Dysfunctional red blood cells in children may be 'root cause' of lupus
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The presence of mature red blood cells that still contain mitochondria is associated with higher systemic lupus erythematosus disease activity, according to data published in Cell.
In a statement released by the Lupus Research Alliance, which partially funded the research, these data, describing problems in the red blood cells, which typically remove their mitochondria as they mature in the bone marrow, could hold clues to the “root cause” of SLE.
“SLE is a very heterogeneous disease,” Simone Caielli, PhD, of the Drukier Institute for Children’s Health, at Weill Cornell Medicine, in New York, told Healio Rheumatology. “Many patients with SLE produce abnormal amounts of [interferons (IFN)], but the triggers and the sources of IFN are not well elucidated. We believe that our observations might permit us to classify better our patients according to the basic mechanisms leading to interferon production and ultimately to disease manifestations.”
To examine whether mitochondrial dysfunction impacts other cell lineages in patients with SLE, Caielli and colleagues analyzed the life cycle of red blood cells, keeping in mind that they typically clear their mitochondria as they mature. Using human cells, the researchers highlighted the steps leading to mitochondrial removal in healthy red blood cells and identified the defect that ultimately leads them to hold onto their mitochondria in patients with SLE.
According to the researchers, the ingestion of mitochondria-containing red blood cells by macrophages causes a flood of type I interferons. As the Lupus Research Alliance press release points out, about 60% to 80% of adults and most children with lupus demonstrate high levels of type I interferons. Altered biological pathways, such as those the researchers identified, lead to excess production of interferon.
“High interferon levels promote autoimmune inflammation,” read the press release, in part. “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.”
According to the Caielli and colleagues, up to 37.2% of mature — CD235a-positive CD71-negative — red blood cells containing mitochondria was reported in 26 patients with SLE, or 69.2% of the total. These cells were not present in any of the eight healthy donors or in the eight participants with juvenile dermatomyositis.
“We found that the red blood cells from a group of SLE patients retain their mitochondria, an organelle that is normally eliminated during red blood cells’ maturation,” Caielli said. “This observation led us to also to understand the mechanism used by healthy red blood cells to remove their mitochondria. In the end, SLE red blood cells containing mitochondria are a new contributor to the interferon production in SLE.”
He added: “In addition to a better patient classification, targeting some of the mechanisms that we found to be altered in the red blood cells of the patients might lead to new treatments.”
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Caielli S, et al. Cell. 2021;doi:10.1016/j.cell.2021.07.021.
Lupus Research Alliance press release.
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