Autoantibodies, lupus and the science of sabotage

被引:33
作者
Rahman, A [1 ]
机构
[1] UCL, Dept Med, Ctr Rheumatol, London W1T 4NJ, England
基金
英国惠康基金;
关键词
D O I
10.1093/rheumatology/keh354
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Anti-double-stranded DNA antibodies (anti-dsDNA) and antiphospholipid antibodies (APL) are important in the pathogenesis of systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS) respectively. Not all anti-dsDNA or APL antibodies can cause clinical effects. Those that are particularly likely to cause tissue damage tend to be of IgG isotype and to possess particular binding properties. Rigorous statistical analysis of published sequences of human monoclonal anti-DNA and APL antibodies showed that IgG antibodies with binding properties characteristic of pathogenicity tend to have multiple somatic mutations in their variable regions. The distribution of these mutations suggests that they have been selected by antigen. This leads to accumulation of certain residues at the antigen-binding sites of these antibodies. Arginine residues are especially important. A computer-generated model of the pathogenic human monoclonal anti-DNA antibody B3 predicted that arginines in the heavy and light chain complementarity-determining regions (CDRs) would interact with dsDNA. We expressed cloned sequences encoding the B3 heavy and light chains in vitro to produce whole IgG. The cloned sequences of the heavy and light chains were manipulated to express a range of variant IgG antibodies. Binding assays on the expressed antibodies showed that altering specific arginine residues reduced binding to dsDNA in a way consistent with computer generated structural models. Changing the pattern of somatic mutations in the light chain altered binding to both dsDNA and histones, but in different ways. A single arginine-to-serine mutation in light-chain CDR1 of B3 reduced binding to both those antigens and may also have reduced the pathogenicity of the expressed antibodies in severe combined immunodeficiency (SCID) mice. Monoclonal human APL were expressed using the same system. Nineteen different heavy-light combinations were expressed. The ability to bind cardiolipin correlated well with the presence of exposed arginine residues in the heavy- and light-chain CDRs. The heavy chain of the pathogenic APL antibody IS4 contains four exposed arginines in CDR3. The results of mutagenesis studies suggested that two of these promote binding to cardiolipin whereas the other two have no such effect.
引用
收藏
页码:1326 / 1336
页数:11
相关论文
共 70 条
[1]   ANTIPHOSPHOLIPID ANTIBODIES AND THE ANTIPHOSPHOLIPID SYNDROME IN SYSTEMIC LUPUS-ERYTHEMATOSUS - A PROSPECTIVE ANALYSIS OF 500 CONSECUTIVE PATIENTS [J].
ALARCONSEGOVIA, D ;
DELEZE, M ;
ORIA, CV ;
SANCHEZGUERRERO, J ;
GOMEZPACHECO, L ;
CABIEDES, J ;
FERNANDEZ, L ;
DELEON, SP .
MEDICINE, 1989, 68 (06) :353-365
[2]   Development of autoantibodies before the clinical onset of systemic lupus erythematosus [J].
Arbuckle, MR ;
McClain, MT ;
Rubertone, MV ;
Scofield, RH ;
Dennis, GJ ;
James, JA ;
Harley, JB .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (16) :1526-1533
[3]   IDENTIFICATION AND CHARACTERIZATION OF A NEW HUMAN DNA REACTIVE MONOCLONAL-ANTIBODY AND A COMMON IDIOTYPE, WRI-176 ID-BETA [J].
BLANCO, F ;
LONGHURST, C ;
WATTS, R ;
KALSI, J ;
WILOCH, HW ;
YOUINOU, P ;
LATCHMAN, DS ;
ISENBERG, DA .
LUPUS, 1994, 3 (01) :15-24
[4]   INDUCTION OF ANTIPHOSPHOLIPID SYNDROME IN NAIVE MICE WITH MOUSE LUPUS MONOCLONAL AND HUMAN POLYCLONAL ANTICARDIOLIPIN ANTIBODIES [J].
BLANK, M ;
COHEN, J ;
TODER, V ;
SHOENFELD, Y .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (08) :3069-3073
[5]   Analysis of the human V-H gene repertoire - Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM(+) and CD5(-)/IgM(+) B cells [J].
Brezinschek, HP ;
Foster, SJ ;
Brezinschek, RI ;
Dorner, T ;
DomiatiSaad, R ;
Lipsky, PE .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (10) :2488-2501
[6]   Antiphospholipid syndrome -: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients [J].
Cervera, R ;
Piette, JC ;
Font, J ;
Khamashta, MA ;
Cervera, R ;
Piette, JC ;
Font, J ;
Khamashta, MA ;
Shoenfeld, Y ;
Camps, MT ;
Jacobsen, S ;
Lakos, G ;
Tincani, A ;
Kontopoulou-Griva, I ;
Galeazzi, M ;
Meroni, PL ;
Derksen, RHWM ;
de Groot, PG ;
Gromnica-Ihle, E ;
Baleva, M ;
Mosca, M ;
Bombardieri, S ;
Houssiau, F ;
Gris, JC ;
Quéré, I ;
Hachulla, E ;
Vasconcelos, C ;
Roch, B ;
Fernández-Nebro, A ;
Boffa, MC ;
Hughes, GRV ;
Ingelmo, M .
ARTHRITIS AND RHEUMATISM, 2002, 46 (04) :1019-1027
[7]   SYSTEMIC LUPUS-ERYTHEMATOSUS - CLINICAL AND IMMUNOLOGICAL PATTERNS OF DISEASE EXPRESSION IN A COHORT OF 1,000 PATIENTS [J].
CERVERA, R ;
KHAMASHTA, MA ;
FONT, J ;
SEBASTIANI, GD ;
GIL, A ;
LAVILLA, P ;
DOMENECH, I ;
AYDINTUG, AO ;
JEDRYKAGORAL, A ;
DERAMON, E ;
GALEAZZI, M ;
HAGA, HJ ;
MATHIEU, A ;
HOUSSIAU, F ;
INGELMO, M ;
HUGHES, GRV ;
CERVERA, R ;
SEBASTIANI, GD ;
FONT, J ;
KHAMASHTA, MA ;
HUGHES, GRV ;
FONT, J ;
CERVERA, R ;
LOPEZSOTO, A ;
VIVANCOS, J ;
INGELMO, M ;
URBANOMARQUEZ, A ;
KHAMASHTA, MA ;
VIANNA, J ;
HUGHES, GRV ;
GIL, A ;
LAVILLA, P ;
PINTADO, V ;
LOPEZDUPLA, M ;
VAZQUEZ, JJ ;
SEBASTIANI, GD ;
DERAMON, E ;
CAMPS, M ;
FRUTOS, MA ;
PERELLO, I ;
SANTOS, PG ;
ABARCA, M ;
NEBRO, AF ;
DOMENECH, I ;
TOKGOZ, G ;
AYDINTUG, AO ;
JEDRYKAGORAL, A ;
MALDYKOWA, H ;
CHWALINSKASADOWSKA, H ;
GALEAZZI, M .
MEDICINE, 1993, 72 (02) :113-124
[8]   Molecular and genetic characterizations of five pathogenic and two non-pathogenic monoclonal antiphospholipid antibodies [J].
Chukwuocha, RU ;
Zhu, M ;
Cho, CS ;
Visvanathan, S ;
Kwang, KK ;
Rahman, A ;
Chen, PP .
MOLECULAR IMMUNOLOGY, 2002, 39 (5-6) :299-311
[9]   Blebs and apoptotic bodies are B cell autoantigens [J].
Cocca, BA ;
Cline, AM ;
Radic, MZ .
JOURNAL OF IMMUNOLOGY, 2002, 169 (01) :159-166
[10]   Structural basis for autoantibody recognition of phosphatidylserine-β2 glycoprotein I and apoptotic cells [J].
Cocca, BA ;
Seal, SN ;
D'Agnillo, P ;
Mueller, YM ;
Katsikis, PD ;
Rauch, J ;
Weigert, M ;
Radic, MZ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (24) :13826-13831