Initiation of AIHA: a study in scarlet

The generation of antibodies against one's own red blood cells can lead to autoimmune hemolytic anemia (AIHA), a severe and potentially life-threatening disease. We now know much about the pathophysiologies of a variety of organ-specific autoimmunity, but the mechanism(s) by which autoimmunity is initiated remains largely a mystery. There are a number of different hypotheses to explain the initiation and propagation of autoimmunity in AIHA.¹  Pathology presumably begins with immune recognition of a self antigen, which may be due to a failure of either central or peripheral tolerance. Such immune dysregulation may be spontaneous, occur due to environmental factors such as super-antigens or chronic inflammation, or represent a case of molecular mimicry, in which the immune response to a foreign antigen (eg, a microbial infection) cross-reacts with host antigens.

Once autoimmunity is initiated, propagation of the response may occur through epitope spreading, ultimately leading to autoimmunization against multiple self epitopes. For example, in experimental autoimmune encephalomyelitis (a model of multiple sclerosis), it has been shown that the order of epitope spreading can be a consistent and predictable process.^2,3  In this issue of Blood, Hall and colleagues have expanded this question to AIHA, using a murine model in which NZB mice spontaneously generate autoantibodies against Band 3. To test whether AIHA requires Band 3 to occur, Hall and colleagues monitored the development of AIHA in NZB mice with a deletion of the Band 3 gene. They demonstrate that AHIA still occurs but that the immunodominant target has switched from Band 3 to alternate molecules, most likely glycophorins; no antibodies against Band 3 are detected.

These findings make a significant and substantial contribution to our understanding of AIHA initiation. From a practical standpoint, they bring into question the feasibility of treating human AIHA by tolerance-induction strategies that are focused on the dominant antigens, since a predisposition to the disease may simply result in responses to an alternate antigen. These results also raise the question of whether immunization in AIHA is a linear sequence of epitope spreading, as removing Band 3 nevertheless allowed full development of the disease. However, it is impossible to rule out the possibility that a common antecedent antigen gives rise to both anti–Band 3 and antiglycophorin in parallel. Alternatively, immunity against glycophorins could precede immunity against Band 3 but only fully develop if spreading to Band 3 is not possible. Nevertheless, the data from Hall et al throw into question the linear model of epitope spreading. Finally, the Band 3–null mice retained a low background of preferential T-cell responsiveness for the immunodominant peptide form Band 3, raising the possibility of environmental exposure to an immunogen that mimics Band 3.

Overall, this study substantially advances our knowledge of AIHA pathogenesis through an elegant gene deletion approach. It is now clear, in an animal model of AIHA, that the dominant antigen is not a requirement for disease. After all, as Sherlock Holmes pointed out, “When you have excluded the impossible, whatever remains, however improbable, must be the truth.”