Team Finds Genetic Mutation May Lead to Increased Autoimmunity

By Eric Sauter

Scientists at The Scripps Research Institute have discovered that a mutation in a known DNA recombination mechanism may result in the onset of autoimmunity and an overexpression of autoreactive antibodies—molecules that attack the host—in animal models.

The new study highlights the role of "recombining sequence," a DNA element involved in the genetic reprogramming of immune system B cells, a process called receptor editing. These new findings could point toward a possible novel therapeutic target for autoimmune diseases such as lupus.

The study will appear in the February 15, 2008, print edition of the journal Immunity.

"This is the first mutation in which we were able to cripple receptor editing but not affect other processes," said David Nemazee, a Scripps Research scientist and professor of immunology, whose laboratory conducted the study. "This produced mice more prone to autoimmunity."

Nemazee notes that the mouse recombining sequence has a human equivalent, the immunoglobulin kappa deleting element. Both are believed to play a role in eliminating or editing certain genes that encode autoreactive antibodies. In other words, both help delete parts of the immune system that could start attacking the body itself in an autoimmune reaction rather than targeting foreign invaders such as bacteria or viruses.

In the study, the mouse mutation removed the recombining sequence recombination signal, blocking gene inactivation mediated by this mechanism. As a result, in the mutant mice receptor editing and self-tolerance were impaired, in some cases leading to increased autoantibody formation.

Schooling for Lymphocytes

Nemazee, who published the first study that identified receptor editing as integral to the body's production of the immune system's B cells in 1993, described the editing process as 'schooling' for lymphocytes.

"B cells get educated early in life," Nemazee said. "As they develop in the bone marrow, they are very malleable. For example, they may start out as reactive to the host, but, through receptor editing, they can be altered so they produce viral antibodies instead. This change can lead to the elimination of the autoreactive antibodies."

When a B cell develops from stem cells in the bone marrow, it rearranges its immunoglobin gene—the gene that codes for the large receptor protein that sits on the surface of the B cell—to recognize antigen (usually part of a bacteria or virus) and the antibody specific to it (which fights off the infection).

The rearrangement involves bringing together the gene segments in various combinations. Because there are multiple copies of gene segments in the genome, this means over a million possible antibody combinations.

Receptor editing allows the immune system to correct a bad receptor rather than throwing the whole cell away. Through editing, the immune system achieves the antibody diversity at the lower cost.

B cells circulate through the blood, lymph nodes, and spleen, where they mature further. Upon recognition of their specific antigen, such as a microbe, B cells begin the process of proliferating and secreting antibodies to mark bacteria and viruses for destruction.

In autoimmune diseases, such as lupus or rheumatoid arthritis, B cells produce antibodies against the host body itself. According to Nemazee, any defect or mutation in the editing process has the potential to increase the risk of autoimmunity.

"There is evidence, although it is somewhat controversial, that in systemic lupus there is an editing defect," Nemazee said. "In our study, the mice with this mutation produced more autoreactive antibodies."

While the new study stopped short of testing whether that overexpression in turn induced autoimmune disease, some research has suggested that an increased production of these antibodies can accelerate autoimmune disease. The Scripps Research team continues to investigate.

Other authors of the study, DNA Rearrangement by the Mouse Immunoglobulin Kappa Deleting Element Recombining Sequence RS Promotes Immune Tolerance and Lambda B Cell Production, are José Luis Vela, Djemel Aït-Azzouzene, Bao Hoa Duong, and Takayuki Ota of The Scripps Research Institute. The paper was part of Vela's doctoral research project.

The study was supported by the National Institutes of Health.

Send comments to: mikaono[at]scripps.edu

"This is the first mutation in which we were able to cripple receptor editing but not affect other processes."

—David Nemazee