The complex web of cells and molecules that is the immune system isgradually yielding some of its secrets. The latest mystery unraveledby scientists concerns the role of the molecule known as CD5.

CD5 is normally expressed by T lymphocytes. It is also found on asubset of B lymphocytes known as B-1, which are mainly present inthe peritoneal and pleural cavities _ but no one knew what thefunction of CD5 was in these cells.

Now Subbarao Bondada, professor in the department ofmicrobiology and immunology at the University of Kentucky inLexington, and colleagues have provided an answer to this question.Their latest research, reported in the Dec. 13 Science, shows that thepresence of CD5 on these cells prevents them from being stimulatedvia the immunoglobulin molecules that they carry on their surfaces.

"For people who work with B-1 lymphocytes, it is a revelation thatCD5 directly regulates the signaling of these cells via theimmunoglobulin receptor," Bondada told BioWorld Today.

Alan Stall, assistant professor in the department of microbiology atColumbia University, in New York, agreed. People have constantlyasked themselves why CD5 is present on the surface of B cells, hesaid. This latest discovery is "absolutely phenomenal. Assuming thattheir data are substantiated, this is a major finding."

Bondada and his colleagues made their discovery because they wereinvestigating how antibodies are produced by B lymphocytes. Thiswork is clinically important because there are many situations wherethese cells fail to make an antibody when it is required, and otherswhere they make antibodies when they are not needed. For example,B cells sometimes make autoantibodies _ antibodies that react withself molecules, leading to autoimmune diseases.

Bondada speculated that CD5 may damp down the response of B-1cells to self molecules, thus normally avoiding autoimmune reactions.He suggested that the same cells may be activated by polysaccharidemolecules expressed by bacteria, but that in this situation they dorespond to fight the infection.

"We predict that this regulation by CD5 is deficient in someautoimmune diseases," he said. "This may also explain whyautoantibodies are common in older people and older animals _ theregulatory mechanisms which normally keep these cells in check arelost somehow and these cells start to behave in ways which areinjurious to the body's function."

In most B cells, stimulation of membrane-bound immunoglobulinmolecules by an antibody causes the cells to grow and divide. Theresult is the development of a clone of antibody-producing B cells _a necessary response to an infection. But when B-1 cells arestimulated in this way, they undergo programmed cell death, alsoknown as apoptosis.

Lack Of CD5 Caused Proliferation, Not Apoptosis

Bondada and his colleagues, in their Science paper entitled "CD5-mediated negative regulation of antigen-receptor induced growthsignals in B-1 B cells," describe how, in B-1 cells from CD5-deficient mice, stimulation of membrane-bound immunoglobulin lednot to apoptosis _ as would normally be expected _ but toproliferation.

To confirm that this result was a direct consequence of the lack ofCD5, the team also cross-linked the CD5 molecules on the surface ofB-1 cells from normal mice before stimulating the cells via themembrane-bound immunoglobulin receptor. Again, instead ofundergoing apoptosis, these cells responded by dividing.

Most B lymphocytes (other than B-1 cells) respond to stimulation byactivating certain transcription factors. For example, the transcriptionfactor nuclear factor kappa B (NF-kappaB) moves from thecytoplasm of B-2 cells (but not B-1 cells) into the nucleus within 2hours of stimulation. Bondada and his colleagues showed that, in B-1cells from CD5-deficient mice, NF-[kappa sign]B moved into thenucleus following stimulation. Bondada says: "This shows that in theabsence of CD5, B-1 cells respond by clonal expansion, but if CD5 ispresent, this important gene _ NF-kappaB _ does not get activated."

Bondada and colleagues conclude that surface CD5 regulates _directly or indirectly _ activation signals which are mediated bymembrane-bound immunoglobulin. They write: "The B-1 cellrepertoire is primarily directed against microbial and self-antigens;thus regulation of the B cell antigen receptor signaling by CD5 mighthave evolved as a mechanism to check the uncontrolled expansion ofB-1 cells." Certain autoimmune states, they add, may be due todefects in CD5-mediated negative regulation of signaling viamembrane-bound immunoglobulin.

Stall adds: "There are a lot of data now saying that by modifying thesignals that go through the antigen receptor you can have an effect onB1 cell development. This now says that CD5 is yet another moleculewhich can have an effect not so much necessarily on the signal thatgoes through the antigen receptor, but on how the cell responds tothat signal." n

-- Sharon Kingman Special To BioWorld Today

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