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Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of
Type I Interferon in Patients With Systemic Autoimmune Disease
#MMPMID27338297
Mavragani CP
; Sagalovskiy I
; Guo Q
; Nezos A
; Kapsogeorgou EK
; Lu P
; Liang Zhou J
; Kirou KA
; Seshan SV
; Moutsopoulos HM
; Crow MK
Arthritis Rheumatol
2016[Nov]; 68
(11
): 2686-2696
PMID27338297
show ga
OBJECTIVE: Increased expression of type I interferon (IFN) and a broad signature
of type I IFN-induced gene transcripts are observed in patients with systemic
lupus erythematosus (SLE) and other systemic autoimmune diseases. To identify
disease-relevant triggers of the type I IFN pathway, this study sought to
investigate whether endogenous virus-like genomic repeat elements, normally
silent, are expressed in patients with systemic autoimmune disease, and whether
these retroelements could activate an innate immune response and induce type I
IFN. METHODS: Expression of type I IFN and long interspersed nuclear element 1
(LINE-1; L1) was studied by polymerase chain reaction, Western blotting, and
immunohistochemistry in samples of kidney tissue from patients with lupus
nephritis and minor salivary gland (MSG) tissue from patients with primary
Sjögren's syndrome (SS). Induction of type I IFN by L1 was investigated by
transfection of plasmacytoid dendritic cells (PDCs) or monocytes with an
L1-encoding plasmid or L1 RNA. Involvement of innate immune pathways and altered
L1 methylation were assessed. RESULTS: Levels of L1 messenger RNA transcripts
were increased in lupus nephritis kidneys and in MSG tissue from patients with
SS. Transcript expression correlated with the expression of type I IFN and L1 DNA
demethylation. L1 open-reading frame 1/p40 protein and IFN? were expressed in MSG
ductal epithelial cells and in lupus nephritis kidneys, and IFN? was detected in
infiltrating PDCs. Transfection of PDCs or monocytes with L1-encoding DNA or RNA
induced type I IFN. Inhibition of Toll-like receptor 7 (TLR-7)/TLR-8 reduced the
induction of IFN? by L1 in PDCs, and an inhibitor of IKK?/TANK-binding kinase 1
abrogated the induction of type I IFN by L1 RNA in monocytes. CONCLUSION: L1
genomic repeat elements represent endogenous nucleic acid triggers of the type I
IFN pathway in SLE and SS and may contribute to initiation or amplification of
autoimmune disease.
|Adult
[MESH]
|Aged
[MESH]
|Autoimmune Diseases/genetics/immunology
[MESH]
|Blotting, Western
[MESH]
|DNA Methylation
[MESH]
|Dendritic Cells/immunology
[MESH]
|Female
[MESH]
|Humans
[MESH]
|I-kappa B Kinase/antagonists & inhibitors
[MESH]
|Immunity, Innate/immunology
[MESH]
|Immunohistochemistry
[MESH]
|Interferon Type I/drug effects/*immunology/metabolism
[MESH]
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