Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells.
OBJECTIVE
The objectives of this study were to determine whether late apoptotic cell material directly induces autoantibodies characteristic of systemic lupus erythematosus (SLE) and to investigate the innate recognition pathways involved.


METHODS
B6, B6.MyD88(-/-), B6.TLR7(-/-) and B6.TLR9(-/-) mice were subcutaneously injected with B6 syngeneic late apoptotic thymocytes (SLATs) without adjuvant on days 0, 10, 24 and 37. Sera were tested for IgG antibodies to histones and double-stranded DNA (dsDNA) by ELISA and Crithidia luciliae indirect immunofluorescence. IgG and C3 deposition in kidney glomeruli was assessed by immunostaining and fluorescence microscopy.


RESULTS
SLAT injections induced anti-dsDNA and anti-histone antibodies of the IgG1 and IgG2b isotypes in B6 but not MyD88(-/-) mice. TLR7(-/-) and TLR9(-/-) mice injected with SLATs produced delayed or slightly more robust responses, respectively. SLAT injections induced IgG deposits in renal glomeruli of B6, TLR7(-/-) and TLR9(-/-) mice that were absent in MyD88(-/-) mice. Unlike B6 and TLR9(-/-) animals, TLR7(-/-) mice failed to exhibit IgG colocalised glomerular C3 deposits and demonstrated autoantibodies of primarily the IgG2a isotype.


CONCLUSIONS
Late apoptotic cell-induced anti-histone and anti-dsDNA antibodies require MyD88 but not Toll-like receptor (TLR)9. Moreover, TLR7 promotes glomerular C3 deposition, possibly through a mechanism of altered antibody isotype switching.
Pan
Zi-jian
ZJ
Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104, USA.
Maier
Shannon
S
Schwarz
Karen
K
Azbill
Jennifer
J
Akira
Shizuo
S
Uematsu
Satoshi
S
Farris
A Darise
AD
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D017209:Apoptosis / Q000276:immunology; D003176:Complement C3 / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007678:Kidney Glomerulus / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D009707:Nucleosomes / Q000276:immunology; D013601:T-Lymphocytes / Q000637:transplantation; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000276:immunology*
D000974:Antibodies, Antinuclear; D003176:Complement C3; D006657:Histones; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009707:Nucleosomes; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7
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