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Thursday, June 5, 2014
theory: Deficiency in CD8 T cells in MS...
Wednesday, 4 June
Deficiency in CD8 T
cells in MS....a reason why EBV is a problem?
Can the Pender
Hypothesis explain the mode of action of the emerging DMTs? #MSResearch #MSBlog
paper from Professor Pender's group supports his theory that MS is due to a
deficiency of CD8+ effector cells; these are the cells that kill virally
infected cells and are responsible for tumour surveillance. His hypothesis is
that a deficiency of these cells against EBV-infected B cells within the brain
lets the EBV cells survive long-term and drive autoimmunity. If we can boost
these cells to kill EBV infected cells then we can down regulate one arm of the
autoimmune loop and switch off inflammation in the CNS."
Pender theory is the recent observation that MSers have a lower incidence of
cancer than the general population; if
MSers had a long-standing deficiency of these CD8+ effector cells we would expect
more tumours, not less. Another observation that goes against this theory would
be the effectiveness of some of the newer DMTs that target the immune system;
in particular natalizumab, fingolimod, alemtuzumab, anti-CD20 and daclizumab
(anti-CD25) therapies. How do these treatments improve the deficiency of CD8+
effector cells in MSers? Natalizumab blocks their entry of CD8+ cells into the
brain; we know this because of PML. CD8+ effector cells are needed to fight the
JC-virus. Fingolimod, drastically reduces circulating numbers of lymphocytes;
although has a greater effect on naive rather than memory cells. According the
Pender theory would expect fingolimod to make MS worse. However, it may depend
on the balance between CD8+ and CD4+
cells entering the brain and spinal cord. Alemtuzumab depletes all cells and
they reconstitute slowly over the next 12 months; T cells, which include the
CD8+ population, take the longest to reconstitute and they never come back to
normal. Anti-CD20 ablates peripheral B-cells and does not target CD8+ cells. In
rheumatoid arthritis patients rituximab treatment does not alter CD4+, CD8+ or
T-regulatory cells numbers. Some would argue that the response of MS to
anti-CD20 would support the Pender hypothesis as it is working via EBV infected
B-cells. This is a possibility, but we have no clear evidence that rituximab
works on B cells within the central nervous system. Daclizumab increases
natural killer cells (NK cells) and reduce T-regulatory and CD8+ cells; the
effectiveness of daclizumab in MS would argue against the Pender hypothesis
unless the NK cells are substituting for the CD8+ effector cells and killing
the EBV-infected B cells within the central nervous system."
"As you can
see immunology is very complex and can be very confusing; it is not helped by
the difficult reproducing results across labs. What is evident that if you do
come up with a causation hypothesis it needs to explain everything and I mean
everything, the epidemiology, the clinical phenotypes, pathology and responses
to treatment to mention a few. There can be no facts, little of big, left
untouched. To quote Thomas Huxley 'the great tragedy of Science: the slaying of
a beautiful hypothesis by an ugly fact.'"