Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation.
Nucleic acid-binding innate immune receptors such as Toll-like receptor 7 (TLR7) and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa, which correlates with a duplication of Tlr7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrated that duplication of the Tlr7 gene was the sole requirement for this accelerated autoimmunity, because reduction of Tlr7 gene dosage abolished the Yaa phenotype. Further, we described new transgenic lines that overexpressed TLR7 alone and found that spontaneous autoimmunity developed beyond a 2-fold increase in TLR7 expression. Whereas a modest increase in Tlr7 gene dosage promoted autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, a substantial increase in TLR7 expression caused fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses.
Deane
Jonathan A
JA
Laboratory of Immunogenetics, NIAID/NIH, Rockville, MD 20852, USA.
Pisitkun
Prapaporn
P
Barrett
Rebecca S
RS
Feigenbaum
Lionel
L
Town
Terrence
T
Ward
Jerrold M
JM
Flavell
Richard A
RA
Bolland
Silvia
S
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018628:Gene Dosage; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis / Q000235:genetics*
D001323:Autoantibodies; D001324:Autoantigens; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D012313:RNA