Red blood cell alterations contribute to lupus

Date:
August 12, 2021
Source:
Weill Cornell Medicine
Summary:
The autoimmune disease lupus may be triggered by a defective process
in the development of red blood cells (RBCs), according to a new
study. The discovery could lead to new methods for classifying
and treating patients with this disease.



FULL STORY ==========================================================================
The autoimmune disease lupus may be triggered by a defective process in
the development of red blood cells (RBCs), according to a study led by researchers at Weill Cornell Medicine. The discovery could lead to new
methods for classifying and treating patients with this disease.


==========================================================================
The researchers, who published their findings August 11 in Cell, found
that in a number of lupus patients, maturing red blood cells fail
to get rid of their mitochondria -- tiny molecular reactors that help
convert oxygen into chemical energy in most cell types, but are normally excluded from red blood cells. This abnormal retention of mitochondria
can trigger the cascade of inappropriate and harmful immune activity
that is characteristic of the disease.

"Our findings support that red blood cells can play a really important
role in driving inflammation in a subgroup of lupus patients," said
senior author Dr.

Virginia Pascual, the Drukier Director of the Gale and Ira Drukier
Institute for Children's Health and the Ronay Menschel Professor of
Pediatrics at Weill Cornell Medicine. "So this adds a new piece to
the lupus puzzle, and could now open the door to new possibilities for therapeutic interventions." The lead author of the study was Dr. Simone Caielli, assistant professor of immunology research at the Drukier
Institute and the Department of Pediatrics at Weill Cornell Medicine.

Lupus, also known as systemic lupus erythematosus, is a chronic disorder
that features intermittent and sometimes debilitating attacks by the
immune system on the body's own healthy tissues, including skin, joints,
hair follicles, heart and kidneys. A common underlying factor is the
abnormally elevated production of immune-activating proteins called type
I interferons. Treatments, which often are taken long-term and have side effects, aim to suppress immune activity, including interferon-driven inflammation. There is no cure for lupus, and how it arises is still
largely mysterious. It is estimated to affect roughly 200,000 people in
the United States, the vast majority of whom are female.

Previous studies have shown defective mitochondria within immune cells
of lupus patients. In the new study, the researchers examined red
blood cells, which are supposed to have no mitochondria at all. They
found that a large number of lupus patients had red blood cells with
detectable levels of mitochondria - - and these cells were especially
frequent in patients with the most severe lupus symptoms. By contrast,
healthy controls had no mitochondria-containing red blood cells.

Dr. Caielli then studied how human red blood cells normally rid themselves
of mitochondria as they mature, as prior studies had mainly examined
this in mice, and why this process could be defective in lupus patients.

Further experiments revealed how these abnormal red blood cells
cause inflammation. In general, as red blood cells age or display
signs of damage they are removed by scavenger immune cells called
macrophages. Antibodies that bind red blood cells also facilitate
their removal. Once ingested by macrophages, the red blood cells'
mitochondrial DNA stimulates a powerful inflammatory pathway called
the cGAS/STING pathway, which in turn drives type I interferon
production. Underlining the relevance of these findings, "those lupus
patients with mitochondria-containing red blood cells and evidence of circulating anti-RBC antibodies had higher interferon signatures compared
to those who didn't," Dr. Caielli said.

The researchers are now continuing to study the complex process by which mitochondria are retained in red blood cells and end up driving abnormal
immune activation. Identifying patients whose lupus symptoms are driven
this way might permit to detect when they are likely to undergo lupus
flares and to identify specific therapies for them.

========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Simone Caielli, Jacob Cardenas, Adriana Almeida de Jesus, Jeanine
Baisch,
Lynnette Walters, Jean Philippe Blanck, Preetha Balasubramanian,
Cristy Stagnar, Marina Ohouo, Seunghee Hong, Lorien Nassi, Katie
Stewart, Julie Fuller, Jinghua Gu, Jacques F. Banchereau, Tracey
Wright, Raphaela Goldbach-Mansky, Virginia Pascual. Erythroid
mitochondrial retention triggers myeloid-dependent type I interferon
in human SLE. Cell, 2021; DOI: 10.1016/j.cell.2021.07.021 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210812135922.htm

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