title: Lack of T cells in Act1-deficient mice results in elevated IgM-specific autoantibodies but reduced lupus-like disease.
abstract: Act1 is a negative regulator of B-cell activation factor of the TNF family (BAFF) and CD40L-induced signaling. BALB/C mice lacking Act1 develop systemic autoimmunity resembling systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). SLE and SjS are characterized by anti-nuclear IgG autoantibody (ANA-IgG) production and inflammation of peripheral tissues. As autoantibody production can occur in a T-cell dependent or T-cell independent manner, we investigated the role of T-cell help during Act1-mediated autoimmunity. Act1-deficiency was bred onto C57Bl/6 (B6.Act1(-/-) ) mice and B6.TCRβ(-/-) TCRδ(-/-) Act1(-/-)  (TKO) mice were generated. While TCRβ/δ-sufficient B6.Act1(-/-)  mice developed splenomegaly and lymphadenopathy, hypergammaglobulinemia, elevated levels of ANA-IgG, and kidney pathology, TKO mice failed to develop any such signs of disease. Neither B6.Act1(-/-)  nor TKO mice developed SjS-like disease, suggesting that epigenetic interactions on the BALB/C background are responsible for this phenotype in BALB/C.Act1(-/-)  mice. Interestingly, BAFF-driven transitional B-cell abnormalities, previously reported in BALB/C.Act1(-/-)  mice, were intact in B6.Act1(-/-)  mice and largely independent of T cells. In conclusion, T cells are necessary for the development of SLE-like disease in B6.Act1(-/-)  mice, but not BAFF-driven transitional B-cell differentiation.
authors.affiliation: Department of Immunology NE40, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Johnson
authors.forename: Laura M
authors.initials: LM
authors.lastname: Davison
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Giltiay
authors.forename: Chairut
authors.initials: C
authors.lastname: Vareechon
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Trine N
authors.initials: TN
authors.lastname: Jørgensen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000097:blood / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000276:immunology*; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008206:Lymphatic Diseases / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D013163:Splenomegaly / Q000276:immunology; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007075:Immunoglobulin M; C515963:Traf3ip2 protein, mouse