The idea that self-tolerance might be actively acquired in B cells had been discarded by most immunologists thirty years ago in 1987. In the absence of adequate analytical methods, popular belief had swung, pendulum-like, against the cornerstone of Burnet’s Nobel-recognised 1959 theory. Belief that “clonal tolerance is dead” was so strong that when I presented transgenic mouse evidence for active B cell tolerance by clonal anergy at the 1989 Cold Spring Harbor Symposium, the first question came from the great Avrion Mitchison: “These results are all very well, but why have you done these experiments when everyone knows there is no such thing as B cell tolerance?”

Students of antibody self-nonself discrimination have been, and still are, on a long odyssey of discovery to understand the origins of the extraordinary specificity of antibodies. Actively acquired tolerance endows antibodies with their extraordinary power to discriminate self and foreign proteins despite differing by a single amino acid, or to discriminate normal and abnormal proteins differing by a chemical modification.

The extraordinary discriminating power of antibodies is crucial to avoid the problems of antigenic mimicry and autoimmunity, but some viruses have discovered its limitations. Viruses that establish life-long infections, notably HIV, LCMV and Lassa Fever, use actively acquired B cell tolerance against us by cloaking their foreign envelope proteins with our own glycans. Successful vaccination against HIV currently turns upon devising ways to elicit antibodies that distinguish [virus-protein + self-glycan] from [self-protein + self-glycan], much like the T cell receptor must distinguish [virus-peptide + self-MHC] from [self-peptide + self-MHC].

Where do these powers of discrimination come from and how can we enhance them? Is there really so much antibody diversity generated by VDJ recombination that we can afford to throw away all antibodies that bind to self in the bone marrow, as Burnet and Lederberg theorized? In this lecture I will discuss this odyssey and recent evidence for a complementary mechanism to Burnet’s throw-away system: autoantibody redemption by activating anergic B cells into germinal centres for mutation away from self.