B Cell Depletion in Lupus
It is believed that B cells play an essential role in autoimmune diseases. Indeed, B cell depletion through the use of the biologic agent rituximab has been approved for use in rheumatoid arthritis and is also being studied for the use in systemic lupus erythematosus (lupus).
What Problem Was Studied?
Lupus is a systemic inflammatory autoimmune disease that is characterized by autoantibodies against an array of nuclear antigens. Special strains of mice have been bred that develop a disease that mimics human lupus and allow depletion of B cells, much like in human lupus. Similar to humans, these mice produce autoantibodies to nuclear antigens, develop nephritis, arthritis and skin lesions. It is thought that B cells play an essential role in the disease process in humans and mice, a theory which is supported by the fact the lupusprone mice that are unable to produce Bcells do not develop the disease.
Autoantibodies: Antibodies are proteins used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. When the immune system makes these proteins in reaction to the body's own tissues, they are called autoantibodies.
Nuclear antigens: An antigen is a substance, such as a bacteria or virus, that stimulates the immune system to produce antibodies. When structures found in a cell's nucleus (such as DNA or RNA) act as antigens, they are called nuclear antigens.
Nephritis: Inflammation of the kidney, often associated with lupus and other autoimmune diseases.
Proteinuria: The presence of excess protein in the urine; a result of nephritis, among other conditions.
A research team in the lab of Dr. Mark Shlomchik from Yale University in New Haven, CT, including Arthritis Foundation-funded scientist Anupama Ahuja, PhD, used a lupus mouse model to better understand how B-cell depletion affects autoimmunity and lupus. One mystery of particular interest to the team was the phenomenon that B-cell depletion in people with lupus is not always as complete or as long-lasting as it is for people with lymphoma or RA who receive rituximab.
What Was Done in the Study?
PMRL/lpr mice, which develop a lupuslike autoimmune disease, were given antibodies that would remove B cells from their bodies, much the way rituximab depletes B cells from humans. Once B-cell numbers were adequately reduced, antibody levels and other laboratory indicators of disease activity were measured.
What Were the Study Results?
The researchers found that it required higher doses and longer duration of treatment to exhaust B cells from the mice with lupus than it did in normal mice. They found that secondary lymphoid tissue, such as the spleen, was particularly resistant to B-cell depletion but peripheral blood leukocytes were depleted of B cells more readily. Because resistance to depletion was independent of drug level in the blood and because it occurred with three different strains of lupusprone mice, the researchers concluded that “inability to deplete B cells seems to associate generally with autoimmunity.” Once the scientists were able to get the B cells adequately removed from the mice, they observed strong effects on disease. There was a clear improvement of nephritis, reduced proteinuria, substantial reductions in antinuclear antibody levels and modest declines in IgG levels.
What Does This Mean for People with Lupus?
Although more studies are needed, these results in mouse models of lupus help scientists understand why all people with lupus do not respond to rituximab therapy. Although testing people with lupus for B-cell depletion by measuring blood levels is possible, the results could be misleading with respect to B-cell levels in lymphoid tissues. Anupama Ahuja indicates that for people with lupus who do not initially respond to rituximab, “longer courses with higher doses may be useful or even required to achieve clinical response.” Likewise, Ahuja points out that despite their best efforts, the research team was unable to completely deplete B cells from the mice, yet they did still observe changes in disease activity. She says “It is reasonable to conclude that partial depletion can lead to partial remission, a point that is relevant for clinical application.”
Ahuja A,Shupe J,Dunn R, KashgarianM, Kehry MR, Shlomchik MJ.Depletion of B cells in murine lupus: efficacy and resistance. J Immunol 2007;179:3351–61.