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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4139-4140. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zimring, J. C. Search for Related Content PubMed Articles by Zimring, J. C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Comment on Hall et al, page 4511 Initiation of AIHA: a study in scarlet James C. Zimring EMORY UNIVERSITY SCHOOL OF MEDICINE Knocking out the immunodominant antigen (Band 3) in a spontaneous model of mouse autoimmune hemolytic anemia demonstrates that full pathology still occurs even in the absence of the normal target of autoantibodies. 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." Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Semple JW and Freedman J. Autoimmune pathogenesis and autoimmune hemolytic anemia. Semin Hematol 2005; 42:122–130.[CrossRef][Medline] [Order article via Infotrieve] Vanderlugt CL, Neville KL, Nikcevich KM, Eagar TN, Bluestone JA, Miller SD. Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. J Immunol 2000; 164:670–678.[Abstract/Free Full Text] Yu M, Johnson JM, Tuohy VK. A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. J Exp Med 1996; 183:1777–1788.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Deletion of the dominant autoantigen in NZB mice with autoimmune hemolytic anemia: effects on autoantibody and T-helper responses Andrew M. Hall, Frank J. Ward, Chia-Rui Shen, Cliff Rowe, Laura Bowie, Anne Devine, Stanislaw J. Urbaniak, Christopher J. Elson, and Robert N. Barker Blood 2007 110: 4511-4517. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zimring, J. C. Search for Related Content PubMed Articles by Zimring, J. C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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