Tuesday, May 31, 2011

More on Toll-like receptors.

We have established that in CLL the action is in the lymph nodes where the proliferation centers allow the interchange of signals between the CLL cells and accessory cells including T cells, 'nurse' cells and stromal cells. It is mainly in the Unmutated cases that all this conversation takes place and it is also established that the BCR (B-cell receptor) is the pathway into the cell since it tends to react with antigens that are pretty commonly present like the products of apoptosis.

However, there are some cases of mutated CLL that also proliferate and we don't think the BCR is implicated in these.

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. One such receptor is found on some CLL cells. CD180 is a molecule that I collaborated on with Peter Lydiard before I retired. It is present on CLL cells with mutated IGHV genes. An update of this work, now in collaboration with Nick Chiorazzi has just been published in the British Journal of Haematology. They have stimulated CLL cells and normal B cells with a monoclonal anti-CD180 antibody. They find that only about half the CD180+ cells respond by proliferation and failing to apoptose.. The same cells that fail to respond also fail to respond to IL-4 + CD40L stimulation, and may be thought of as anergic. Responding cells signal via ZAP70/syk, p38MAPK, ERK and Akt. Inability to activate Akt in particular seems to be a feature of anergic cells.

Thus it may be that CD180, a TLR that highjacks the normal BCR signaling mechanism may be responsible for proliferative and anti-apoptotic signals in the proliferation centers of some mutated CLLs.

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