Prion-like Aggregation of Mitochondrial Antiviral Signaling Protein in Lupus Patients Is Associated With Increased Levels of Type I Interferon.
Arthritis Rheumatol
; 68(11): 2697-2707, 2016 11.
Article
in En
| MEDLINE
| ID: mdl-27110677
ABSTRACT
OBJECTIVE:
Increased levels of type I interferon (IFN) and type I IFN-regulated genes are found in patients with systemic lupus erythematosus (SLE) and may be central to its pathogenesis. Mitochondrial antiviral signaling protein (MAVS) is a key regulator of type I IFN that undergoes a dramatic prion-like aggregation and self propagates the activation signal from viral RNA to amplify downstream IFN production. We undertook this study to determine whether such MAVS aggregates might play a role in the sustained increased production of type I IFN in SLE.METHODS:
Peripheral blood mononuclear cells were isolated and mitochondrial extracts were prepared. MAVS aggregation was detected by semidenatured agarose gel electrophoresis and confirmed by immunofluorescence staining. MAVS-associated signaling proteins were analyzed by Western blotting. MAVS aggregation-associated gene expression signature was analyzed by microarray.RESULTS:
In blood cells from 22 of 67 SLE patients, essentially all MAVS was in a high molecular weight aggregated form. None of 6 rheumatoid arthritis patients and only 3 of 33 healthy controls had abnormal MAVS. Compared to MAVS aggregate-negative patients, MAVS aggregate-positive SLE patients had significantly higher serum levels of IFNß and significantly increased levels of autoantibodies against Sm and U1 RNP. Gene array data revealed a characteristic gene expression pattern in these patients, with altered expression of genes involved in IFN signaling and membrane trafficking.CONCLUSION:
Persistent MAVS aggregates may lead to increased type I IFN production and result in unmitigated signals leading to autoimmunity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukocytes, Mononuclear
/
Interferon Type I
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Adaptor Proteins, Signal Transducing
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Protein Aggregation, Pathological
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Lupus Erythematosus, Systemic
Type of study:
Observational_studies
/
Risk_factors_studies
Limits:
Adult
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Arthritis Rheumatol
Year:
2016
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
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US
/
USA