Do reshuffled genes cause autoimmunity?

Deep in the bone marrow of mammals, immune cells called B lymphocytes, or B cells, gear up to distinguish enemies from friends. The lymphocytes shuffle their genes to produce a diverse population of cells that makes millions of distinct antibodies, ready to battle whatever microorganism may come along (SN: 11/7/98, p. 302).

Once the immune system devises an antibody that can recognize and latch onto an enemy organism, it mass-produces the particular type of B cell that made the antibody. These and the antibodies they make are then sent out into the fray. Poorly programmed B cells that might attack healthy tissues are typically weeded out in the bone marrow.

The gene shuffling that produces B cell variations is guided by proteins encoded by recombinase activating genes, RAG1 and RAG2. Researchers have believed that the shuffling ceases once the mature B cells leave the marrow. Recent studies, however, have shown that some B cells continue to rearrange their genes in the spleen or lymph tissue.

Researchers report in the Jan. 28 Nature that one class of B cells, B-1, continues to reshuffle its genes in the peritoneal cavity of the abdomen. The findings in mice suggest a possible mechanism behind autoimmune diseases, in which immune cells attack the body's own tissues. The mouse breed used in the study shows an autoimmune disease similar to human lupus.

Researchers found 10 to 20 times more RAG gene activity in B-1 cells in the animals' peritoneal cavity than in normal mice, says study coauthor and immunologist Michel C. Nussenzweig of the Howard Hughes Medical Institute at Rockefeller University in New York City. The reason for this gene rearrangement outside the bone marrow remains elusive, as does any hard link to the chronic autoimmune problems these mice face.

Antibodies produced by B-1 cells are less specialized than those made by other B cells. Nussenzweig suggests that because many foreign microorganisms leak into the peritoneal cavity from the adjacent digestive tract, one role for B-1 cells there might be to generate a population of antibodies able to deal with whatever comes along. The gene rearrangements he and his colleagues detected may maintain the diversity of these B-1 cells, Nussenzweig says.

That strategy could have repercussions, however. These shoot-first-and-ask-questions-later antibodies constantly flow out of the peritoneal cavity into the blood and lymph systems, where they contact healthy tissues. This leakage might represent the still-theoretical autoimmune connection. The picture is incomplete, Nussenzweig says, because autoimmune reactions probably require other genetic factors.

"This study shows a low but measurable frequency of these cells having gene rearrangement" in the peritoneal cavity, says immunologist Mark S. Schlissel of Johns Hopkins Medical Institutions in Baltimore. "That's unusual for mature B cells."

Nussenzweig is studying fluid from arthritic joints in people--common sites of inflammatory autoimmune reactions--to see if the RAG genes there are stimulating gene shuffling in B cells.