Endogenous double-stranded Alu RNA elements stimulate IFN-responses in relapsing remitting multiple sclerosis

Area of Science:

• Immunology
• Neuroscience
• Genetics

Background:

• Eukaryotic cells possess sensors for double-stranded RNA (dsRNA), typically of viral origin, which trigger interferon (IFN) responses.
• Elevated IFN responses are observed in various human autoimmune diseases, including relapsing-remitting multiple sclerosis (RRMS), but their source is unclear.

Purpose of the Study:

• To investigate the origins of IFN responses in leukocytes during relapsing-remitting multiple sclerosis.
• To determine if endogenous RNAs contribute to IFN responses in RRMS.

Main Methods:

• Quantified IFN responses in leukocytes from RRMS patients at different disease stages.
• Isolated endogenous RNAs from RRMS patient blood cells.
• Transfected these endogenous RNAs into naïve cells to assess IFN response induction.
• Characterized the nature of these endogenous RNAs, including their sequence elements and transcriptional origins.

Main Results:

• Leukocytes in RRMS patients exhibited increased IFN responses across distinct disease stages.
• Endogenous double-stranded RNAs isolated from RRMS patients' blood cells induced IFN responses when transfected into naïve cells.
• These endogenous dsRNAs contained Alu and Line elements and were transcribed from leukocyte enhancers.

Conclusions:

• Transcribed endogenous retrotransposon elements can activate pattern recognition sensors.
• This activation leads to IFN responses in relapsing-remitting multiple sclerosis.
• Endogenous dsRNAs from retrotransposons are a likely source of IFN responses in RRMS.