The structural basis of repertoire shift in an immune response to phosphocholine

被引:30
作者
Brown, M
Schumacher, MA
Wiens, GD
Brennan, RG
Rittenberg, MB
机构
[1] Oregon Hlth Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA
[2] Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA
[3] Oregon Hlth Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA
关键词
immunoglobulin; somatic mutation; X-ray crystallography; antibody affinity; affinity maturation;
D O I
10.1084/jem.191.12.2101
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The immune response to phosphocholine (PC)-protein is characterized by a shift in antibody repertoire as the response progresses. This change in expressed gene combinations is accompanied by a shift in fine specificity toward the carrier, resulting in high affinity to PC-protein. The somatically mutated memory hybridoma, M3C65, possesses high affinity for PC-protein and the phenyl-hapten analogue, p-nitrophenyl phosphocholine (NPPC). Affinity measurements using related PC-phenyl analogues, including peptides of varying lengths, demonstrate that earlier determinants contribute to binding affinity and that somatic mutations alter this recognition. The crystal structure of an M3C65-NPPC complex at 2.35-Angstrom resolution allows evaluation of the three light chain mutations that confer high-affinity binding to NPPC. Only one of the mutations involves a contact residue, whereas the other two have indirect effects on the shape of the combining site. Comparison of the M3C65 structure to that of T15, an antibody dominating the primary response, provides clear structural evidence for the role of carrier determinants in promoting repertoire shift. These two antibodies express unrelated variable region heavy and light chain genes and represent a classic example of the effect of repertoire shift on maturation of the immune response.
引用
收藏
页码:2101 / 2111
页数:11
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共 80 条
  • [1] 3-DIMENSIONAL STRUCTURE DETERMINATION OF AN ANTI-2-PHENYLOXAZOLONE ANTIBODY - THE ROLE OF SOMATIC MUTATION AND HEAVY LIGHT CHAIN PAIRING IN THE MATURATION OF AN IMMUNE-RESPONSE
    ALZARI, PM
    SPINELLI, S
    MARIUZZA, RA
    BOULOT, G
    POLJAK, RJ
    JARVIS, JM
    MILSTEIN, C
    [J]. EMBO JOURNAL, 1990, 9 (12) : 3807 - 3814
  • [2] 3-DIMENSIONAL STRUCTURE OF AN ANTIGEN-ANTIBODY COMPLEX AT 2.8-A RESOLUTION
    AMIT, AG
    MARIUZZA, RA
    PHILLIPS, SEV
    POLJAK, RJ
    [J]. SCIENCE, 1986, 233 (4765) : 747 - 753
  • [3] ANTI-PHOSPHOCHOLINE HYBRIDOMA ANTIBODIES .2. FUNCTIONAL-ANALYSIS OF BINDING-SITES WITHIN 3 ANTIBODY FAMILIES
    ANDRES, CM
    MADDALENA, A
    HUDAK, S
    YOUNG, NM
    CLAFLIN, JL
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1981, 154 (05) : 1584 - 1598
  • [4] Binding of phenylphosphocholine-carrier conjugates to the combining site of antibodies maintains a conformation of the hapten
    Barbar, E
    Martin, TM
    Brown, M
    Rittenberg, MB
    Peyton, DH
    [J]. BIOCHEMISTRY, 1996, 35 (09) : 2958 - 2967
  • [5] Affinity dependence of the B cell response to antigen: A threshold, a ceiling, and the importance of off-rate
    Batista, FD
    Neuberger, MS
    [J]. IMMUNITY, 1998, 8 (06) : 751 - 759
  • [6] STRUCTURE OF TYPE-27 STREPTOCOCCUS-PNEUMONIAE (PNEUMOCOCCAL) CAPSULAR POLYSACCHARIDE
    BENNETT, LG
    BISHOP, CT
    [J]. CANADIAN JOURNAL OF CHEMISTRY-REVUE CANADIENNE DE CHIMIE, 1977, 55 (01): : 8 - 16
  • [7] MOLECULAR EVENTS DURING MATURATION OF THE IMMUNE-RESPONSE TO OXAZOLONE
    BEREK, C
    GRIFFITHS, GM
    MILSTEIN, C
    [J]. NATURE, 1985, 316 (6027) : 412 - 418
  • [8] MUTATION DRIFT AND REPERTOIRE SHIFT IN THE MATURATION OF THE IMMUNE-RESPONSE
    BEREK, C
    MILSTEIN, C
    [J]. IMMUNOLOGICAL REVIEWS, 1987, 96 : 23 - 41
  • [9] BOUND WATER-MOLECULES AND CONFORMATIONAL STABILIZATION HELP MEDIATE AN ANTIGEN-ANTIBODY ASSOCIATION
    BHAT, TN
    BENTLEY, GA
    BOULOT, G
    GREENE, MI
    TELLO, D
    DALLACQUA, W
    SOUCHON, H
    SCHWARZ, FP
    MARIUZZA, RA
    POLJAK, RJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (03) : 1089 - 1093
  • [10] USE OF MOLECULAR REPLACEMENT IN THE SOLUTION OF AN IMMUNOGLOBULIN FAB FRAGMENT STRUCTURE
    BIZEBARD, T
    MAUGUEN, Y
    SKEHEL, JJ
    KNOSSOW, M
    [J]. ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1991, 47 : 549 - 555