What is going on in the lymph nodes in CLL?

A couple of articles recently have described what is going on in the lymph nodes in CLL. I think it is pretty clear by now that the business end of CLL is in the lymph nodes and to a lesser extent the liver, spleen and bone marrow. Normally a lymph node is about the size of a split pea, so if you can feel them at all they are enormously enlarged. Most people with CLL don't have palpably enlarged lymph nodes or if they do, only one or two are enlarged. However, in some people the nodes are huge, bigger than a hen's egg, and this is generally an indication that treatment is indicated.

Lymph nodes are there to respond to infections. They are organs where B lymphocytes are brought into contact with the antigens that they have been designed for (every lymphocyte has a pre-designed pattern of immunoglobulin structure so that there is one for every antigen possible) and undergo a maturation process so that they can learn to produce the antibody that fits best to the antigen. This process is facilitated by the presence of T lymphocytes which help and control the maturation. Recognition of the driving antigen is through the BCR, a special arrangement of the lymphocyte's immunoglobulin molecule on the cell surface so that it can receive and transmit a signal through the cell's second messenger service. B lymphocytes leaving the lymph nodes are either memory cells that circulate, waiting to meet the infective agent again or turning into plasma cells which end up as antibody factories that reside mainly in the bone marrow.

In CLL this process has been circumvented. Instead of reactive follicles in the lymph nodes training the lymphocytes to make antibodies, there are what are known as pseudofollicular proliferation centers. These centers are geared up to make the B lymphocytes reproduce themselves and avoid death. Perhaps 30% of all CLL cases have a very restricted set of antibodies on their cell surfaces (so-called stereotyped BCRs) that seems to react with certain autoantigens that are exposed when cells enter apoptosis (programmed cell death). Most of these stereotyped BCRs comprise unmutated Ig and it is mainly the unmutated CLLs that produce proliferation center-laden lymph nodes.

Although the whole process of proliferation seems to be driven via the BCR it is not necessarily antigen dependent. It seems that inflammation can also be stimulatory, acting through what are known as Toll-like receptors (TLR). Stimulation of TLR by so called 'danger signals' sets in train events that keep CLL cells alive and makes them home in on lymph nodes. In any case many CLL cells express functional chemokine receptors CXCR3, CXCR4 and CXCR5. Within proliferation centers are many CD4+ T cells which express CD40L. These support the growth of CLL cells through CD40 ligation. Stromal cells and nurse-like cells interact with CLL cells to prevent apoptosis and the interaction of CD38 on the cell surface and its natural ligand CD31 also favors the twin effects of anti-apoptosis and proliferation. Cytokines such as IL-4 and chemokines like CXCL13/SDF-1 produced in proliferation centers promote the up-regulation of anti-apoptotic genes like BCL2, SURVIVIN and MCL1.

The whole effect can be summarized like this: First you need a BCR that will take messages and transmit them. This will usually,but not exclusively, be one with unmutated IgHV genes. Such CLL cells will circulate to the lymph nodes and may even be attracted there by chemokines responding to either antigenic signaling or TLR signaling. Once in the lymph node the presence of T helper cells has an effect on the CLL cell to keep it alive and cause it to divide. This effect is mediated through cell-to-cell contact and through cytokines and specific ligands. One of the effects is to up-regulate CD38. When we see CD38+ cells in the peripheral blood it is a sure sig that cell has recently visited a lymph node. Other stromal cells and nurse-like cells also participate in this dance, chuck in in their two-penneth into the cytokine soup.

So CLL cells survive and divide. and this proliferation is what is necessary for further genetic mistakes to be made, particularly ones that disable the TP53 pathway. This pathway is necessary to maintain the genetic integrity of the cell. Its function is to recognize genetic mistakes when they occur and to put the cell into stasis while a repair is made. If the cell is irreparable the TP53 is supposed to kill it off. It is a feature of cells in which the TP53 pathway is disabled that they accumulate further irreparable genetic damage and behave very wildly indeed. Clinically such disabling presages prolymphocytoid transformation or Richter's syndrome and in any case renders the cell unkillable by conventional cytotoxic drug combinations like FCR.

How can what's going on in the lymph nodes be stopped? Agents that specifically disable the CLL second messenger system, like CAL-101 and PCI32765, seem to be the best hope, but revlimid may also be useful. What the great danger is, is leaving the patient too long untreated so that TP53 pathway events occur.