title: Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2.
abstract: Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene. As DOCK2 regulates lymphocyte trafficking and Toll-like receptor signaling, this raised the possibility that some of the protective effects attributed to IRF5 deficiency in the mouse lupus models may instead have been due to DOCK2 deficiency. We have therefore here evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model in the absence of the DOCK2 mutation. We find that IRF5-deficient (IRF5-/-) MRL/lpr mice develop much less severe disease than their IRF5-sufficient (IRF5+/+) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4+ T cell numbers, IRF5-/- MRL/lpr mice have similar numbers of all splenic B cell subsets compared to IRF5+/+ MRL/lpr mice, suggesting that IRF5 is not involved in B cell development up to the mature B cell stage. However, IRF5-/- MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells. Serum levels of B lymphocyte stimulator (BLyS) were markedly elevated in the MRL/lpr mice but no effect of IRF5 on serum BLyS levels was seen. Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus.
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Kei
authors: K
authors: Yasuda
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Amanda A
authors: AA
authors: Watkins
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Guneet S
authors: GS
authors: Kochar
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Gabriella E
authors: GE
authors: Wilson
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Bari
authors: B
authors: Laskow
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Christophe
authors: C
authors: Richez
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Ramon G
authors: RG
authors: Bonegio
authors: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Ian R
authors: IR
authors: Rifkin
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D053264:B-Cell Activating Factor / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D007132:Immunoglobulin Isotypes / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009154:Mutation; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology; D016019:Survival Analysis; D018417:Th1 Cells / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D007132:Immunoglobulin Isotypes; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse