August 8, 2024 —

Researchers have made a significant breakthrough in understanding how the immune system is over-activated in systemic lupus erythematosus (SLE). In a new study partly funded by the Lupus Research Alliance (LRA), Jessica Hamerman, Ph.D. from the Benaroya Research Institute, and colleagues discovered that certain antibodies, previously understudied in lupus, can ramp up the activity of immune cells, leading to stronger inflammatory responses in this chronic autoimmune disease. These findings, published in Science Translational Medicine, offer promising new directions for developing more effective treatments for lupus.

In healthy individuals, the immune system makes antibodies that fight off foreign substances, such as bacteria, viruses and allergens. But in lupus, the immune cells produce autoantibodies—antibodies that mistakenly target the body’s own molecules, including DNA, RNA, and associated proteins.

These autoantibodies form large clusters with their targets, called immune complexes, which can cause many disease symptoms by lodging in organs such as the kidney or skin. While most research has focused on a type of antibody called IgG, this study highlights the important role of another antibody type, called IgA, in lupus.

About 50% of people with lupus have IgA antibodies that target their own DNA, and these are linked to indicators of more severe disease symptoms. Dr. Hamerman’s research, supported by her 2020 LRA Lupus Mechanisms and Targets Award, shows that immune complexes with IgA antibodies can enhance the production of pro-inflammatory type I interferons from plasmacytoid dendritic cells (pDCs).

The team analyzed blood samples from people with lupus and found that most had immune complexes containing both IgA and IgG antibodies. Each type of antibody attaches to cells through specific receptors. Dr. Hamerman identified the IgA-specific receptor, called FcαR, on pDCs.

Immune complexes containing both IgG and IgA prompted a much stronger pro-inflammatory interferon response from pDCs compared to immune complexes with IgG alone. This response required receptors for both IgA and IgG antibody types, suggesting that the two antibodies are working together.

Further investigation showed that pDCs from people with lupus have an increased ability to bind immune complexes and have higher levels of the IgA receptor FcαR than those from healthy individuals. The team also established a link between FcαR levels on pDCs and genes triggered by interferons in people with lupus, highlighting the receptor’s significant role in the disease.

According to Dr. Hamerman, “This study sheds light on a previously underappreciated mechanism driving lupus disease by demonstrating that IgA autoantibodies boost type I interferon production by pDCs.”

Future research may explore therapeutic strategies targeting the IgA receptor FcαR. “These findings open up new avenues for developing treatments that could more effectively reduce inflammation and disease severity, offering hope for better management of this chronic and debilitating condition,” Dr. Hamerman concluded.