title: Lupus autoantibodies to native DNA preferentially bind DNA presented on PolIV.
abstract: While immunoglobulin G (IgG) antibodies to double-stranded (ds)DNA are serological markers of systemic lupus erythematosus (SLE), not all antibodies to DNA (anti-DNA) are able to cause tissue damage to a similar extent. It has been proposed that anti-DNA-induced renal damage could be linked to differences in the fine specificity of the antibodies. In an attempt to gain insight into their fine binding properties, we investigated the cross-reactivity of two human lupus monoclonal IgG anti-dsDNA (B3 and RH14) to a recently described Escherichia coli PolIV (a DNA polymerase). These autoantibodies possess distinct pathogenic properties in severe combined immunodeficient (SCID) mice. Although both antibodies cause proteinuria, only RH14 induces early histological features of lupus nephritis. Both RH14 and B3 bound PolIV; however, they exhibited a marked difference in their reactivity to the PolIV-dsDNA complex. Alhough RH14 exhibited significant activity to the complex, the binding of B3 to PolIV complexed with dsDNA was almost abolished. Furthermore, there was a significant difference in the way the lupus sera recognized naked dsDNA and that presented on PolIV. Although 67% of lupus sera bound naked dsDNA, approximately 90% of these sera (93% calf thymus DNA; 90% synthetic oligonucleotide) reacted to the complex when dsDNA was presented on PolIV. Thus, the IgG anti-dsDNA likely to exist in lupus patients may be distinguished into those that recognize dsDNA in the context of PolIV and those which do not. This difference in binding ability may help to distinguish those dsDNA antibodies that are more pathogenic.
authors.affiliation: Centre for Rheumatology, Department of Medicine, University College London Hospital, London, UK. sanjeev.kumar@antisoma.com
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Karen A
authors.initials: KA
authors.lastname: Bunting
authors.forename: Jatinderpal
authors.initials: J
authors.lastname: Kalsi
authors.forename: John A
authors.initials: JA
authors.lastname: Hinks
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: David A
authors.initials: DA
authors.lastname: Isenberg
mesh_terms: D000328:Adult; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism*; D000918:Antibody Specificity / Q000276:immunology; D015551:Autoimmunity; D003429:Cross Reactions / Q000276:immunology; D019951:DNA Polymerase beta / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged
chemical_list: D000974:Antibodies, Antinuclear; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D019951:DNA Polymerase beta
references.citation: Mol Cell. 2001 Jul;8(1):7-8
references.pmid: 11515498
references.citation: Curr Opin Microbiol. 2001 Oct;4(5):586-94
references.pmid: 11587937
references.citation: Cell. 2001 Oct 5;107(1):9-12
references.pmid: 11595180
references.citation: Arthritis Rheum. 1979 Mar;22(3):226-35
references.pmid: 311204
references.citation: J Immunol. 1981 Feb;126(2):538-9
references.pmid: 6161179
references.citation: J Immunol. 1982 Mar;128(3):1341-5
references.pmid: 7057035
references.citation: Biochemistry. 1982 Sep 28;21(20):4940-5
references.pmid: 6182906
references.citation: Mol Immunol. 1983 Jun;20(6):581-8
references.pmid: 6192329
references.citation: J Immunol. 1984 Feb;132(2):872-6
references.pmid: 6690621
references.citation: J Immunol Methods. 1985 Apr 22;78(2):191-8
references.pmid: 2580912
references.citation: Arthritis Rheum. 1985 Sep;28(9):999-1007
references.pmid: 3876101
references.citation: Immunology. 1987 Jul;61(3):375-81
references.pmid: 3497092
references.citation: Scand J Immunol. 1989 Jul;30(1):51-63
references.pmid: 2787927
references.citation: Arthritis Rheum. 1990 Feb;33(2):153-9
references.pmid: 2407246
references.citation: Annu Rev Immunol. 1992;10:731-57
references.pmid: 1591002
references.citation: Curr Opin Rheumatol. 1992 Aug;4(4):509-15
references.pmid: 1503874
references.citation: Ann Rheum Dis. 1993 Jan;52(1):14-20
references.pmid: 8427508
references.citation: Clin Exp Immunol. 1993 Apr;92(1):39-45
references.pmid: 8385586
references.citation: Medicine (Baltimore). 1993 Mar;72(2):113-24
references.pmid: 8479324
references.citation: J Immunol. 1993 Aug 1;151(3):1614-26
references.pmid: 8393048
references.citation: Q J Med. 1993 Jul;86(7):447-58
references.pmid: 8210301
references.citation: J Immunol. 1994 Mar 1;152(5):2601-12
references.pmid: 7510750
references.citation: J Clin Invest. 1995 Mar;95(3):1398-402
references.pmid: 7883986
references.citation: Clin Exp Rheumatol. 1994 Nov-Dec;12 Suppl 11:S27-31
references.pmid: 7539349
references.citation: Eur J Immunol. 1995 Jul;25(7):1897-904
references.pmid: 7621866
references.citation: J Immunol. 1996 Feb 15;156(4):1668-75
references.pmid: 8568274
references.citation: Biochemistry. 1996 Feb 6;35(5):1624-33
references.pmid: 8634294
references.citation: Methods. 1997 Jan;11(1):44-54
references.pmid: 8990088
references.citation: Br J Rheumatol. 1997 Feb;36(2):229-33
references.pmid: 9133936
references.citation: Curr Opin Rheumatol. 1997 Sep;9(5):387-92
references.pmid: 9309193
references.citation: Arthritis Rheum. 1997 Sep;40(9):1725
references.pmid: 9324032
references.citation: Eur J Immunol. 1998 Jan;28(1):339-50
references.pmid: 9485213
references.citation: J Exp Med. 1998 Jul 6;188(1):29-38
references.pmid: 9653081
references.citation: Biochemistry. 1999 Jan 12;38(2):560-8
references.pmid: 9888795
references.citation: Crit Rev Immunol. 1999;19(2):117-26
references.pmid: 10352900
references.citation: J Biol Chem. 2000 Nov 10;275(45):35129-36
references.pmid: 10893224
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):3838-43
references.pmid: 10760255
references.citation: Mol Cell. 1999 Aug;4(2):281-6
references.pmid: 10488344
references.citation: J Mol Biol. 2001 May 4;308(3):527-39
references.pmid: 11327785
references.citation: Mol Cell. 2001 Mar;7(3):571-9
references.pmid: 11463382