Thursday, October 22, 2015

Depletion of "hybrid" B cells could explain benefits of anti-CD20 immunotherapy in MS patients

Multiple Sclerosis (MS) is believed to be an autoimmune disease. During MS, the patient's own immune cells attack peripheral nerves' myelin sheath disrupting proper signal transmission. In mouse model of MS, called experimental autoimmune encephalomyelitis (EAE), several myelin proteins have been identified as such targets (such as MBP and MOG). 

While self-specific T cells are widely thought to play a pathogenic role in MS progression, clinical trials revealed surprising benefits of B cell depletion in MS. Mechanism is unknown.    

Now new paper is Science Translational Medicine provided initial data suggesting that depletion of pro-inflammatory GM-CSF secreting B cell subset could explain the clinical benefits of anti-CD20 antibody therapy in MS.

First, the authors showed that activated peripheral B cells from healthy donors express pro-inflammatory cytokine GM-CSF. Interestingly, this B cell population does not overlap with B cell population expressing anti-inflammatory cytokine IL-10.

Next, the authors showed that activated B cells from MS patients tend to express more GM-CSF compared to B cells from healthy donors.

In vitro co-culture of B cells and macrophages revealed that B cell-derived GM-CSF contributed to Th1-type macrophage polarization.

More complex co-culture experiments showed that macrophages derived from MS patients soon after B cell depletion produced less of pro-inflammatory cytokine IL-12p40.

And more importantly, this tendency was maintained even after 1 year of B cell depletion, even though new B cell came back by this time.

This points to a re-configuration of cytokine network in anti-CD20 antibody treated MS patients such as reversal of B cell-derived GM-CSF/IL-10 ratio.

In summary, this study provides additional clues why anti-CD20 antibody depletion might benefit MS patientsAntibody-independent function of B cells is a novel concept [and not widely known or accepted]. One of the reasons for this resistance is lack or inadequate knowledge of B cell receptor specificity of such specialized B cell subset. We need to go one step further and connect the dots between BCR specificity or other innate receptors and B cell's "hybrid" function. Only by developing this biological "framework" can we fully understand the role B cells play in health or diseases.

If you are interesting in science of MS, I will recommend a book by Susan Quinn's "Human Trials: Scientists, Investors, And Patients In The Quest For A Cure" (2001).

David Usharauli

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