Most high-affinity alloantibodies are produced by helper T cell-dependent activation of alloreactive B cells, much like antibodies against other protein antigens (see Chapter 11). The antigens most frequently recognized by alloantibodies in graft rejection are donor HLA molecules, including both class I and class II MHC proteins. The likely sequence of events leading to the generation of these alloantibody-producing cells is that naive B lymphocytes recognize foreign MHC molecules, internalize and process these proteins, and present peptides derived from them to helper T cells that were previously activated by the same peptides presented by dendritic cells. Thus, activation of alloreactive B cells is an example of indirect presentation of alloantigens. Anti-HLA antibodies contribute significantly to allograft rejection, as we will discuss below.
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