BioWorld International Correspondent

LONDON - New insights into a molecule that acts as a brake on cells of the immune system could one day lead to novel therapies for autoimmune diseases or for certain cancers of white blood cells, such as myeloma.

A recent study has shown that the "brake" molecule, a receptor called FcgRIIb, is present on plasma cells. Cross-linking FcgRIIb on those cells causes them to undergo apoptosis (programmed cell death), raising hopes that a similar strategy could be used to kill the malignant plasma cells that arise in myeloma.

The finding also could have implications for better understanding of how autoimmune diseases develop, and thus how to prevent the immune system from producing antibodies that attack the body's own tissues, as happens in diseases such as systemic lupus erythematosus (SLE or lupus) and rheumatoid arthritis.

Kenneth Smith, Genzyme professor of experimental medicine at the University of Cambridge, told BioWorld International: "The exciting thing about this work is that it suggests a way in which we could target these cells, which are resistant to conventional treatments, which might then give us advantages in treating both autoimmunity and myeloma."

Smith and his colleagues, together with collaborators in Australia, Germany, and Sweden, report their work in a paper in Nature Immunology, titled "FcgRIIb controls bone marrow plasma cell persistence and apoptosis."

Jeffrey Ravetch, head of the Laboratory of Molecular Genetics and Immunology at the Rockefeller University in New York, told BioWorld International, "These findings provide a mechanism for observations we and others have made over the past decade regarding the role of the inhibitory FcgRIIB receptor in the immune response, and in particular, in its role in autoimmunity."

He added: "While it has been clear for some time now that modulating FcgRIIB expression on B cells and now - based on Smith's findings - on plasma cells as well, would provide a potential mechanism for restoring tolerance in autoimmune individuals, how this can be done in a therapeutic setting in humans is still very much an open question."

Similarly, Ravetch cautioned that cross-linking FcgRIIB to induce cell death would "still require significant research and development before an effective therapeutic can be introduced into the clinic for the treatment of multiple myeloma."

Smith and his team set out some years ago to investigate the regulation of the immune system, and in particular, what causes autoimmune disease to develop.

Other researchers had shown that mice deficient in FcgRIIb developed autoimmune disease similar to human SLE.

Mutations in FcgRIIB also have been associated with SLE in people. Smith's group, and others, went on to show that one such mutation abolished FcgRIIB's ability to inhibit the immune system. "This defect in the receptor," Smith said, "results in immunological 'brake failure, which causes autoimmunity. It was clear that FcgRIIB was involved in controlling the immune system in a way that prevents autoimmune disease."

During the immune response to infection or vaccination, B cells mature into plasma cells, differentiated cells that produce antibodies. These cells live in the bone marrow, ready to produce their particular antibody if the relevant antigen is encountered again.

Unfortunately, in someone who has autoimmune disease, some of the plasma cells produce antibodies that attack the person's own tissues and organs. In lupus, for example, they produce antibodies against components of cell nuclei.

Smith said: "We put all this together, and wondered if the FcgRIIb receptor might be expressed in plasma cells, where it might help control them."

The team's experiments showed that their hunch was correct. Plasma cells remove most molecules from their surfaces, but FcgRIIb is one of those that persists.

Further studies showed that cross-linking FcgRIIB on plasma cells causes the cells to die. The researchers also were able to trigger apoptosis in a subset of myeloma cell lines that express FcgRIIB, by cross-linking the receptors.

Unfortunately for the researchers, mice that are prone to lupus do not express FcgRIIB on their plasma cells, so they could not test whether the cross-linking strategy would work therapeutically for these animals.

"Interestingly, if we put [FcgRIIB] there by crossing these mice with a transgenic mouse that restores expression of it, then the cells become susceptible [to cross-linking]. What that tells us is that actually, part of the problem in autoimmunity could be failure to control these plasma cells because they no longer express the receptor," Smith said. But he added that although this is true in mice, no one knows if it holds for humans.