The hallmark of type-II hypersensitivity reaction is the antibody-mediated destruction of cells. One of the commonest type-II reactions occur during blood transfusion reactions. During blood transfusion reactions, host antibodies react with foreign antigens expressed by incompatible transfused blood cells and cause the destruction of these cells.
IgM and IgG antibody subtypes bind to cell surface antigens and antigenic components of extracellular matrix and mediate type-II hypersensitivity reactions.
Once the antibodies bind with the antigens, they sensitize the cells for attack and destruction. The binding of antibodies to antigens initiates type-II hypersensitivity reaction by two ways:
First, antibodies may mediate cell destruction by activating the complement system resulting in the formation of pores on the membrane of the foreign cell. Thus, complement activation mediates antibody-dependent cell destruction that belongs to this class.
Second, antibodies can mediate cell destruction by a process called antibody-dependent cell mediated cytotoxicity.
1. COMPLEMENT-DEPENDENT MECHANISM
The first step in the complement-dependent mechanism of type-II reaction is the binding of antibodies to antigens on target cells. The antibodies bind to antigens on target cells using their Fab region. The Fc regions of the antibodies bind complement. Binding of complement to the Fc region activates complement, which results in the production of many complement fragments.
Recall that the activation of complement mediated by antibodies is through the classical pathway.
Activation of classical pathway of complement results in the generation of bioactive complement products, which cause variable degree of damage to target cells.
a. C5b-C9 (membrane attack complex) cause severe lysis of target cells
C5b, C6, C7, C8 and C9 fragments of complement come together and form structures called membrane attack complexes. Membrane attack complexes insert themselves into membrane of target cells, forming pores (perhaps poking holes) on the membrane of target cell. Water and electrolytes enter the cell through these pores and cause the cell to burst due to the loss of osmotic balance.
b. C3b fragment is a good opsonin
Activation of complement results the production of C3b fragments of complement. C3b fragments deposit themselves on the antigen-antibody complexes formed the membranes of target cells.
Macrophages and neutrophils (the major phagocytic cells of the body) express surface receptors for C3b fragment of complement. Moreover, macrophages and neutrophils bind to C3b (which deposit themselves on target cell membrane) using their specific receptors for C3b.
Thus, C3b serves to bridge target cells to macrophages and neutrophils. The bridging of macrophages and neutrophils to target cells, through C3b receptors activates the phagocytic cells. Activated phagocytes engulf and destroy the target cell.
c. C3a and C5a fragments of complement are powerful chemoattractants
C3a and C5a fragments of complement, being powerful chemoattractants attract neutrophils and macrophages (phagocytic cells) and other inflammatory cells to the site of the hypersensitivity reaction.
2. ANTIBODY-DEPENDENT CELL MEDIATED CYTOTOXICITY (ADCC) ALSO CALLED ANTIBODY-DEPENDENT CELL MEDIATED CYTOLYSIS
However, if target cells are too large for phagocytes to engulf, phagocytes bind to target cell-bound antibodies and release their granular and lysosomal contents on target cells ultimately destroying the target cells. Phagocytes and other immune cells are the final mediators of ADCC though the process is dependent on antibodies.
CLINICAL CONDITIONS CAUSED BY TYPE-II HYPERSENSITIVITY REACTIONS
Type-II reaction is the main mechanism of tissue damage in most autoimmune diseases. Moreover, type-II reactions also underpin incompatibility in blood transfusion.
Incompatibility in blood transfusion
In the ABO blood group system, there are four major blood groups called blood group A, B, AB, and O. What determines the name is the presence or absence of antigen A and antigen B on the surfaces of red blood cells. The A and B antigens are carbohydrate antigens expressed on the surfaces of red blood cells.
An individual has blood group A if his red blood cells express antigen A on their surface membranes.
In addition, an individual has blood group B if his red blood cells express antigen B on their surfaces.
An individual with blood group AB has both A and B antigens expressed on the surfaces of his red blood cells.
Individuals with blood group O has neither A nor B antigens on their red blood cells.
Antibodies to A and B antigens on red blood cells occur naturally; these antibodies are of IgM subtype.
- Individuals with blood group A have anti-B antibodies in their plasma,
- Individuals with blood group B have anti-A antibodies in their plasma,
- Individuals with blood group AB have neither anti-A nor anti-B antibodies in their plasma,
- Individuals with blood group O have both anti-A and anti-B antibodies in their plasma
For instance, if an individual with blood group B receives blood from blood group A or AB, anti-A antibodies found in his plasma bind to B antigens on the red blood cells of the transfused blood. The antibodies bind to red blood cell antigens through their Fab region. The Fc region of the red blood cell bound antibody is free, and binds complement. Binding of complement to Fc regions of antibodies activate complement through the classical pathway. The complement activation leads to the lysis of transfused red blood cells with consequent transfusion reactions.
Anti-B antibodies in the plasma of an individual with blood group A will bind to and react with B antigens if transfused with blood group B. Anti-B antibodies in plasma of recipient react to B antigens on the surfaces of the donors red blood cells.
Individuals with blood group AB have neither A nor B antibodies, as such, they can receive blood from A, B, O, and AB blood groups. Therefore, AB blood group persons called universal recipient and receive blood from all blood groups.
Conversely, individuals with blood group O have both anti-A and anti-B antibodies in their plasma and can only receive blood from blood group O donors. Anti-A and anti-B antibodies in plasma of blood group O individuals react to antigens found on the cell surfaces of blood group A, B and Ab donors.
The red blood cells of individuals with blood group O do not carry A or B antigen, due to this, there is no incompatibility reaction when an O individual donates blood to A, B or AB blood groups.
Agglutination and incompatibility in blood occurs due to antigen-antibody reactions. The antigen-antibody reactions occur between A and B antigens on red cell membrane of donor and anti-A and anti-B antibodies in plasma of recipient.
In our next lecture, we shall consider other clinical conditions that occur due to type-II hypersensitivity reactions.