title: Fatty Acid Amide Hydrolase Regulates Peripheral B Cell Receptor Revision, Polyreactivity, and B1 Cells in Lupus.
abstract: C57BL/6 mice bearing the Sle2(z) lupus-susceptibility congenic interval on chromosome 4 display high titers of polyclonal autoantibodies with generalized B cell hyperactivity, hallmarks of systemic lupus erythematosus. In B6.Sle2(z)HEL(Ig).sHEL BCR-transgenic mice, Sle2(z) did not breach central tolerance, but it led to heightened expression of endogenous Ig H and L chains in splenic B cells, upregulation of RAG, and serological polyreactivity, suggestive of excessive receptor revision. Fatty acid amide hydrolase (FAAH), a gene in the minimal subcongenic interval generated through recombinant mapping, was found to be upregulated in Sle2(z) B cells by microarray analysis, Western blot, and functional assays. Pharmacological inhibition of FAAH reversed the increase in receptor revision, RAG expression, and polyreactive autoantibodies in lupus-prone mice. These studies indicate that increased peripheral BCR revision, or selective peripheral expansion of BCR-revised B cells, may lead to systemic autoimmunity and that FAAH is a lupus-susceptibility gene that might regulate this process.
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biomedical Engineering, University of Houston, Houston, TX 77204;
authors.forename: Simanta
authors.initials: S
authors.lastname: Pathak
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Kirthi Raman
authors.initials: KR
authors.lastname: Kumar
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Hasna
authors.initials: H
authors.lastname: Kanta
authors.affiliation: Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Ferdicia
authors.initials: F
authors.lastname: Carr-Johnson
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Jie
authors.identifier: http://orcid.org/0000-0002-6553-7197
authors.initials: J
authors.lastname: Han
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Anna
authors.initials: A
authors.lastname: Bashmakov
authors.affiliation: Center for Plant Lipid Research, University of North Texas, Denton, TX 76203.
authors.forename: Lionel
authors.initials: L
authors.lastname: Faure
authors.affiliation: Department of Biomedical Engineering, University of Houston, Houston, TX 77204;
authors.forename: Huihua
authors.identifier: http://orcid.org/0000-0002-7530-8953
authors.initials: H
authors.lastname: Ding
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biomedical Engineering, University of Houston, Houston, TX 77204;
authors.forename: Kamala
authors.initials: K
authors.lastname: Vanarsa
authors.affiliation: Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Shaheen
authors.identifier: http://orcid.org/0000-0002-1472-8129
authors.initials: S
authors.lastname: Khan
authors.affiliation: Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Quan-Zhen
authors.identifier: http://orcid.org/0000-0002-7257-0489
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Center for Plant Lipid Research, University of North Texas, Denton, TX 76203.
authors.forename: Kent
authors.identifier: http://orcid.org/0000-0003-0489-3072
authors.initials: K
authors.lastname: Chapman
authors.affiliation: Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.
authors.forename: Edward K
authors.identifier: http://orcid.org/0000-0002-7107-0992
authors.initials: EK
authors.lastname: Wakeland
authors.affiliation: Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biomedical Engineering, University of Houston, Houston, TX 77204; Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and texascmohan@gmail.com.
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001323:Autoantibodies; D011947:Receptors, Antigen, B-Cell; D000099252:Fatty Acid Amide Hydrolases