Dysfunctional Red Blood Cells in Children Identified as a Potential Root Cause of Lupus

Research Funded by the Lupus Research Alliance Published in Today's 'Cell'

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Aug 11, 2021, 11:03 ET

NEW YORK, Aug. 11, 2021 /PRNewswire/ -- Pediatric lupus expert Virginia Pascual, MD together with her junior colleague Simone Caielli, PhD and their team at Weill Cornell Medicine in New York identified problems in the red blood cells of children with active Systemic Lupus Erythematosus (SLE) which may hold clues to a root cause of lupus. These results, just published in the prestigious journal Cell, suggest new targets for future lupus therapies. The research was partly funded by the Lupus Research Alliance (LRA).

Dr. Pascual's work built upon growing evidence that mitochondrial function is connected to the development of SLE and inflammation. Mitochondria are the "powerhouses" inside cells that convert energy from food into chemical fuel. Mitochondrial dysfunction – when these cellular "powerhouses" do not work properly – contributes to many diseases, including autoimmune diseases.

Previously, Drs. Pascual and Caielli had described mitochondrial dysfunction in two types of immune cells, neutrophils and CD4 T cells, in children with SLE. However, it was not known if mitochondrial dysfunction in other cells circulating in the blood contributes to SLE development or its progression.

Dr. Pascual and her team chose to look at red blood cells (RBCs) since they are unique compared to other cells. Normal RBCs, which carry oxygen around the body, remove their mitochondria as they mature in the bone marrow. The research team looked at the RBCs in pediatric patients with active SLE and in healthy children. "We found that a significant number of children with SLE had mature red blood cells which still contained mitochondria. In fact, the presence of RBCs containing mitochondria was linked to higher lupus disease activity," said Dr. Pascual, the senior author, the Drukier Director of the Drukier Institute for Children's Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine.

Using human cells, the investigators elucidated the steps leading to mitochondrial removal in healthy RBCs and pinned down the defect ultimately leading to RBCs keeping mitochondria in SLE patients. RBCs are removed from the blood by macrophages, a type of immune cell which essentially eats and destroys any cellular debris and foreign cells. Antibodies binding to RBCs, which are common in SLE patients, facilitate this process. Ingestion of mitochondria-containing RBCs by macrophages cause a flood of type I interferons.

Research has shown that the vast majority – 60-80 percent of adults and most children with lupus – have high levels of type I interferons. Altered biological pathways, such as what Drs. Caielli and Pascual found, lead to excess production of interferon. High interferon levels promote autoimmune inflammation. In theory, fixing the RBC mitochondria pipeline would stop the type I interferon flood and therefore reduce SLE disease activity in patients carrying these abnormal RBCs.

"Our findings support the idea that we need to separate patients according to the dysregulated pathways that lead to increased interferon production," said Dr. Pascual. "Thanks to the funding support from the LRA we identified a new defective pathway, which could help us classify SLE patients more effectively and ultimately target specifically this dysfunction. We hope this discovery will also lead to new modalities of treatment for lupus and other autoimmune diseases."

Dr. Pascual is the recipient of the LRA's 2017 Lupus Insight Prize, which recognizes an outstanding researcher who has developed a novel scientific discovery relevant to lupus. Dr. Caielli is a recipient of LRA's 2020 Lupus Innovation Award which provides support for pioneering, high-risk, high-reward approaches to major challenges in lupus research.

Teodora Staeva, PhD, Chief Scientific Officer at the Lupus Research Alliance, said, "We are delighted about these groundbreaking findings from Dr. Pascual and her colleagues which provide valuable new insight into the biological mechanisms of SLE and hold implications for children as well as adults. The potential addition of new therapeutic targets may expand the treatment opportunities for lupus patients."

About Lupus
Lupus is a chronic, complex autoimmune disease that affects millions of people worldwide. More than 90 percent of people with lupus are women; lupus most often strikes during the childbearing years of 15-45. African Americans, Latinx, Asians and Native Americans are two to three times at greater risk than Caucasians. In lupus, the immune system, which is designed to protect against infection, creates antibodies that can attack any part of the body impacting a wide range of tissues and organs including kidneys, brain, heart, lungs, blood, skin, and joints. Its treatment can also have serious side effects; one of the common medications for lupus, oral corticosteroids, for example, can lead to organ damage, infections, heart disease, osteoporosis weakening bones and cataracts affecting vision.^i,ii

About the Lupus Research Alliance
The Lupus Research Alliance is the largest non-governmental, non-profit funder of lupus research worldwide. The organization aims to transform treatment by funding the most innovative lupus research, fostering diverse scientific talent, and driving discovery toward better diagnostics, improved treatments and ultimately a cure for lupus. Because the Lupus Research Alliance's Board of Directors fund all administrative and fundraising costs, 100% of all donations goes to support lupus research programs.

Dr. Virginia Pascual has received consulting honoraria from Sanofi, AstraZeneca and Moderna and is the recipient of a research grant from Sanofi and a contract from AstraZeneca.

ⁱ Ruiz-Arruza I, Ugarteet A, Cabezas-Rodriguez I, et al. Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2014;53(8):1470-1476.
ⁱⁱ Al Sawah S, Zhang X, Zhu B, et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus—the Hopkins Lupus Cohort. Lupus Sci Med. 2015;2(1):e000066.

SOURCE Lupus Research Alliance