Alloantibody, Alloantigen
 
Alloantigens are allelic variants that can induce, when injected into animals of the same species but having a distinct genetic background, the production of the corresponding alloantibodies. The most commonly known example of alloantigens are the blood group substances, which define the basic ABO blood groups in humans. Blood group substances have long been identified as being derived from a polysaccharide core that is found in pneumococcus group XIV, onto which three genes encoding for glycosyl transferases will serially add units that will confer a specific antigenicity to the newly derived molecule. Three genes operate this system in humans: A, B, and H. The H gene is present in all individuals and will add one residue of fucose, leading to the so-called H substance. In individuals who possess the A gene, an additional GalNAC (N-acetylgalactosamine) will be added, providing the A substance, which is expressed at the red blood cell surface and confers the A group. In those who have the B gene, a galactose residue is added to H, making the B substance, which is also expressed at the cell surface of red cells in individuals of group B. The A and B genes are codominant, so an individual will express the A, the B, or both the A and B molecules at the red blood cell surface, depending upon what A and B genes are present. If neither the A nor B allele is present, the group will be O. There are many other blood groups in humans, with special reference to the Lewis groups, which are also derived from the same polysaccharide backbone by addition of different units. What is peculiar regarding the ABO blood group system is the fact that individuals who lack the A or the B specificity spontaneously produce alloantibodies directed against the missing substance. So an individual of group A will make anti-B alloantibodies, an individual of group B will produce anti-A, and one of group O will have both. Very severe accidents in blood transfusion would result from the agglutination of the donor red blood cells by the alloantibodies of the recipient. The reverse situation, agglutination of the host red blood cells by antibodies of an incompatible donor, should also be avoided, although accidents are less severe. Antigen compatibility between donor and recipient is therefore a must. ABO compatibility should also be observed in allografts.
Even if the genetic determinism of these alloantigens is straightforward, it still is not clear why the alloantibodies corresponding to the nonexpressed substance(s) are produced. The prevalent explanation is that blood groups cross-react with bacteria normally present in the intestinal flora, which would stimulate the immune system to produce the corresponding crossreacting antibodies. It should be stressed that these “natural” antibodies are of the IgM type, which may be directly related to the fact that they are the result of the stimulation by a T-independent polysaccharide antigen. The titer of alloantibodies varies greatly between individuals, but may be considerably elevated upon an incompatible transfusion.
Another famous case of alloantigen in the blood groups is the Rhesus factor, which was responsible for the dramatic hemolytic disease of the newborn, due to the immunization of an Rh mother against red blood cells of an Rh⁺ fetus. This occurs during the delivery because some fetal red cells may enter the maternal circulation and induce the formation of IgG antibodies that will actively cross the placental barrier in a subsequent pregnancy and then provoke lysis of Rh⁺ fetus red cells. Treatment involves complete transfusion of the newborn with Rh blood. It has now been generalized to prevent the immunization by injecting the Rh mother with anti-D (anti-Rhesus) antibodies immediately after delivery, to trap the red blood cells from the newborn that would have penetrated the maternal circulation at birth.
Many other alloantigens are known, but alloantibodies are generally not produced unless the antigen is given. This is the case of the major histocompatibility complex (MHC) molecules, which constitute a major problem in transplantation. The name of major histocompatibility complex indicates by itself how these molecules were first discovered as a major target for graft rejection, as the result of a very severe alloimmune response, characterized primarily by the production of cytotoxic T lymphocytes. Many other systems may behave as potential alloantigens, which simply reflects the existence of allelic variants. The case of allotypes of immunoglobulins has been studied particularly by immunologists and has provided remarkable genetic markers for the study of immunoglobulin biosynthesis and diversity at the time.