title: Elucidation of the enigmatic IgD class-switch recombination via germline deletion of the IgH 3' regulatory region.
abstract: Classical class-switch recombination (cCSR) substitutes the Cμ gene with Cγ, Cε, or Cα, thereby generating IgG, IgE, or IgA classes, respectively. This activation-induced deaminase (AID)-driven process is controlled by the IgH 3' regulatory region (3'RR). Regulation of rare IgD CSR events has been enigmatic. We show that μδCSR occurs in mouse mesenteric lymph node (MLN) B cells and is AID-dependent. AID attacks differ from those in cCSR because they are not accompanied by extensive somatic hypermutation (SHM) of targeted regions and because repaired junctions exhibit features of the alternative end-joining (A-EJ) pathway. In contrast to cCSR and SHM, μδCSR is 3'RR-independent, as its absence affects neither breakpoint locations in Sμ- and Sδ-like (σ(δ)) nor mutation patterns at Sμ-σ(δ) junctions. Although mutations occur in the immediate proximity of the μδ junctions, SHM is absent distal to the junctions within both Sμ and rearranged VDJ regions. In conclusion, μδCSR is active in MLNs, occurs independently of 3'RR-driven assembly, and is even dramatically increased in 3'RR-deficient mice, further showing that its regulation differs from cCSR.
authors.affiliation: UMR CNRS 7276, Centre National de la Recherche Scientifique, Université de Limoges, 87025 Limoges, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Rouaud
authors.forename: Alexis
authors.initials: A
authors.lastname: Saintamand
authors.forename: Faten
authors.initials: F
authors.lastname: Saad
authors.forename: Claire
authors.initials: C
authors.lastname: Carrion
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lecardeur
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.forename: Yves
authors.initials: Y
authors.lastname: Denizot
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D015139:Blotting, Southern; D003001:Cloning, Molecular; D003564:Cytidine Deaminase / Q000276:immunology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007072:Immunoglobulin D / Q000235:genetics / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007150:Immunohistochemistry; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D017931:DNA Primers; D007072:Immunoglobulin D; D007143:Immunoglobulin Heavy Chains; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
references.citation: Adv Immunol. 2010;108:45-109
references.pmid: 21056729
references.citation: Mol Immunol. 2000 Oct;37(15):871-87
references.pmid: 11282392
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2466-70
references.pmid: 15684074
references.citation: Blood. 2005 Jul 15;106(2):593-600
references.pmid: 15827133
references.citation: Annu Rev Immunol. 1998;16:163-200
references.pmid: 9597128
references.citation: Adv Immunol. 2011;110:1-26
references.pmid: 21762814
references.citation: Proc Natl Acad Sci U S A. 1981 Mar;78(3):1800-4
references.pmid: 6262826
references.citation: Adv Immunol. 2009;101:163-89
references.pmid: 19231595
references.citation: Science. 2012 May 18;336(6083):931-4
references.pmid: 22539552
references.citation: PLoS One. 2012;7(9):e44719
references.pmid: 23028592
references.citation: Scand J Gastroenterol. 2006 Apr;41(4):430-6
references.pmid: 16635911
references.citation: Immunol Rev. 2005 Aug;206:32-63
references.pmid: 16048541
references.citation: J Exp Med. 1998 Apr 20;187(8):1169-78
references.pmid: 9547329
references.citation: Adv Immunol. 2011;110:27-70
references.pmid: 21762815
references.citation: Immunol Rev. 2010 Sep;237(1):160-79
references.pmid: 20727035
references.citation: J Exp Med. 2013 Jul 29;210(8):1501-7
references.pmid: 23825188
references.citation: Eur J Immunol. 2003 Aug;33(8):2069-73
references.pmid: 12884279
references.citation: Eur J Immunol. 2010 Dec;40(12):3306-11
references.pmid: 21080376
references.citation: Nat Immunol. 2009 Aug;10(8):889-98
references.pmid: 19561614
references.citation: Immunol Lett. 2012 Nov-Dec;148(1):23-33
references.pmid: 22902399
references.citation: J Immunol. 2010 Apr 1;184(7):3545-53
references.pmid: 20207993
references.citation: J Exp Med. 2007 Jan 22;204(1):181-90
references.pmid: 17227912
references.citation: J Immunol. 2010 Apr 1;184(7):3710-7
references.pmid: 20176739
references.citation: Blood. 2010 Sep 16;116(11):1895-8
references.pmid: 20538806
references.citation: J Biol Chem. 2012 Mar 9;287(11):8356-60
references.pmid: 22270371
references.citation: Nat Immunol. 2004 Jul;5(7):707-12
references.pmid: 15195091
references.citation: Mol Immunol. 2008 Nov;46(1):45-61
references.pmid: 18760480
references.citation: J Immunol. 2005 Apr 15;174(8):4567-78
references.pmid: 15814678
references.citation: J Exp Med. 1998 Oct 19;188(8):1421-31
references.pmid: 9782119
references.citation: J Immunol. 2011 Dec 1;187(11):5772-82
references.pmid: 22039300
references.citation: J Immunol. 2007 Nov 1;179(9):6033-42
references.pmid: 17947677
references.citation: Nature. 2007 Sep 27;449(7161):478-82
references.pmid: 17713479
references.citation: J Immunol. 2002 Jan 1;168(1):57-64
references.pmid: 11751946
references.citation: Mol Cell Biol. 1991 Nov;11(11):5660-70
references.pmid: 1922069
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10723-8
references.pmid: 16818885
references.citation: J Immunol. 2002 Oct 15;169(8):4408-16
references.pmid: 12370374
references.citation: Immunol Rev. 2012 May;247(1):11-23
references.pmid: 22500828
references.citation: Cell. 1994 Jun 3;77(5):737-47
references.pmid: 8205622
references.citation: Int Immunol. 1996 Jan;8(1):91-9
references.pmid: 8671593
references.citation: Immunity. 2001 Aug;15(2):187-99
references.pmid: 11520455
references.citation: Adv Immunol. 2012;116:1-49
references.pmid: 23063072
references.citation: Blood. 2003 May 15;101(10):4029-32
references.pmid: 12521993
references.citation: J Immunol. 2009 Jun 1;182(11):6926-32
references.pmid: 19454689
references.citation: J Immunol. 2013 Jun 15;190(12):5949-60
references.pmid: 23667108