Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization

• DOI: 10.1084/jem.20151978
• Publication Date: 2016-06-13T14:21:59Z
• Authors: Joanne H. Reed; Jennifer Jackson; Daniel Christ; Christopher C. Go...
• Keywords: Clonal anergy; Immunogen; Naive B cell

Clonal anergy is an enigmatic self-tolerance mechanism because no apparent purpose 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 lymphocytes, cause cold agglutinin disease, are carried 5% of naive that anergic. We analyzed the specificity three IgG antibodies isolated from healthy donors immunized against foreign rhesus D alloantigen or vaccinia virus. Each was expressed either in a hypermutated immune state after reverting each antibody its unmutated preimmune ancestor. In case, ancestor bound intensely normal human I/i antigen. Self-reactivity removed single somatic mutation paradoxically decreased binding immunogen, whereas other mutations conferred increased binding. These data demonstrate existence for away self-reactivity humans. Because 2.5% switched memory use >43% these have remove binding, clonal redemption anergic appears efficient during physiological responses.