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

JH Reed, J Jackson, D Christ… - Journal of Experimental …, 2016 - rupress.org
Journal of Experimental Medicine, 2016rupress.org
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 …
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.
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