Modulation of autoimmunity by TLR9 in the chronic graft-vs-host model of systemic lupus erythematosus.
Chronic graft-vs-host (cGVH) disease is induced in nonautoimmune mice by the transfer of alloreactive T cells that recognize foreign MHC class II. It closely resembles systemic lupus erythematosus, with antinuclear Abs and immune-mediated nephritis. Recent work has implicated TLRs, particularly TLR9, in the recognition of certain autoantigens in vitro and in vivo. To explore further the role of TLR9 in systemic autoimmunity, we induced cGVH disease in C57BL/6 (B6) mice lacking TLR9, including B6 mice expressing the anti-DNA-encoding IgH transgenes 3H9 or 56R (B6.3H9.TLR9(-/-), B6.56R.TLR9(-/-)). We found that cGVH disease caused breakdown of B cell tolerance to chromatin and DNA in TLR9(-/-) recipients of alloreactive cells, yet that nephritis was less severe and that some autoantibody titers were lower compared with B6-cGVH controls. Spleen lymphocyte analysis showed that cGVH disease strikingly depleted marginal zone B cells in B6 mice, but did not influence T cell subsets in either B6 or B6-TLR9(-/-) hosts. B6.56R.TLR9(-/-) mice had less spontaneous production of autoantibodies than B6.56R mice, but there were no significant differences between B6.56R and B6.56R.TLR9(-/-) postinduction of cGVH disease. Taken together, these results suggested that TLR9 may worsen some aspects of systemic autoimmunity while alleviating others.
Ma
Zhongjie
Z
Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Chen
Fangqi
F
Madaio
Michael P
MP
Cohen
Philip L
PL
Eisenberg
Robert A
RA
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000473:pathology; D002843:Chromatin / Q000276:immunology; D002908:Chronic Disease; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011507:Proteinuria / Q000276:immunology; D012217:Rheumatoid Factor / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D002843:Chromatin; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA; D012217:Rheumatoid Factor