title: Genetic Interaction between Lyn, Ets1, and Btk in the Control of Antibody Levels.
abstract: Tight control of B cell differentiation into plasma cells (PCs) is critical for proper immune responses and the prevention of autoimmunity. The Ets1 transcription factor acts in B cells to prevent PC differentiation. Ets1(-/-) mice accumulate PCs and produce autoantibodies. Ets1 expression is downregulated upon B cell activation through the BCR and TLRs and is maintained by the inhibitory signaling pathway mediated by Lyn, CD22 and SiglecG, and SHP-1. In the absence of these inhibitory components, Ets1 levels are reduced in B cells in a Btk-dependent manner. This leads to increased PCs, autoantibodies, and an autoimmune phenotype similar to that of Ets1(-/-) mice. Defects in inhibitory signaling molecules, including Lyn and Ets1, are associated with human lupus, although the effects are more subtle than the complete deficiency that occurs in knockout mice. In this study, we explore the effect of partial disruption of the Lyn/Ets1 pathway on B cell tolerance and find that Lyn(+/-)Ets1(+/-) mice demonstrate greater and earlier production of IgM, but not IgG, autoantibodies compared with Lyn(+/-) or Ets1(+/-) mice. We also show that Btk-dependent downregulation of Ets1 is important for normal PC homeostasis when inhibitory signaling is intact. Ets1 deficiency restores the decrease in steady state PCs and Ab levels observed in Btk(-/-) mice. Thus, depending on the balance of activating and inhibitory signals to Ets1, there is a continuum of effects on autoantibody production and PC maintenance. This ranges from full-blown autoimmunity with complete loss of Ets1-maintaining signals to reduced PC and Ab levels with impaired Ets1 downregulation.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jessica
authors.initials: J
authors.lastname: Mayeux
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Brian
authors.initials: B
authors.lastname: Skaug
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203; and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Russell
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203; and.
authors.forename: Shinu
authors.initials: S
authors.lastname: John
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203; and.
authors.forename: Prontip
authors.initials: P
authors.lastname: Saelee
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Hansaa
authors.initials: H
authors.lastname: Abbasi
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, NY 14203; and anne.satterthwaite@utsouthwestern.edu leesinha@buffalo.edu.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Garrett-Sinha
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390 anne.satterthwaite@utsouthwestern.edu leesinha@buffalo.edu.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D004843:Epistasis, Genetic; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000906:Antibodies; D001323:Autoantibodies; C494042:Ets1 protein, mouse; D007075:Immunoglobulin M; D050784:Proto-Oncogene Protein c-ets-1; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases