Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization.
Clonal anergy is an enigmatic self-tolerance mechanism because no apparent purpose is served by retaining functionally silenced B cells bearing autoantibodies. Human autoantibodies with IGHV4-34*01 heavy chains bind to poly-N-acetyllactosamine carbohydrates (I/i antigen) on erythrocytes and B lymphocytes, cause cold agglutinin disease, and are carried by 5% of naive B cells that are anergic. We analyzed the specificity of three IGHV4-34*01 IgG antibodies isolated from healthy donors immunized against foreign rhesus D alloantigen or vaccinia virus. Each IgG was expressed and analyzed either in a hypermutated immune state or after reverting each antibody to its unmutated preimmune ancestor. In each case, the preimmune ancestor IgG bound intensely to normal human B cells bearing I/i antigen. Self-reactivity was removed by a single somatic mutation that paradoxically decreased binding to the foreign immunogen, whereas other mutations conferred increased foreign binding. These data demonstrate the existence of a mechanism for mutation away from self-reactivity in humans. Because 2.5% of switched memory B cells use IGHV4-34*01 and >43% of these have mutations that remove I/i binding, clonal redemption of anergic cells appears efficient during physiological human antibody responses.
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia j.reed@garvan.org.au c.goodnow@garvan.org.au.
Joanne H
JH
Reed
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
Jennifer
0000-0003-4237-5233
J
Jackson
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia.
Daniel
D
Christ
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia j.reed@garvan.org.au c.goodnow@garvan.org.au.
Christopher C
CC
Goodnow
D000914:Antibodies, Viral / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology; D005260:Female; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D008297:Male; D012204:Rh-Hr Blood-Group System / Q000008:administration & dosage* / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000187:drug effects / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*
D000914:Antibodies, Viral; D001323:Autoantibodies; D007074:Immunoglobulin G; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen