DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia

SWAlexander

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DNA sensing by RBCs
Red blood cells (RBCs) have historically been considered immunologically inert. In this study, however, Lam et al. demonstrated that RBCs promote inflammation through expression of Toll-like receptor 9 (TLR9) on the cell surface. The authors observed that RBC-expressed TLR9 bound DNA from bacteria, plasmodia, and mitochondria in vitro, and RBC-bound DNA was enriched in humans and mice during sepsis. This drove erythrophagocytosis by splenic macrophages, resulting in acute anemia. Last, the authors show that RBC-bound mitochondrial DNA was enriched in the peripheral blood of patients with viral pneumonia or sepsis secondary to coronavirus disease 2019 (COVID-19). Together, these findings show that RBCs are essential components of inflammatory responses. https://www.science.org/doi/10.1126/scitranslmed.abj1008
 

Pyrrhus

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Thanks for posting!

Here's the abstract from this (Lam et al., 2021) paper:
Red blood cells (RBCs) are essential for aerobic respiration through delivery of oxygen to distant tissues. However, RBCs are currently considered immunologically inert, and few, if any, secondary functions of RBCs have been identified.

Here, we showed that RBCs serve as critical immune sensors through surface expression of the nucleic acid–sensing Toll-like receptor 9 (TLR9). Mammalian RBCs expressed TLR9 on their surface and bound CpG-containing DNA derived from bacteria, plasmodia, and mitochondria.

RBC-bound mitochondrial DNA was increased during human and murine sepsis and pneumonia. In vivo, CpG-carrying RBCs drove accelerated erythrophagocytosis and innate immune activation characterized by increased interferon signaling. Erythroid-specific deletion of TLR9 abrogated erythrophagocytosis and decreased local and systemic cytokine production during CpG-induced inflammation and polymicrobial sepsis.

Thus, detection and capture of nucleic acid by TLR9-expressing RBCs regulated red cell clearance and inflammatory cytokine production, demonstrating that RBCs function as immune sentinels during pathologic states. Consistent with these findings, RBC-bound mitochondrial DNA was elevated in individuals with viral pneumonia and sepsis secondary to coronavirus disease 2019 (COVID-19) and associated with anemia and severity of disease. These findings uncover a previously unappreciated role of RBCs as critical players in inflammation distinct from their function in gas transport.
 

SWAlexander

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Very interesting. I have mild anemia, probably hemolytic, so this would be a fitting explanation. Considering that TLRs 3 and 4 are already identified in ME, an involvement of TLR9 is likely.
Me too and since early childhood low anemia. "Chloroquine tlr9 (genetic marker) inhibitor its analog quinacrine are also known to act as therapeutic agents for autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, of which therapeutic activity is due to suppression of TLR9 activity as shown by researchers."
 

pattismith

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Interesting I have always had low RBC (typically 3.6 to 3.8) so just below range for a woman. Docs say not worth follow up. But I am always interested in mechanisms of low grade RBC take down.
Me too and since early childhood low anemia. "Chloroquine tlr9 (genetic marker) inhibitor its analog quinacrine are also known to act as therapeutic agents for autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, of which therapeutic activity is due to suppression of TLR9 activity as shown by researchers."
have you checked your ferritine level and your transferrine saturation level to rule out any iron deficiency?
 

SWAlexander

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Seeking advice on low Folate (folc acid).
July: 3.5 ng/ml
Aug: 4.3 ng/ml normal range 4.6 - 18.7

von Willebrand disease (VWF9): 167.4
Lupus (dRVVT) : 2.09
 
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