Hypersensitivity Type II: Mechanism and Clinical Manifestation

Unlike Type I hypersensitivity, Type II hypersensitivity reaction is an immediate reaction, showing a “hyper” or exaggerated response to harmless antigens within 24 hours. Type II hypersensitivity reaction is also known as antibody-mediated cytotoxic hypersensitivity since it destroys cells with the involvement of antibodies. Interference with normal cellular function is another mechanism that generates stimulation or inhibition of various chemical signals.

A hypersensitivity reaction type II requires a target cell with bound antigen and antibody, which activates mechanisms to damage the target cell. It is mediated by IgG or IgM antibodies against antigens on cells or extracellular space.

Components of Hypersensitivity Type II

  1. Antigen

Antigens involved in type II hypersensitivity reactions are intrinsic and exogenous antigens.

Intrinsic antigen

  • Protein on the cell membrane, e.g., Rh ag on RBCs
  • An antigen on a space/matrix between cells, like on a basement membrane
  • Self-antigen (causing autoimmune diseases)
  • Receptors antigens on cells, like hormone receptors

Exogenous antigens

  • Microbes, parasites, drugs
  • Antigens of blood transfusion reaction
  1. Antibody

Hypersensitivity type II takes place by the involvement of mainly IgG and occasionally IgM antibodies. Rarely IgA can give such reactions.

  1. The effector cells

The effector cells of hypersensitivity type II reaction are macrophages, neutrophils, eosinophils, and natural killer (NK) cells.


Hypersensitivity type II reactions affect the cells where the target antigens are present. Hence such reactions are not often systemic. But sometimes, target antigens may be present on the surface of mobile cells like erythrocytes and leukocytes, affecting the whole body.

Type II hypersensitivity has three mechanisms: A target cell is restricted either by antibody and complement-mediated lysis or by antibody-dependent cell-mediated cytotoxicity (ADCC) or dysfunction of the target cell.

  1. Antibody and complement-mediated destruction

Here, the destruction is mediated either by a complement system or antibodies via opsonization.

The antibody attaches to the antigen on the surface of cells and activates the complement system via the classical pathway. This leads to the formation of membrane attack complex (MAC), which creates pores in foreign cell membranes leading to cell lysis. In opsonization, antibodies coat an antigen and make it a target for phagocytosis.

Examples of this mechanism are erythroblastosis fetalis and mismatched blood transfusion reaction.

  1. ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity)

If antigen-antibody complexes are too large to be phagocytosis, these are recognized by different immune/cytotoxic cells, like macrophages, NK cells, eosinophils, and neutrophils. These cells have Fc-receptor and, therefore, bind to the Fc region of the antibody and release cytotoxic granules on the target cell, and this causes cell death.

An example of such a mechanism can be a medication acting as a hapten and binding to cells of a specific tissue.

  1. Target cell dysfunction

It is a non-cytotoxic mechanism. Autoantibodies binding typical cellular receptors or other proteins may interfere with the functions of these receptors or proteins and cause disease without inflammation or tissue damage. However, the cell function is impaired, causing an abnormal activation/blockade of the signaling process. Examples are Myasthenia Gravis, Graves disease, and pernicious anemia.

Clinical Manifestation

Various clinical manifestations are seen as a result of hypersensitivity type II reactions.

  1. Transfusion reactions

ABO or blood group incompatibility is a type of hypersensitivity reaction. The red blood cell surface bears a large number of proteins and glycoproteins. An individual acquiring one allelic form of a blood group antigen can recognize other allelic forms on transfused blood as foreign, stimulating an antibody response.

Antibodies to A, B, and O antigens are called isohemaglutinins and usually of the IgM class.

Blood group A recipient reacts with a type AB or B donor as it has anti-B antibodies. Group B recipient reacts with a type AB and A donor as it has anti-A antibodies. Blood group O recipient reacts with type AB, A, and B donor as it has anti-A and anti-B antibodies.

Massive intravascular hemolysis of transfused RBCs by antibody and complement takes place if mismatched blood is transferred. Immediately ABO blood-group incompatibilities are seen, which lead to complement-mediated lysis triggered by IgM isohemagglutinins. Within hours, free hemoglobin can be detected in the plasma, filtered through the kidneys, and leads to hemoglobinuria. Some hemoglobin is converted to bilirubin, a high toxic level. Fever, chills, nausea, clotting within blood vessels, urticaria, respiratory distress, and hypotension are seen.
By repeated incompatible transfusion, the transfused blood induces clonal selection. It produces IgG against various blood-group membrane antigens, resulting in fever, low hemoglobin, increased bilirubin, mild jaundice, and anemia.

  1. Hemolytic disease of the newborn

This is known as erythroblastosis fetalis, occurring against RBCs and RhD-incompatibility. It is also antibody and complement-mediated. When a Rhesus-negative woman conceives a rhesus-positive fetus, fetal RBCs leak into the mother. It survived long enough to elicit an IgG response. During the second pregnancy, maternal anti-D antibodies cross the placenta and attack fetal RBC of the second rhesus-positive fetus. The symptoms may vary from self-limiting hemolytic anemia to hydrops fetalis.

  1. Goodpasture syndrome

Antibodies attack antigens in the basement membrane of alveoli (causing pulmonary hemorrhage) and kidneys (causing nephritis). Systemic complaints, followed by renal (hematuria) and pulmonary symptoms (dyspnea, hemoptysis, cough), are seen.

  1. Grave disease

It is an autoimmune disease. A follicular cell of the thyroid gland has receptors for thyroid stimulating hormones (TSH). Severe illness occurs when a body mistakenly produces autoantibodies, thyroid stimulating immunoglobulin (TSI). TSI binds to TSH receptors, activate them to cause high T3 and T4, and results in hyperthyroidism.

  1. Myasthenia Gravis

Autoimmune antibodies block or destroy acetylcholine (ACH) receptors, which limits communication between neurons and skeletal muscle. It leads to muscle weakness. E.g., droopy eyelids.

  1. Autoimmune hemolytic anemia (against RBCs)

IgG-mediated (warm autoimmune hemolytic anemia) or IgM-mediated (cold autoimmune hemolytic anemia). Common symptoms are weakness, shortness of breath, anemia, jaundice, icterus, and dark urine from hemolysis.

  1. Pernicious anemia (against intrinsic factor)

Some antibodies prevent the absorption of vitamin B12 in the ileum, causing B12 deficiency. It shows general symptoms of anemia, glossitis, paresthesias, etc.

  1. Drug-induced hemolytic anemia, thrombocytopenia, or neutropenia

Antibiotics like penicillin, cephalosporin, and streptomycin can adsorb non-specifically to proteins on membranes of RBC. It forms a complex similar to the hapten-carrier complex. This induces complement-mediated lysis of RBC, and thus, progressive anemia occurs. It disappears in the removal of the drug.

Similarly, thrombocytopenia or neutropenia may also result from medication.

Penicillin is remarkable because it can induce all four types of hypersensitivity with different clinical manifestations.

  1. Autoimmune thrombocytopenic purpura

In this case, phagocytes destroy sensitized platelets in the blood. Thus, there is an increased bleeding risk leading to severe hemorrhage.

  1. Acute rheumatic fever

Antibodies against the cell wall of Streptococcus pyogenes react with the self-antigen on myocardial cells. It results in arthritis, fever, carditis, and subcutaneous nodules.

Lab Diagnosis

Diagnosis is based on the type of disease observed:

  • Coombs test is done in transfusion reaction and anemia.
  • In pernicious anemia, CBC and vitamin levels are examined.
  • To diagnose erythroblastosis fetalis, pregnancy history is required; ultrasound, fetal lab test, and maternal antibody test are performed.
  • TSH and TFT help know graves disease.
  • In rheumatoid arthritis, CRP, ASO, and ESR are performed.


  • Hypersensitivity type II is controlled according to the symptoms and disease.
  • A blood transfusion reaction is controlled by rapid cessation of transfusion, and supportive care is required. Urine flow should be maintained with a diuretic; acute tubular necrosis can occur because of hemoglobin accumulation.
  • Control of disseminated intravascular coagulation (DIC) and bleeding control should be carried out in thrombocytopenic purpura.
  • Glucocorticoids, immunosuppressive drugs, and appendectomy may require in autoimmune hemolytic anemia.
  • Antithyroid drugs, Thyroidectomy, or immunotherapy are used for Grave’s disease.
  • Antibiotics against Streptococcus are used to control rheumatic fever.
  • Erythroblastosis fetalis prevention is conducted by giving anti-RhD at 28 weeks gestation and within 72 hours of birth.


Srijana Khanal

Hello, I am Srijana Khanal. Former faculty teacher in Microbiology Department at National College, NIST. Involved in the field of teaching for almost 10 years. I am very passionate about writing (academic as well as creative). My areas of interest are basic science, immunology, genetics, and research methodology.

We love to get your feedback. Share your queries or comments

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Recent Posts