cells (cells that produce antibodies) have paradoxical roles in autoimmunity, exerting both pathogenic
and protective effects. Pathogenesis may be antibody independent, as B
cell depletion therapy (BCDT) leads to amelioration of disease
irrespective of autoantibody ablation.
However, the mechanisms of
pathogenesis are poorly understood. We demonstrate that BCDT alleviates
central nervous system autoimmunity through ablation of IL-6-secreting
pathogenic (disease causing) B cells. B cells from mice with experimental autoimmune
encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B
cells from naive controls, and mice with a B cell-specific IL-6
deficiency showed less severe disease than mice with normal B cells.
Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B
cells. This mechanism of pathogenesis may also operate in multiple sclerosis
(MS) because B cells from MS patients produced more IL-6 than B cells
from healthy controls, and this abnormality was normalized with B cell
reconstitution after Rituximab treatment. This suggests that BCDT
improved disease progression, at least partly, by eliminating
IL-6-producing B cells in MS patients. Taking these data together, we
conclude that IL-6 secretion is a major mechanism of B cell-driven
pathogenesis in T cell-mediated autoimmune disease such as EAE and MS.
There is no doubt that treatment of MSers with a B cell depleting antibody can inhibit the development of relapsing disease. But how does this work, is it because it stops the production of damaging antibody?, maybe not but if not what is it doing. Is it because it is stopping the antigen presenting function of B cells to activate T cells or is it potentially killing a reservoir of virus, such as Epstein barr Virus that lives in B cells. From looking at mice they beleive that interleukin-6 producing cells may be the target for the rituximab. Interleukin 6 (IL-6) can do many things such as causing fever, but it also facilitates the growth of Th17, which immunologists are causing autoimmunity. Using interleukin six deficient mice they infere that this is the working mechanism of anti-CD20 antibodies such as rituzimab. Then look in MSers and find that some B cells are producing more IL-6 and this excessive production of IL-6 is lost in B cells from rituzimab-treated individuals. This suggests that rituximab is killing the IL-6 producing B cells.
Whilst this is feasible explanation, it should be said that the study showed that anti-CD20 treatment only had a very mild inhibitory effect on the neurological course of disease in mice, as has been shown by others with similar antibodies. The influence of anti-CD20 is thus much less marked than the effect that occurs in humans. However, at the time, in relation to disease course of a mouse the study was done, it is known that T cells are inducing most of the action. Inhibition of interleukin6 can have dramatic effects on EAE, but because IL-6 can do many differnt things it may not be the best target for a novel therapy, but it would be a possibility.
Labels: IL-6, Rituximab