Recurrent pregnancy loss (miscarriage) is a serious problem for some women with systemic lupus erythematosus (SLE, or lupus), and in many cases is due to a condition known as antiphospholipid syndrome (APS). People with APS have antiphospholipid (aPL) antibodies—abnormal antibodies that target molecules in normal body tissues—and are also prone to potentially life-threatening blood clots. The primary therapy for pregnant women with lupus and APS, which involves taking anti-clotting drugs throughout pregnancy, has potential complications and is not always effective.
In an article in the December 2003 issue of the Journal of Clinical Investigation, a team of researchers led by Jane Salmon, MD, an Alliance for Lupus Research (ALR)funded investigator at the Hospital for Special Surgery in New York, reports new details on the causes of fetal injury and pregnancy loss in a mouse model of APS in which aPL antibodies from patients are injected into pregnant mice. Understanding the detailed mechanisms of pregnancy loss associated with lupus and APS should enable the development of safer and more effective therapies.
In previous studies, Dr. Salmon showed that an early and essential step in fetal injury and pregnancy loss caused by aPL antibodies in mice is the activation of a group of blood proteins known as “complement.” These immune system proteins, which normally have a protective role, cause inflammation and tissue damage when targeted against the body’s own tissues. Dr. Salmon’s findings challenged the belief that aPL antibodies cause pregnancy loss primarily by triggering abnormal clotting in the placenta.
Dr. Salmon’s latest work more precisely pinpoints factors that are critical for aPL antibodyassociated fetal injury and pregnancy loss in mice. In particular, she found that a specific complement component, known as C5a, is a key mediator of this process, and that treatments that block the actions of C5a prevent pregnancy loss. Dr. Salmon also found that white blood cells known as neutrophils, which are attracted to the placenta and activated by C5a, play a crucial role. Neutrophils “are very potent killers of bacteriaÉbut when misdirected to attack the body’s own tissues, they destroy the patient’s own cells with the very same weapons they use against bacteria,” Dr. Salmon explains.
What it means for people with lupus: “Identifying the specific factors required for pregnancy loss in the mouse model of APS will translate to a variety of therapeutic options for pregnant women with lupus if pregnancy loss operates by the same mechanism in humans as in the mouse model,” says Dr. Salmon. On the basis of the findings from her ALR-funded work in mice, she recently received a $5.7 million grant from the National Institutes of Health to address this question in a multicenter study of women with lupus and APS. Information from these human studies should enable doctors to identify patients at risk for problems before they occur, and allow the development and testing of more effectively targeted and less toxic therapies for preventing miscarriage and other pregnancy complications in these patients.
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