title: Accumulation of VH Replacement Products in IgH Genes Derived from Autoimmune Diseases and Anti-Viral Responses in Human.
abstract: VH replacement refers to RAG-mediated secondary recombination of the IgH genes, which renews almost the entire VH gene coding region but retains a short stretch of nucleotides as a VH replacement footprint at the newly generated VH-DH junction. To explore the biological significance of VH replacement to the antibody repertoire, we developed a Java-based VH replacement footprint analyzer program and analyzed the distribution of VH replacement products in 61,851 human IgH gene sequences downloaded from the NCBI database. The initial assignment of the VH, DH, and JH gene segments provided a comprehensive view of the human IgH repertoire. To our interest, the overall frequency of VH replacement products is 12.1%; the frequencies of VH replacement products in IgH genes using different VH germline genes vary significantly. Importantly, the frequencies of VH replacement products are significantly elevated in IgH genes derived from different autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and allergic rhinitis, and in IgH genes encoding various autoantibodies or anti-viral antibodies. The identified VH replacement footprints preferentially encoded charged amino acids to elongate IgH CDR3 regions, which may contribute to their autoreactivities or anti-viral functions. Analyses of the mutation status of the identified VH replacement products suggested that they had been actively involved in immune responses. These results provide a global view of the distribution of VH replacement products in human IgH genes, especially in IgH genes derived from autoimmune diseases and anti-viral immune responses.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Miles D
authors.initials: MD
authors.lastname: Lange
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Pediatrics, Philipps-University Marburg , Marburg , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zemlin
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA ; The Eppley Cancer Institute, University of Nebraska Medical Center , Omaha, NE , USA ; Department of Internal Medicine, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Kaihong
authors.initials: K
authors.lastname: Su
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE , USA ; The Eppley Cancer Institute, University of Nebraska Medical Center , Omaha, NE , USA.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Zhang
keywords: B-cell; IgH genes; VH replacement; VH replacement footprint; anti-viral response; antibody; autoimmune disease; cryptic RSS
references.citation: Nature. 1995 Jan 19;373(6511):252-5
references.pmid: 7816141
references.citation: Nature. 1983 Apr 14;302(5909):575-81
references.pmid: 6300689
references.citation: Clin Immunol. 2013 Jan;146(1):46-55
references.pmid: 23220404
references.citation: Immunity. 1999 Mar;10(3):289-99
references.pmid: 10204485
references.citation: J Immunol. 2004 Apr 1;172(7):4298-307
references.pmid: 15034044
references.citation: Ann N Y Acad Sci. 2003 Apr;987:270-3
references.pmid: 12727651
references.citation: J Immunol. 2005 Feb 15;174(4):1775-81
references.pmid: 15699102
references.citation: Front Immunol. 2014 Feb 10;5:40
references.pmid: 24575092
references.citation: Ann N Y Acad Sci. 1997 Apr 5;815:423-6
references.pmid: 9186688
references.citation: Nat Immunol. 2000 Nov;1(5):379-85
references.pmid: 11062496
references.citation: J Exp Med. 2000 Jun 5;191(11):1813-7
references.pmid: 10839798
references.citation: Blood. 2001 Mar 1;97(5):1511-3
references.pmid: 11222402
references.citation: EMBO J. 1984 Jun;3(6):1209-19
references.pmid: 6086308
references.citation: Cell. 1989 Dec 22;59(6):1035-48
references.pmid: 2598259
references.citation: Immunity. 1997 Jan;6(1):97-105
references.pmid: 9052841
references.citation: Immunity. 1998 Feb;8(2):199-207
references.pmid: 9492001
references.citation: Nature. 1986 Aug 28-Sep 3;322(6082):843-6
references.pmid: 3092106
references.citation: J Clin Invest. 2001 Oct;108(7):1061-70
references.pmid: 11581307
references.citation: EMBO J. 1992 Feb;11(2):611-8
references.pmid: 1311252
references.citation: Adv Immunol. 1994;56:27-150
references.pmid: 8073949
references.citation: PLoS One. 2013;8(2):e57877
references.pmid: 23469094
references.citation: Immunity. 2006 Jul;25(1):43-53
references.pmid: 16860756
references.citation: Cell. 1998 Jan 23;92(2):173-82
references.pmid: 9458042
references.citation: Nature. 1996 Jun 27;381(6585):751-8
references.pmid: 8657279
references.citation: Immunity. 1997 Sep;7(3):357-68
references.pmid: 9324356
references.citation: Cell. 1988 Apr 8;53(1):107-15
references.pmid: 3349523
references.citation: J Immunol. 2006 Nov 15;177(10):7007-14
references.pmid: 17082616
references.citation: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W503-8
references.pmid: 18503082
references.citation: J Immunol. 2006 Jul 15;177(2):1120-8
references.pmid: 16818769
references.citation: J Immunol. 2005 Jun 1;174(11):6599-607
references.pmid: 15905498
references.citation: Ann N Y Acad Sci. 2005 Dec;1062:175-81
references.pmid: 16461800
references.citation: Nucleic Acids Res. 1994 May 25;22(10):1785-96
references.pmid: 8208601
references.citation: Nat Med. 2005 Jan;11(1):85-9
references.pmid: 15619631
references.citation: Trends Immunol. 2007 Mar;28(3):132-7
references.pmid: 17258935
references.citation: Immunity. 2003 Jul;19(1):21-31
references.pmid: 12871636
references.citation: Science. 1990 Jun 22;248(4962):1517-23
references.pmid: 2360047
references.citation: Front Immunol. 2012 Dec 20;3:392
references.pmid: 23267360
references.citation: Science. 1987 Nov 20;238(4830):1088-94
references.pmid: 3317826
references.citation: J Immunol. 2000 Nov 15;165(10):5970-9
references.pmid: 11067960
references.citation: Immunity. 1995 Dec;3(6):747-55
references.pmid: 8777720
references.citation: J Immunol. 1997 Dec 15;159(12):5795-801
references.pmid: 9550375
references.citation: Nature. 1986 Aug 28-Sep 3;322(6082):840-2
references.pmid: 3092105
references.citation: Immunity. 2005 Apr;22(4):519-31
references.pmid: 15845455
references.citation: Nature. 1979 Aug 30;280(5725):838-40
references.pmid: 112480
references.citation: J Exp Med. 2007 Dec 24;204(13):3195-208
references.pmid: 18056287
references.citation: Immunity. 1998 Jul;9(1):115-25
references.pmid: 9697841
references.citation: Immunol Rev. 2004 Feb;197:231-42
references.pmid: 14962199
references.citation: Arthritis Rheum. 1993 May;36(5):631-41
references.pmid: 8489540
references.citation: Immunity. 1996 Dec;5(6):505-11
references.pmid: 8986711
references.citation: Science. 2001 Feb 23;291(5508):1541-4
references.pmid: 11222858
references.citation: Science. 1996 Jun 14;272(5268):1649-52
references.pmid: 8658139
references.citation: J Immunol. 2013 Jun 1;190(11):5559-66
references.pmid: 23630348