The MHC Determines the Ability of Two Unrelated Individuals of the Same Species to Accept or Reject Grafts

The major histocompatibility complex was discovered, as its name implies, as the genetic locus that controls acceptance or rejection of tissue grafts. At a time when tissue culture had not yet been developed to the stage where tumor-derived cell lines could be propagated in the laboratory, investigators relied on serial passage of tumor tissue in vivo (that is, transplanting a tumor from one mouse to another). It was quickly observed that a tumor that arose spontaneously in one inbred strain of mice could be propagated successfully in the strain in which it arose, but not in a genetically distinct strain of mice. Genetic analysis soon showed that a single major genetic locus was responsible for this behavior. Similarly, transplantation of healthy skin was feasible within the same strain of mice, but not when the recipient was of a genetically distinct background. Genetic analysis of transplant rejection likewise identified a single major locus—the same one responsible for tumor rejection—that controlled acceptance or rejection, which is an immune reaction. As we now know, all vertebrates that possess an adaptive immune system have a genetic region that corresponds to the major histocompatibility complex as originally defined in the mouse.

In mice, the genetic region responsible for graft rejection is called the H-2 complex (Figure 23-21a). In humans, the genetic region encoding the MHC was uncovered during the study of patients who underwent multiple blood transfusions that provoked an immune response. The human MHC region is called the HLA complex (Figure 23-21b). The typical mammalian MHC contains dozens of genes, many encoding proteins of immunological relevance. All vertebrate MHCs encode a highly homologous set of proteins, although the details of organization and gene content show considerable variation between species, as seen for domestic chickens, mice, and humans. Most cells in vertebrates express MHC proteins and thus have the potential to present antigenic peptides for recognition by the immune system.

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FIGURE 23-21 Organization of the major histocompatibility complex in mice and in humans. The major loci are depicted with schematic diagrams of their encoded proteins below. Class I MHC proteins are composed of an MHC-encoded single-pass transmembrane glycoprotein in noncovalent association with a small subunit, called β2-microglobulin, which is not encoded in the MHC and is not membrane bound. Class II MHC proteins consist of two nonidentical single-pass transmembrane glycoproteins, both of which are encoded by the MHC.

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Interestingly, the human fetus may be considered a tissue graft in the mother: the fetus shares only half of its genetic material with the mother, the other half being contributed by the father. Antigens encoded by the paternal alleles may differ sufficiently from their maternal counterparts to elicit an immune response in the mother. Such a response can occur because in the course of pregnancy, fetal cells that slough off into the maternal circulation can stimulate the maternal immune system to mount an antibody response against the paternal antigens. We now know that these antibodies recognize proteins encoded by the human MHC. The fetus itself is spared rejection because of the specialized organization of the placenta, which prevents initiation of an immune response by the mother against fetal tissue.