Messengers of the immune system, which are normally engaged in the targeted deployment of defense cells, also appear to assign malignant cells to specific sites in the body. This novel discovery about Hodgkin’s lymphoma, a malignant condition that involves the lymph nodes, has just been announced by Dr. Martin Lipp (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch) at an international conference on ”Cell Migration in Development and Disease” at the MDC in Berlin (Germany). He has been able to show that  Hodgkin’s cells are only able to establish themselves in certain regions of the lymph nodes, the so-called T-cell zones.

Hodgkin’s disease, whose cause remains unknown, is a lymphoma since it is associated with swelling of the lymph nodes. Other symptoms include fever, tiredness and itching. A key characteristic of Hodgkin’s disease are the mononuclear Hodgkin’s cells and the occurrence of huge, polynuclear Reed-Sternberg cells in the lymph nodes. The disease is treated by radio- and chemotherapy. It is a relatively rare condition first described in 1832 by the English physician, Thomas Hodgkin (1798-1866). Every year about 2,000 Germans are affected. Researchers believe that a group of malignant altered immune cells, B-lymphocytes, are responsible for triggering Hodgkin’s lymphoma.

Lymphocytes are released from the bone marrow and they can be subdivided into two main groups: the T-lymphocytes – called after the small organ that lies above the heart, where they mature, the thymus gland - and the B-lymphocytes (B-cells), which develop in the bone marrow. However, the mature B- and T-cells are not yet fully functional. They must first migrate to one of a number of different sites – such as the spleen and lymph nodes – in order to receive their program of instructions. There they meet other triggers which have already been harnessed and recruited by immune cells and whose characteristics need to be memorized by B- and T-cells.

T- and B-cell regions in the lymph organs

This takes place in the T-cell and B-cell regions of the lymph nodes as well as in the so-called germinal centers,  and the spleen. There the lymphocytes mature and prepare themselves for the role they are to play in the body’s immune defense system. In the germinal centers the B-cells receive instructions so that they do not simply produce highly active antibodies to combat pathogens, they also develop their ”immunological memory”. In the lymph organs they also exchange information about intruders, in order to be able to mobilize an Armada of specialized cells to repel them. If such an encounter is unable to take place, perhaps because the immune cells are unable to locate the ”information center” or germinal centers, then this has an adverse effect on the body’s immune response.

In their role as messengers, immune cells make use of certain agents, chemokines that are able to find their way to these strategically important information sites in the lymph organs. The chemokines are also responsible for attracting immune cells to any site of infection or inflammation. Chemokines are signaling agents that are formed by the body’s own cells. They bind to so-called chemokine receptors, antenna-like molecules on the surface of cells, and so are able to indicate the right direction to be followed. Several years ago, Dr. Lipp and his colleagues were able to show for the first time that there was a chemokine receptor on B-lymphocytes which controlled the targeted journey of immune cells so that they reached B-cell regions and germinal centers.

Homing in of malignant cells

Dr. Lipp, in collaboration with pathologist Prof. Harald Stein, from the University Hospital Benjamin Franklin, Berlin, has now been able to show that the chemokine system also appears to control the way in which Hodgkin’s lymphoma cells spread within lymph nodes. The Hodgkin’s cells are lured by different chemokines, depending on which form of Hodgkin’s lymphoma is involved, to go to either T-cell or B-cell regions.

In the common form of classic Hodgkin’s lymphoma, the chemokine receptor CCR7 plays a key role in recruiting these malignant cells to settle in the T-cell regions of the lymph nodes. On the other hand, in a rarer form, the so-called ”lymphocyte-predominant Hodgkin’s lymphoma”, which affects about five percent of patients, only the chemokine receptor CXCR4 is active, while CCR7 is not. These Hodgkin’s cells only settle in B-cell regions.

The researchers were able to show that CCR7 is controlled by certain gene regulation factors (NF-kappaB). These factors normally transmit signals for a variety of immune reactions, such as in the case of viral infections and inflammatory conditions. In the malignant altered cells of Hodgkin’s lymphoma one particular NF-kappa-B factor is retained permanently in the cell nucleus and no longer returns to the cytoplasm. Why this should occur remains unknown. However, it shows that these Hodgkin’s cells are able to develop unhindered.

Apparently, switching on these chemokine factors on the surface of Hodgkin’s cells triggers migration and also residence in particular regions of the lymph nodes. Future research will show whether it will be possible to block these chemokine receptors, thereby preventing Hodgkin’s cells from establishing themselves in the lymph nodes, boosting the body’s own defense system and offering an opportunity for better treatment. Now, the scientist want to elucidate, if chemokines and chemokine receptors play a role in the onset of lymphnode metastasis, a result of breast cancer and colon cancer, for example.

Barbara Bachtler

Press and Public Affairs

Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch

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