Mechanism behind autoimmune disorder

Northwestern Medicine scientists discovered a previously-unknown mechanism of disease behind a specific autoimmune disorder. The scientists observed antibodies that targeted phosphatidylethanolamine, an important phosopholipid, from within the endosomes of cells. This discovery was the first observation of a pathogenic mechanism behind anti-phosphatidylethanolamine (aPE) autoimmunity, an immune system disorder that's been correlated with thrombosis, transplant failure and pregnancy loss.

It was first reported decades ago, but exactly how aPE autoimmunity worked had remained a mystery despite a large body of literature documenting its prevalence, according to Ming Zhao, PhD, associate professor of Medicine in the Division of Cardiology and senior author on the paper. Autoimmune diseases usually develop when antibodies-proteins which neutralize pathogens erroneously attack cells while circulating through the bloodstream. To target those cells, the antibodies bind to accessible antigen targets on the exterior surface of cells.

The internalization happens through the endosome, a part of the cell that samples the external environment and gathers in signaling molecules. In this case, the endosome also draws in the antibodies, making the cells vulnerable.This creates an opportunity for anti-PE antibodies that are brought into the cells to bind to the PE in these tiny vesicles and attack the cells from within a miniature 'Trojan Horse' process, this causes chaos within the cell, sending it into an inflammatory state, leading to a greater risk of blood clot formation and pregnancy complications.

It's important to note the inflammatory response may be the principal effect of aPE because it means anti-inflammatory treatment is likely to be more effective than anti-coagulants. These novel discoveries shed light on how cellular vulnerability to aPE is mediated and explain some of its clinical symptoms, according to the study. Because endosomes are an integral part of nearly every type of cell, linking the activity of aPE antibodies to clinical symptoms will be a priority for scientists in future investigations.
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Blood clotting disorder causes miscarriages

Women with the rare autoimmune disorder Antiphospholipid syndrome APS are prone to successive pregnancy losses. APS causes abnormal blood clots in the arteries or veins along with the risks that go with clotting, including stroke and Deep Vein Thrombosis. For pregnant women the effects of the disorder can be devastating, causing about half of them to be at risk of sequential miscarriages, spontaneous abortions or premature births.

Researchers have identified a protein that may protect against APS miscarriages. The researchers used purpose-bred mice injected with the antibodies that cause the condition to test the effects of the proteins CD39 and CD73, which work together to produce a molecule known as adenosine.

Adenosine has anti-inflammatory, anti-oxidant and anti-clotting properties. APS occurs when there is an increased level of circulating antibodies-the proteins designed to attack invading pathogens in the system but which, in the case of autoimmune diseases such as APS, attack the body's own cells. It was known that these antibodies were linked to clotting but not all patients with them go on to have APS.

The rates of miscarriages were compared in mice that lacked CD39 and CD73, in normal mice, and in mice with large amounts of the two proteins in their blood. The study found, as hypothesised, that mice that lacked CD39 and CD73 both had increased rates of miscarriages. Those with no CD39 lost 20% of fetuses. That is a six-fold increase compared with normal mice which lost 3.67% of fetuses. The mice with no CD73 had a three-fold increase. Mice with large amounts of CD39 had reduced miscarriage rates compared to those without it.
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