Type II hypersensitivity reaction refers to an antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens with the resultant cellular destruction, functional loss, or damage to tissues. Damage can be accomplished via three different mechanisms:

• Antibody binding to cell surface receptors and altering its activity
• Activation of the complement pathway.[1]
• Antibody dependant cellular cytotoxicity.[2]

The type II hypersensitivity immune reaction develops in response to modifications of cell surface or matrix-associated antigens generating antigenic epitopes that are regarded as foreign by the immune system.

The most common causes include medications like penicillin, thiazides, cephalosporins, and methyldopa. The drug molecule either binds to the surface of cells resulting in a neoantigen or alter the epitopes of the existing self-antigen on the cell surface. This directs the immune system to recognize modified antigens as foreign with the breakdown of the immune tolerance and the production of antibodies directed to self-antigens.[3]

Immune tolerance is the phenomenon by which the immune system recognizes its antigens and does not generate an antibody response against its antigens. Factors that contribute to the breakdown of tolerance promote the production of antibodies against its self-antigens.[4]

Epidemiological data regarding hypersensitivity reactions are scarce. One-third of the adverse reactions occurring due to drugs are, in fact, hypersensitivity reactions. These hypersensitive reactions can prove to be lethal and can also prolong hospitalizations. Genetic predisposing factors remain unexplored, but it is possible that in the future, we can identify high-risk populations with advancing genetic studies.[5]

Coombs and Gell described immune-mediated immediate hypersensitivity reactions (IHR) as an antibody driven response that occurs within 24 hours and classified them into type I, II, and III hypersensitivity reactions. These reactions involve IgE, IgM, and IgG antibodies. In type II hypersensitivity, following exposure to the inciting agent, autoantibodies are produced (IgG and IgM) to the host cells (sensitization phase), promoting a series of pathogenic outcomes (effector phase).[6]

The pathophysiology of type II hypersensitivity reactions can be broadly classified into three types:

• Cell depletion or destruction without inflammation
• Inflammation mediated by complement or Fc receptor
• Cellular dysfunction by antibodies[1]

The process involves a series of immune-mediated events that might take different forms.

Cell depletion or destruction without inflammation:

Antibodies can bind to the surface of the target cell, particularly IgG antibodies, and through their Fc portion, they bind to their respective Fc receptor on the surface of macrophages and thus act as an opsonin. An opsonin is any molecule that enhances the phagocytosis of any substance. Thus by binding to both the target cell and the Fc receptor of the macrophage, it activates the macrophage and causes it to phagocytose the target cell.[7]

Antibodies can also bind to the target cell and activate the complement pathway resulting in the formation of complement component C3b, which also acts as an opsonin and binds to the receptors on the surface of macrophages. This, in turn, activates the macrophages causing them to engulf the cell resulting in depletion of the cell.[7]

Antibodies can also bind to the target cell resulting in complement pathway activation and formation of the complex known as membrane attack complex involving complement components C5b6789. The membrane attack complex creates a channel to induce lysis of cells. A single channel is sufficient to induce lysis of anucleated cells like erythrocytes, but nucleated cells require multiple membrane attack complexes to destroy such cells.[8]

Antibody dependant cell-mediated cytotoxicity is a phenomenon by which antibodies bind to the target cell and then the effector cells of the immune system. These are mostly natural killer cells that attach to the Fc portion of the antibody and then are activated, releasing perforins and granzymes, causing lysis of the target cell.

This type of cell depletion or destruction without inflammation is seen in autoimmune hemolytic anemia, autoimmune thrombocytopenia, certain blood transfusion reactions, and erythroblastosis fetalis.

Inflammation mediated by complement or Fc receptor:

Antibodies can activate the complement pathway by binding to self-antigens resulting in the formation of complement components C3a and C5a, which act as chemotactic factors for neutrophils, causing the recruitment of neutrophils to the site and resulting in the activation of neutrophils. These neutrophils then release enzymes and reactive oxygen species, which damage the tissues. For example, in Goodpasture syndrome, autoantibodies are directed against collagen in glomerular and alveolar basement membranes. The binding of these antibodies leads to strong activation of the complement system, which recruits leukocytes resulting in inflammation.[9]

Antibodies against foreign antigens can also trigger complement activation and inflammation by a mechanism of molecular mimicry. This is the hallmark of acute rheumatic fever in which antibodies directed against streptococcal antigens structurally mimic cardiac myosin in the human heart, leading to cross-reactivity of these antibodies against bacterial and host antigens, and therefore binding to the myosin and damaging the heart tissue.[10]

Cellular Dysfunction by Antibodies

Autoantibodies bind to the receptors on target cells, causing dysfunction without causing inflammation or destruction. For example, in Graves’ disease, the autoantibodies bind to the thyrotropin receptor on thyroid follicular cells resulting in overproduction of thyroid hormones. Normally the production of thyrotropin by the pituitary is regulated by levels of thyroid hormones in the blood, but these antibodies lead to autonomous production of thyroid hormones by the follicular cells, which are not inhibited by high levels of thyroid hormones in the blood resulting in much higher levels than cause symptoms of thyrotoxicosis.[11]

In myasthenia gravis, autoantibodies directed against the nicotinic acetylcholine receptor do not allow acetylcholine to bind to its receptor on muscle cells leading to muscle weakness.[12]

Immunohistopathology of type II hypersensitive reactions illustrates antibody-mediated cytotoxicity (IgG and IgM) together with other disease-specific features. In Graves' disease, there is diffuse hyperplasia of the follicular cells of the thyroid with an increased follicle/stroma ratio.[13] Acute rheumatic fever with the involvement of the myocardium shows dense valvular inflammatory infiltrate and Aschoff bodies, which is the characteristic finding of rheumatic inflammation of the heart.[14] 

In Goodpasture syndrome, renal biopsy under a light microscope shows crescentic glomerulonephritis. Immunofluorescence shows the linear deposition of IgG with a complement along the basement membrane.[15] In pemphigus vulgaris, histopathology shows suprabasal clefting and the "tombstone" appearance of the basal cells. Immunofluorescence shows intercellular deposition of antibodies against IgG and C3.[16]