Introduction to Hypersensitivity Reactions:
When an individual has been immunologically primed, further contact with the antigen leads to a secondary immune response, boosting. However, if the antigen is present in relatively large amounts or if the humoral and cellular immune state is at a heightened level, the reaction may be excessive and may lead to gross tissue changes known as Hypersensitivity. Type I, Type II, Type III, and Type IV hypersensitivity reactions are the four different forms of hypersensitivity reactions. Antibody-mediated complement activation in a type II hypersensitivity reaction can either cause holes in a foreign cell’s membrane or cause antibody-dependent cell-mediated cytotoxicity (ADCC), which kills the cell. Here, cytotoxic cells with FcR bind to the Fc portion of the antibody on the target cell and promote cell killing. An antibody bound to an antigen can also serve as an opsonin, enhancing phagocytosis of a coated foreign cell. Faulty blood transfusions can show Type II hypersensitivity reactions.
Type II Hypersensitivity in Blood Transfusion Reactions:
The membrane of RBC has a large number of proteins and glycoproteins encoded by different genes, each of which has several alternative alleles. An individual having one allelic form of blood group antigen can recognize the other allelic form and treat it as foreign and mount an immune response. In some cases, antibodies are already induced by natural exposure to similar epitopes on variety of microorganisms present in normal flora of gut, as in case of ABO blood group antigen. Antibodies to A, B, and O antigens, called isohemagglutinins, usually belong to the IgM class of antibodies. Blood group A individuals have the surface antigen A, are able to identify B-like epitopes, and produce isohemagglutinins to B-like epitopes, but are tolerant of A-like epitopes. If a type A individual is transfused with blood containing Type B cells, a transfusion reaction takes place where anti-B isohemagglutinin binds to the B blood cell epitope and causes complement-mediated cell lysis. If repeated transfusions are made, antibodies to other blood group antigens can occur because of a minor allelic difference in the antigen, which stimulates immunoglobulins of the IgG class. Transfusion reaction is accompanied by massive intravascular hemolysis of transfused blood cells by antibody and complement. Reactions that begin immediately are associated with ABO blood typing causing complement mediated lysis favored by IgM isohemagglutinin. Within hours, free hemoglobins are detected in the plasma filtered through the kidney, causing blood in the urine. Some hemoglobin can be converted to bilirubin, whose high level is toxic. Manifestations like fever, blood clots, and pain in the lower back are observed. Treatment is done by prompt stoppage of transfusion and maintenance of urine flow with a diuretic, as hemoglobin accumulation in the kidney can cause acute tubular necrosis. Delayed reaction can occur in individual who have received repeated transfusion of ABO compatible blood that is incompatible for other blood group antigens. Reactions develop between 2-6 days of transfusion. Transfused blood induces clonal selection and production of IgG against a variety of blood group membrane antigens like Rh, Kelly, Duffy antigens. As IgM is a better complement fixer than IgG, complement-mediated lysis is incomplete, and many transferred cells are destroyed by opsonization, agglutination, and phagocytosis by macrophages. Symptoms like fever, low hemoglobin, anemia, an increase in bilirubin, and mild jaundice are seen.
Figure: A Type II hypersensitivity hemolytic transfusion reaction (HTR) leading to hemolytic anemia
This explains that this is a Type II hypersensitivity hemolytic transfusion reaction (HTR) leading to hemolytic anemia. Blood from a type A donor is transfused into a type B recipient. The recipient’s anti-A isohemagglutinin IgM antibodies bind to the donor’s type A RBCs, triggering the complement cascade and resulting in the destruction of the donor RBCs.
Hemolytic Disease of the Newborn (Erythroblastosis Fetalis):
Hemolytic disease of the newborn: Hemolytic disease of the newborn is caused by Rh incompatibility, whereby maternal IgG antibody specific for fetal blood group antigen crosses the placenta and destroys fetal RBC. Such a hemolytic disease of the newborn is called Erythroblastosis fetalis. If a Rh- woman has a Rh+ partner and if the fetus is Rh+, as during pregnancy fetal RBCs are separated from the mother’s circulation by a placental barrier, in a first pregnancy with R+ fetus, the Rh- mother is not exposed to enough fetal RBC to activate her Rh specific B cell. But during delivery, separation of the placenta from the uterine wall allows contact of fetal blood of the umbilical cord with the mother’s circulation. This activates Rh-specific B cells, converting them to plasma cells and memory B cells in the mother. Secreted IgM clears Rh+ fetal RBC from the mother’s circulation, but since memory cells remain, during a second pregnancy with a Rh+ fetus, the memory cells get activated to form anti-Rh IgG antibody that crosses the placental barrier and damages fetal RBC. Mild to severe anemia can develop in the fetus and sometimes can be fatal. Also, hemoglobin conversion to bilirubin can accumulate in the brain and cause brain damage in the baby. Hemolytic disease of a subsequent baby can be prevented by administering an antibody called Rhogam against the Rh antigen to the mother within 24-48 hours after the first delivery. Rhogam binds to any fetal RBC that enters the mother’s circulation during the delivery of the first baby and clears B-cell activation so that no memory can form. The intensity of the reaction determines the course of treatment. For severe cases, intrauterine blood exchange transfusion can be given to the fetus to replace fetal Rh+ RBC cells with Rh- cells, done every 10-21 days until delivery. In less severe cases, the infant is exposed to low-level UV light to break down bilirubin and prevent cerebral damage. Mother can be treated during pregnancy by Plasmapheresis, which separates the mother’s blood into cells and plasma. Plasma having antibodies is discarded, and cells are reinfused into the mother in albumin. Minor manifestations can occur by ABO incompatibility if mother is Type 0 and baby is Type A or B and develop IgG to A or B either by natural exposure or through exposure to fetal blood A or B in successive pregnancy. Manifestations are less complicated, like the appearance of jaundice in a newborn.
Figure: This illustrates the mechanism of Rh incompatibility between a mother and fetus, leading to hemolytic disease of the fetus and newborn (HDFN), and how anti-Rh antibody treatment (Rh immunoglobulin) prevents this condition. The figure is divided into two panels: (a) showing the natural progression of Rh incompatibility, and (b) showing prevention with anti-Rh antibody treatment.
References:
- Owen JA, Jones PP, Kuby J, Punt J, Stranford SA. Kuby Immunology. 7th ed. New York: W.H. Freeman; 2013.
- Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 7th ed. Philadelphia: Elsevier/Saunders; 2012.
- Vamvakas EC, Blajchman MA. Transfusion-related mortality: The ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15):3406–17.
- Reali G. Forty years of anti-D immunoprophylaxis. Blood Transfus. 2007;5(2):72–3.
- Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia: Elsevier; 2020. Chapter on Hypersensitivity Reactions.
- Cunningham FG, Leveno KJ, Bloom SL, Dashe JS, Hoffman BL, Casey BM, et al. Williams Obstetrics. 25th ed. New York: McGraw-Hill Education; 2018. Chapter on Fetal Disorders.