previously-demonstrated in mouse (Moulin V et al., 2000. B
lymphocytes regulate dendritic cell (DC) function in vivo: increased
interleukin 12 production by DCs from B cell-deficient mice results in
T helper cell type 1 deviation. J Exp Med. 192(4):475-82; Reviewed in
Kalinski & Moser. 2005. Consensual immunity: success-driven
development of T-helper-1 and T-helper-2 responses. Nat Rev Immunol.
5(3):251-60).
Such alternative explanation (enhanced Th1 or Th17 responses in the
patient receiving Rituximab would be compatible with the
currently-reported exacerbation of psoriatic lesions in the two
patients who had previously documented psoriasis.
Evaluation of the Th1 and Th17 immunity in correlation with the
changes in the Fatigue score following anti-CD20 treatment would help
to address this possibility.
Pawel Kalinski,
Pittsburgh, PA
No competing interests declared.
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RE: Rituximab-driven Improvement of CFS Symptoms: Suppression of
Autoantibody-mediated Autoimmunity or Enhanced Cell-mediated Immunity
Following B Cell Depletion?
Fluge replied to Pawel on 31 Oct 2011 at 17:37 GMT
To the Editor,
We thank dr. Kalinski for his comment and suggestion for an
alternative mechanism for the observed improvement of selfreported
Fatigue-score during follow-up. In our study [1], the responses on
CFS/ME related symptoms were delayed compared to the rapid B-cell
depletion following start of Rituximab infusions. The responders
started to improve between 2 -7 months after intervention, but the
differences between the Rituximab and Placebo groups were most evident
between 6 =96 10 months. Generally, all CFS/ME related symptoms improved
when the responses occurred.
This delay of clinical improvement relative to rapid B-cell depletion
is one observation that made us speculate that CFS/ME could be a form
of autoimmune disease and that the effects could be mediated at least
in part through gradual elimination of disease-specific
autoantibodies. Other aspects that could indicate such a mechanism in
CSF is the majority of female gender in CFS/ME, the reported genetic
predisposistion [2], and frequencies of other autoimmune diseases in
patients or first-degree relatives (in our study).
Importantly, this is a hypothesis for further work, and we have not
demonstrated that CFS/ME is an autoimmune disease. In the discussion,
we have also mentioned alternative mechanisms such as influence on
B-cell antigen presentation to T-cells, effects on other players in
the immune systen such as dendritic cells, cytokine changes, or
elimination of B-lymphotropic viruses.
The alternative mechanism proposed by dr. Kalinski, in which the
symptoms could be maintained through a sustained imbalance in Th1 and
Th2 responses, with restoration towards enhanced Th1 cell mediated
immunity after elimination of activated B-cells, is certainly one
possibility that should be investigated. This postulate was proposed
in a hypothesis article on mechanisms for the related Gulf War
Syndrome in 1997 [3]. We will try to pursue his suggestions in our
further research.
Certainly, the immunological disturbances behind the CFS/ME disease
will turn out to be complicated, and a joint effort will be needed to
elucidate the pathogenesis. We believe that the hypotheses for further
research should also include our observation that in a subset of
CFS/ME patients B-cell depletion targets a mechanism for symptom
maintenance, either directly or indirectly.
1. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, et al.
(2011) Benefit from B-cell depletion using the monoclonal anti-CD20
antibody Rituximab in chronic fatigue syndrome. A double-blind and
placebo-controlled study. PLoS One.
2. Albright F, Light K, Light A, Bateman L, Cannon-Albright LA (2011)
Evidence for a heritable predisposition to Chronic Fatigue Syndrome.
BMC Neurol 11: 62.
3. Rook GA, Zumla A (1997) Gulf War syndrome: is it due to a systemic
shift in cytokine balance towards a Th2 profile? Lancet 349:
1831-1833.
=D8ystein Fluge and Olav Mella
Department of Oncology and Medical Physics
Haukeland University Hospital
Competing interests declared: Haukeland University Hospital has
patents and pending patent applications on the issue of B-cell
depletion therapy for chronic fatigue syndrome. Family members of
WO2009083602 A1 are pending, as well as granted US 12/348024. The two
authors =D8F and OM are named as inventors in these applications.
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