CLINICAL SIGNIFICANCE OF TYPE II HYPERSENSITIVITY REACTION AND HAEMOLYTIC DISEASE OF THE NEWBORN (HDN)

Type II hypersensitivity (which can also be referred to as a cytotoxic allergic reaction) is an immediate-type hypersensitivity that is mainly observed in blood transfusion reactions and haemolytic disease of the newborn (HDN). The effector molecules of Type II hypersensitivity reaction are IgG and IgM antibodies. Type II hypersensitivity reaction can also be called a cytolytic allergic reaction because it often result in the destruction or killing of host cells. In Type II hypersensitivity, the antibody-mediated arm of the immune system is stimulated or provoked to produce antibodies against host self-molecules or receptors found on the membranes of host cells. Type II hypersensitivity is an antibody-mediated destruction of host cells in which immunoglobulins directed against antigens or allergens activate the complement system to cause complement-mediated lysis of host cells. Activation of complements can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) or it can create holes on the cell membrane of the invading antigen, thus making the cell membrane porous.

Cytotoxic cells with receptors for FC region of antibodies binds to the FC region of the produced immunoglobulins (mainly IgM and IgG) already attached to target cells and this promotes the killing of host cells. Type II hypersensitivity reaction can also be observed in some autoimmune diseases (e.g., Graves disease) and in tissue or organ transplants – in which the grafted organ is rejected because the recipient host has preformed immunoglobulins against the grafted tissue or organ. This ultimately results in the rejection of the transplanted organ few hours or days after transplantation. The cell surface of red blood cells (RBCs) or erythrocytes of humans is normally lined with specialized antigens known as the ABO blood groups antigens. These specialized antigens (i.e., the ABO blood groups antigens) are generally known as glycoproteins found on the cell membrane of erythrocytes or RBCs.

It is the ABO blood groups antigens that are used to elucidate the particular blood group of an individual in blood group typing in the laboratory. Every individual possess naturally occurring antibodies known as isohaemagglutinins – which are produced against foreign blood group antigens not found on the cell surface of the host’s RBCs. The ABO blood groups antigens of humans are normally encoded by different genes that belong to multiple allelic groups. And since an individual with an allelic form of blood group antigen can also recognize other allelic forms of blood groups on transfused blood, the recipient host will immediately mount an immunological response against the foreign blood group antigen. This phenomenon is always taken into consideration in clinical medicine whenever blood transfusion between two different donors and recipients is contemplated or anticipated.

And in order to prevent transfusion reaction in the recipient host,it is critical to know the compatibility of the recipient and donor blood groups through ABO blood group typing or determination in the laboratory. An individual with group A blood has anti-B antibodies (i.e., isohaemagglutinins) and the reverse is also the case for persons with group B blood who has anti-A antibodies. Persons with the AB blood group have neither anti-A antibodies nor anti-B antibodies while people with blood group O possess both anti-A antibodies and anti-B antibodies. People with the AB blood group are known as universal recipients because they lack the anti-A and anti-B antibodies and thus can receive blood from other blood groups. However, those with the O blood group are known as universal donors because they can donate blood to other blood groups since they possess the anti-A and anti-B antibodies or isohaemagglutinins.

TRANSFUSION REACTION

Transfusion reaction is a type II hypersensitivity reaction. It mainly occurs when mismatched or incompatible blood is transfused between a donor and a recipient. This results in a clinical condition in which the donors RBCs becomes rapidly coated with the recipients isohaemagglutinins, and thus activating the complement system of the host or recipient in an adverse manner. The ABO blood groups antigens of humans and their respective isohaemagglutinins is shown in Table 1. Typical example of a transfusion reaction occurs when an individual with blood group B (the recipient) receives blood from a person with blood group A (the donor). In such scenario, the anti-A isohaemagglutinins of the recipient host rapidly coats the group A blood cells of the donor. This mediate a cytolytic reaction in which the donors blood cells are destroyed or haemolyzed through complement activation (i.e., complement-mediated lysis) and the action of antibodies. Haemoglobinuria (i.e., the presence of haemoglobin or blood in urine), fever, clotting of blood in blood vessels and kidney problems are some clinical manifestations of transfusion reaction in humans.        

Table 1. ABO blood groups antigens of humans

Blood groups (Phenotypes)Genotypes*IsohaemagglutininsAgglutinins (antigens on RBCs)
    
A  AA or AOAnti-BA
B  BB or BOAnti-AB
AB  ABNoneA and B
OOOAnti-A and Anti-BNone
*Isohaemagglutinins comprises mainly of the immunoglobulin M (IgM) class.

HAEMOLYTIC DISEASE OF THE NEWBORN (HDN)

Haemolytic disease of the newborn (HDN) is also known as erythroblastosis fetalis. HDNis a type II hypersensitivity reaction. In haemolytic disease of the newborn (HDN) or erythroblastosis fetalis, the maternal antibodies (specifically IgG) produced against fetal Rhesus (Rh) antigens or RBCs crosses the placenta to cause haemolysis in the neonate. This crossing of the maternal antibodies (IgG) into the neonate through the placenta leads to the destruction of fetal RBCs. Erythroblastosis fetalis shows the Rh factor incompatibility that exists between the mother and her foetus or unborn child. And this clinical and/or immunological reaction is mainly experienced in unborn foetus or neonates whose mothers have been previously exposed to blood group antigens on the RBCs of the foetus especially in their first pregnancy. Typical example is when the mother is Rhesus factor negative (Rh) and the foetus is Rhesus factor positive (Rh+). The mother produces anti-Rh antibodies against the fetal blood, and the antibody crosses the placenta to cause haemolysis of fetal RBCs thus causing severe or mild anaemia depending on the severity of the disease.  

Most people are Rh+. However, during delivery (especially in a first pregnancy) there is usually a mixture of fetal red blood cells (i.e., a Rh+ fetal blood) with that of the mother (a Rhmother only) during child birth. This provokes the mother’s immune system to produce antibodies (inclusive of IgM and IgG) whose function is to clear the maternal blood circulation from every trace of fetal blood. At this stage, the mother’s immune system is sensitized and memory B cells will be produced to counter future Rh+ fetal RBCs. In the first pregnancy, the Rh mother is not exposed to enough fetal blood (usually Rh+ blood cells) in order to activate her Rh specific B cells against possible futuristic Rh+ RBC from neonates in subsequent pregnancy.

The first child is usually not affected when the blood of the foetus leak into the blood circulation of the mother. HDN is mainly experienced in subsequent pregnancies especially when the mother is not clinically treated against the disease condition. The memory B cells produced in the mother remain in the maternal circulation to produce antibodies against the fetal Rh+ blood in subsequent pregnancy. In subsequent pregnancy, the memory B cells become activated in a rapid fashion to produce anti-Rh antibodies (mainly of the IgG class) that cross the placenta to haemolyze or lyse the fetal red blood cells i.e., if the ensuing foetus is Rh+. Activation of the complement system mediated by the memory B cells in the mother causes erythroblastosis fetalis in the neonate; and this is usually observed clinically as mild or life-threatening anaemia in utero.

The Rhesus status of the newborn and that of the parents are illustrated in Table 2. Erythroblastosis fetalis occurs in cases of Rhesus incompatibility i.e., in clinical conditions in which the mother is Rh and the foetus is Rh+. However, passive immunization of the mother through parenteral administration of antibodies (e.g., RhoGAM) against the Rhesus antigens to the mother few hours after her first delivery (e.g., 24-72 hours) prevents Rhesus incompatibility and thus erythroblastosis fetalis in subsequent pregnancies. Neonates in subsequent pregnancies will be prevented from possible HDN because the RhoGAM (anti-Rh antibodies) binds any fetal blood that entered the mother’s blood circulation during delivery in order to clear the maternal blood from fetal Rh+ blood prior to B cell activation and memory B cell production. Immunized mothers are not likely to produce IgG anti-Rh antibodies that will cross the placenta to cause the haemolysis of fetal blood; and it is advisable that Rh mothers be properly immunized after delivery so that they will not generate Rh specific memory B cells in the mother.

Table 2. Haemolytic disease of the newborn (HDN) and Rhesus status

Aside the agglutinogens (i.e., the ABO blood group factors) in which human blood is mainly classified, the Rhesus antigen or factor usually expressed as “Rh(D) antigen” is another basis on which human blood can be classified. Rhesus factor is an antigen found in red blood cells (RBCs), and it is a crucial factor considered in human blood grouping techniques. Each of the human blood groups including blood groups ‘A, AB, B and O’ can either be Rhesus negative Rh(D) or Rhesus positive Rh(D)+. A detrimental antigen-antibody reaction is bound to occur when a Rh(D) individual is transfused with a Rh(D)+ blood. Similar adverse antigen-antibody reaction as aforementioned also occur when a mother that is Rh(D)has a foetus or neonate whose blood group is bearing the Rh(D)+ antigen probably inherited from the father (that is Rh(D)+). The Rh(D)+ blood of the foetus crosses the placenta of the mother during the delivery of the first child (harbouring Rh(D)+ blood) and enters her blood circulation where it stimulate the production of antibodies (specifically anti- Rh(D)+ antibodies).

In subsequent deliveries (especially in Rh(D)+pregnancies), the anti- Rh(D)+ antibodies of the mother produced in the first delivery crosses the placenta and enters the blood circulation of the neonate or foetus, and this results in erythroblastosis fetalis otherwise known as haemolytic disease of the newborn (HDN). In HDN, there is a rapid lysis or destruction of the neonate’s RBCs. In summary, HDN is a blood disease that affects neonates, and it is mainly caused by an immunological reaction that occurs between the Rhesus factor of the mother and that of the neonate (i.e., if the foetus is Rh(D)+). Most individuals are Rh(D)+. And a Rh(D)person should not be transfused with a Rh(D)+  blood to avoid the development of antibodies against the blood in the individual. Rhesus factor compatibility is a key factor taken into consideration during blood transfusion and even in pregnant or expectant mothers especially those that are Rh(D).


Further reading

William E.P (2003). Fundamental Immunology. 5th edition. Lippincott Williams and Wilkins Publishers, USA.

Stevens, Christine Dorresteyn (2010). Clinical immunology and serology. Third edition. F.A. Davis Company, Philadelphia.

Silverstein A.M (1999). The history of immunology. In Paul, WE (ed): Fundamental Immunology, 4th edition. Lippincott Williams and Wilkins, Philadelphia, USA.

Paul W.E (2014). Fundamental Immunology. Seventh edition. Lippincott Williams and Wilkins, USA.

Male D, Brostoff J, Roth D.B and Roitt I (2014). Immunology. Eight edition. Elsevier Saunders, USA.

Levinson W (2010). Review of Medical Microbiology and Immunology. Twelfth edition. The McGraw-Hill Companies, USA.

Berzofsky J.A and Berkower J.J (1999). Immunogenicity and antigen structure. In Fundamental Immunology, 4th edition., W.E. Paul, ed., Lippincott-Raven, Philadelphia. 

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