title: Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells.
abstract: VH replacement provides a unique RAG-mediated recombination mechanism to edit nonfunctional IgH genes or IgH genes encoding self-reactive BCRs and contributes to the diversification of Ab repertoire in the mouse and human. Currently, it is not clear how VH replacement is regulated during early B lineage cell development. In this article, we show that cross-linking BCRs induces VH replacement in human EU12 μHC(+) cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling-induced VH replacement is dependent on the activation of Syk and Src kinases but is inhibited by CD19 costimulation, presumably through activation of the PI3K pathway. These results show that VH replacement is regulated by BCR-mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments.
authors: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Jing
authors: J
authors: Liu
authors: Miles D
authors: MD
authors: Lange
authors: Sang Yong
authors: SY
authors: Hong
authors: Wanqin
authors: W
authors: Xie
authors: Kerui
authors: K
authors: Xu
authors: Lin
authors: L
authors: Huang
authors: Yangsheng
authors: Y
authors: Yu
authors: Götz R A
authors: GR
authors: Ehrhardt
authors: Michael
authors: M
authors: Zemlin
authors: Peter D
authors: PD
authors: Burrows
authors: Kaihong
authors: K
authors: Su
authors: Robert H
authors: RH
authors: Carter
authors: Zhixin
authors: Z
authors: Zhang
mesh_terms: D018941:Antigens, CD19 / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004789:Enzyme Activation; D015321:Gene Rearrangement; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D014066:Palatine Tonsil / Q000166:cytology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases
references: Cell. 1989 Dec 22;59(6):1035-48
references: 2598259
references: Nature. 1995 Jan 19;373(6511):252-5
references: 7816141
references: Adv Immunol. 1994;56:27-150
references: 8073949
references: Immunity. 1999 Mar;10(3):289-99
references: 10204485
references: Immunity. 2008 May;28(5):609-19
references: 18482567
references: J Immunol. 2002 Jun 1;168(11):5596-604
references: 12023356
references: Immunity. 2003 Jul;19(1):21-31
references: 12871636
references: Immunity. 1995 Dec;3(6):747-55
references: 8777720
references: Science. 2001 Feb 23;291(5508):1541-4
references: 11222858
references: J Exp Med. 1993 Apr 1;177(4):999-1008
references: 8459227
references: J Exp Med. 2000 Jun 5;191(11):1813-7
references: 10839798
references: Arthritis Rheum. 2001 Oct;44(10):2275-84
references: 11665968
references: Cell. 2004 Jan 23;116(2):299-311
references: 14744439
references: Curr Opin Immunol. 1997 Jun;9(3):309-18
references: 9203415
references: Immunity. 1997 Jan;6(1):97-105
references: 9052841
references: Nature. 1986 Aug 28-Sep 3;322(6082):843-6
references: 3092106
references: Blood. 2005 Apr 15;105(8):3247-54
references: 15644414
references: J Biol Chem. 2008 Nov 21;283(47):32650-9
references: 18818202
references: Cell. 1998 Dec 23;95(7):875-8
references: 9875841
references: Clin Immunol. 2013 Jan;146(1):46-55
references: 23220404
references: PLoS One. 2013;8(2):e57877
references: 23469094
references: Science. 2002 May 31;296(5573):1641-2
references: 12040177
references: Immunity. 2006 Jul;25(1):43-53
references: 16860756
references: Cell. 1998 Jan 23;92(2):173-82
references: 9458042
references: Nature. 1996 Jun 27;381(6585):751-8
references: 8657279
references: Curr Opin Immunol. 2003 Apr;15(2):182-9
references: 12633668
references: J Immunol. 2006 Nov 15;177(10):7007-14
references: 17082616
references: J Immunol. 2006 Jul 15;177(2):1120-8
references: 16818769
references: J Exp Med. 1993 Apr 1;177(4):1009-20
references: 8459201
references: Nat Immunol. 2008 Jun;9(6):613-22
references: 18469817
references: Blood. 2005 Jun 1;105(11):4390-8
references: 15701725
references: Annu Rev Immunol. 2000;18:19-51
references: 10837051
references: Blood. 2003 Feb 1;101(3):1030-7
references: 12393550
references: J Immunol. 2007 May 15;178(10):6332-41
references: 17475862
references: Trends Immunol. 2007 Mar;28(3):132-7
references: 17258935
references: Adv Immunol. 1994;55:221-95
references: 8304234
references: Trends Genet. 1992 Dec;8(12):413-6
references: 1492366
references: Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7125-30
references: 21471456
references: J Exp Med. 1998 Oct 5;188(7):1231-8
references: 9763602
references: Nat Immunol. 2005 Dec;6(12):1272-9
references: 16286921
references: J Immunol. 1997 Dec 15;159(12):5795-801
references: 9550375
references: Nature. 1986 Aug 28-Sep 3;322(6082):840-2
references: 3092105
references: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9267-72
references: 9256471
references: J Exp Med. 2007 Dec 24;204(13):3195-208
references: 18056287
references: Curr Opin Immunol. 2005 Jun;17(3):237-43
references: 15886112