DNA graphic

Simone Caielli, PhD

Assistant Professor

Weill Cornell Medical College



Erythroid mitochondrial dysfunction in lupus pathogenesis

There is some evidence that defects in mitochondria—the “powerhouse” of every cell—may be involved in the development of lupus. While examining how this happens, Dr. Caielli found a population of red blood cells in some lupus patients that have mitochondria in them—which was very strange, since mature red blood cells don’t usually have anything in them besides hemoglobin! Moreover, he showed that these red blood cells can induce the inflammation that is so problematic in people with lupus and other immune disorders. He was able to generate more of these cells in the lab and hopes to use them to figure out if they correlate with more severe disease activity and progression.


What this study means for people with lupus


With his funding from the Lupus Research Alliance, Dr. Caielli aims to identify the underlying causes of lupus by examining how the defective, mitochondria-containing red blood cells he has found in lupus patients induce inflammation. Only by first understanding the root causes of the rogue inflammation that is so damaging to those with lupus and other immune disorders can we hope to devise effective treatments.

Accumulating evidence indicates that mitochondrial-Damage Associated Molecular Patterns (mito-DAMPs) plays an important roles in Systemic Lupus Erythematosus (SLE) pathogenesis. Thus, SLE neutrophils extrude oxidized mitochondrial DNA (ox mtDNA) that potently stimulate the production of interferons (IFNs) by plasmacytoid dendritic cells (pDCs). Furthermore, ox mtDNA-activated pDCs drive the generation of a novel subset of extrafollicular helper T cells (Th10) that support B cell differentiation and antibody production. During the course of investigating mitochondrial quality control defects in SLE blood cells we identified, in SLE patients, with high disease activity (DA), a fraction of atypical mature red blood cells containing functional mitochondria (RBCs+). This is surprising, as during terminal erythroid differentiation mammalian erythroblasts remove their organelles, including mitochondria and ribosomes. This defective mitochondrial removal can be recapitulated in erythroid precursors generated in vitro from SLE pheripheral blood mononuclear cells (PBMCs) and it is the result of impaired metabolic rewiring and subsequent proteasome activation in those cells. Furthermore, RBCs+ as they carry mito-DAMPs, are proinflammatory and induce human monocytes to release IL1b and IP-10.
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