II. Rh blood groups.

III. Major histocompatibility complex

IV. Organ transplantation.

Terms

Errata Page 368, paragraph 3: "...HLA complex consists of four neighboring genes..." HLA-D is itself a complex of Class II genes that contains three gene clusters. See III.D. Page 369, paragraph 4: "...it is rare that anyone will be genetically identical to anyone else for the HLA genes." Except sibs. See III.E.

I. The ABO blood groups were the first antigens to be discovered on red blood cells (1900). Indeed, their discovery was a major landmark in the development of both immunology and genetics and provided the basis for understanding the rules that govern blood transfusions.

A. There are four main ABO blood types: A, B, AB, and O.
1. When blood samples are mixed, either in vitro or in vivo, some are compatible and do not agglutinate, others are incompatible and agglutinate.

2. Landsteiner (1900) and other pioneers proved that there are three alleles: A, B, and O. A and B are codominant with respect to each other; both are dominant to O.

3. There is a corresponding antibody present in plasma for any ABO antigen that is not present on the red cells, e.g. a person with type A cells has anti-B but not anti-A.

B. In blood transfusions, the ABO type must always be matched. Otherwise, antibodies in the plasma of the recipient will react with transfused cells, causing them to lyse. This causes jaundice, with potential damage to organs such as the liver and brain and death in severe cases.

C. The ABO blood groups are highly polymorphic among World populations. The frequencies of the three alleles vary considerably different populations. Indeed, it is the existence of polymorphism that allows us to recognize traits such as blood groups. If everyone were identical for a blood group antigen, then everyone would match everyone else. There are, in fact, antigens controlled by genes at other loci for which all but a few persons are identical. These few have been found because of unexpected transfusion reactions or HDN (see II.C).

A. Rh antibodies occur only as a consequence of immunization by red cells that differ in their Rh types from those of the recipient.
1. In 1939, Philip Levine studied a family in which hemolytic disease of the newborn (HDN, aka erythroblastosis fetalis) occurred. He demonstrated that the fetal red cells had an antigen that was inherited from the father and that was not present in the mother. She formed antibodies to it during the pregnancy, and the antibodies crossed the placenta into the fetal circulation, destroying the red cells of the fetus.

2. Also in 1939, Al Wiener injected Rhesus monkey red cells into rabbits, leading to formation of antibodies that reacted with all Rhesus red cells and 85% of human red cells.

3. Comparison of the two systems showed them to be the same.

4. The system was named the Rhesus blood group, symbolized Rh.

B. There are many alleles at the Rh locus, which is on chromosome 1. However, the alleles can be grouped into those that are Rh-positive and Rh-negative. For most purposes, one can consider the Rh locus as a two-allele system, with alleles R and r, genotypes RR, Rr, and rr, and phenotypes Rh+ (RR and Rr) and Rh– (rr).

C. HDN commonly occurs when an Rh– mother carries a fetus that is Rh+.

1. At the time of birth, fetal cells escape into the maternal circulation. They may induce antibodies against any antigen that is not present in the mother, but the Rh+ antigens are especially effective antigens.

2. Once immunized against Rh+ red cells, the mother's antibodies can cross into the fetal circulation in subsequent pregnancies and agglutinate Rh+ red cells.

3. HDN can be prevented by injecting anti-Rh+ antibodies into the Rh– mother soon after she has delivered an Rh+ child.

D. The Rh locus is highly polymorphic in human populations.

A. The MHC was discovered because the protein products are strong antigens.
1. MHC was first detected by skin transplants in mice. Patches of skin can be transplanted among genetically identical (isogenic) mice, but transplants among different strains are always rejected. The difference among strains was traced to a complex locus, called H-2.

2. Persons who receive multiple blood transfusions occasionally form antibodies to white blood cells. These human leukocyte antigens (HLA) were traced to variation at a complex locus on chromosome 6. They were shown to involve the same complex that was discovered in mice, and the general name major histocompatibility complex was applied to both.

B. There are two kinds of MHC products, Class I and Class II, that differ in their structures and functions. Both are glycoproteins (proteins to which sugars are bound) located in the cell membrane.

C. MHC molecules are necessary for immune responses. In order for a T-cell to recognize an antigen, the antigen must be "presented" to it bound to an MHC molecule that is "self". MHC is also thought to play a role in developing immune tolerance.

D. The MHC is the most variable genetic region known. In humans, there are dozens of alleles at each of the three HLA Class I loci, designated A, B, and C. A large number also occur at the Class II loci, designated DP, DQ, and DR. Since recombination is very low within this short region (which is about 2 cM long), the allelic combinations (haplotypes) are transmitted as a unit. There are potentially many hundreds of haplotypes. The likelihood that a person would be homozygous for a particular haplotype is quite small except in the case of inbreeding.

E. Since the allele combination within a haplotype is transmitted as a unit, the haplotype complex can be treated as a single locus for purposes of analyzing transmission in families. For example, the four haplotypes that two parents might have can be represented as ab × cd. There would be four offspring combinations: ac, ad, bc, and bd. The likelihood that two sibs would match for MHC haplotypes is therefore 1/4.

F. Many disorders, expecially those that are thought to have an autoimmune component, occur more frequently in persons with certain MHC alleles than in other persons. The reasons for this are not known. However, the Class I and Class II gene products have important functions in immune response. It is possible that the various MHC alleles respond somewhat differently in the presence of a specific foreign antigen.

A. In the case of a recipient who lacks functional bone marrow, either because of SCID or because of treatment with whole-body radiation or high levels of chemotherapeutic agents, matching with donor MHC types is critical in a bone marrow transplant in order to minimize risk of graft-versus-host disease. This occurs when immunologically competent marrow cells are transplanted into someone who has no immunity. The transplanted cells recognize the recipient host as "foreign" and reject the host.

B. In the case of transplant of other organs, matching is carried out to avoid organ rejection by the recipient. Some mismatch may be tolerated, especially in the case of kidney transplants.

C. Matching of donors with recipients varies with the organ.

1. One kidney and bone marrow can be removed without killing the donor. Any pair of sibs has a 1/4 chance of being identical for MHC. Therefore the search for suitable donors starts with sibs.

2. For other organs, the likelihood of a match with a relative or a stranger is very small. Nevertheless, heart, liver, and other organ transplants depend on the fortuitous near matches between donors, who are usually accident victims, and recipients.

D. Because of the shortage of organ donors for transplants, the possibility of using organs from other species has been considered and has been tried in several cases. Because of the massive differences in cellular antigens in different species, it is unlikely that such xenotransplants will be successful in the forseeable future.

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