Type II Hypersensitivity Reaction

Type II hypersensitivity, also known as antibody-mediated cytotoxic hypersensitivity, is caused by immunoglobulin G (IgG) and IgM antibodies directed against antigens on cells or extracellular materials. The reaction leads to cytotoxic processes involving antibodies and the complement system. Interference with the normal cellular operation generating either stimulatory or inhibitory dysfunction is another mechanism that occurs. The inciting antigen can be intrinsic or part of the host cell. Extrinsic antigens such as blood products or medications can provoke a similar reaction. For diagnosis, laboratory tests and invasive procedures are utilized, depending on the system affected. Management of resulting disease ranges from supportive care to antibiotics, immunosuppressive medications, and surgery.

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  • Hypersensitivity reaction
    • A “hyper” or exaggerated response to what should be considered harmless environmental antigens
    • Types I, II, and III are immediate reactions occurring within 24 hours.
    • Type IV reaction develops over several days.
  • Type II hypersensitivity reaction
    • Hypersensitivity reaction mediated by immunoglobulin M (IgM) and IgG antibodies (Ab) that bind to:
      • Intrinsic antigens on cell surfaces (e.g., RBCs) or extracellular materials (e.g., basement membrane)
      • Extrinsic antigens (e.g., blood products, drugs)
    • Antibody (AB)-antigen complex leads to processes resulting in cell lysis, tissue damage, and/or dysfunction.


Activation of the complement system

The following mechanisms are triggered by the binding of Ab-antigen complexes:

  • Complements: large, distinct proteins involved in a sequential enzyme cascade for host defense
  • Complement numbers (C1-4) do not indicate the order of activation; they reflect the order of discovery.
  • Pathways from C1 are mobilized by Ab-antigen complexes → C3 → cleaved to C3a and C3b → C3b cleaves C5 to C5a and C5b
  • C3a, C4a, and C5a
    • Mediators of inflammation = anaphylatoxins
    • Mast cell and basophil degranulation
    • C5a also causes neutrophil chemotaxis.
  • C5b and C6, C7, C8, C9: 
    • Membrane attack complex (MAC) 
    • Attaches to cell membrane and creates ion-permeable channels causing osmotic changes and cell lysis
  • C3b: 
    • An opsonin (tags antigens for elimination by phagocytes = opsonization) mediating phagocytosis of target cells
  • Examples: transfusion reaction, autoimmune hemolytic anemia

Antibody-dependent cell-mediated cytotoxicity (ADCC)

  • Antibodies, or opsonins, bind their antigen-binding fragment (Fab) sites to antigens and tag them for phagocytosis.
  • If antigen-Ab complexes are too large to be phagocytosed, Fc-receptor–bearing effector cells, mainly natural killer (NK) cells, are recruited.
  • NK cells bind to Fc receptor of Ab → release toxic granules into cells → perforin and granzymes boreholes in membrane → cell lysis 
    • Examples: transplant rejection, immune reaction against neoplasm

Antibody-mediated cellular dysfunction

  • Non-cytotoxic; cell function impaired without cell injury or inflammation
  • Autoantibodies bind to cell-surface receptors to produce an abnormal activation/blockade of the signaling process. 
  • Examples: 
    • Myasthenia gravis (Ab causes blockade of acetylcholine receptor)
    • Graves’ disease (Ab causes stimulation of thyroid stimulating hormone (TSH) receptor) 
    • Pernicious anemia (Ab against intrinsic factor)
Antibody-dependent cellular cytotoxicity hypersensitivity

Antibody-dependent cellular or cell-mediated cytotoxicity: antibody binds the surface antigens of the target cell. Fc-bearing effector cell (natural killer or NK cell) binds the antibody Fc region and releases cytotoxic granules leading to lysis of the target cell.

Image by Lecturio.

Clinical Presentation

Type II hypersensitivity can result from the following conditions:

Transfusion reactions (ABO or blood group incompatibility)

  • Blood group A or O recipient would react with a type AB or B donor (due to the presence of anti-B antibodies)
  • Blood group B or O recipient would react with type A or AB donor (due to the presence of anti-A antibodies)
  • Symptoms: fever, itching, urticaria; serious reaction results in respiratory distress and hypotension
Transfusion reactions induced by type ii hypersensitivity reactions

Transfusion reactions induced by type II hypersensitivity reactions. This diagram shows blood type groups and their corresponding antibodies and antigens.

Image by Lecturio.

Autoimmune hemolytic anemia (against RBCs)

  • Can be IgG-mediated (warm autoimmune hemolytic anemia) or IgM-mediated (cold autoimmune hemolytic anemia)
  • Manifested by weakness, shortness of breath, pallor from anemia to jaundice, icterus, dark urine from hemolysis

Pernicious anemia (against intrinsic factor)

  1. Ab prevents absorption of vitamin B12, causing B12 deficiency anemia.
  2. B12 deficiency can lead to general symptoms of anemia, glossitis, paresthesias, gait problems.

Hemolytic disease of the fetus and newborn (against RBCs; RhD incompatibility)

  • First pregnancy: Rhesus-negative woman conceives a rhesus-positive fetus.
  • Labor: During labor, fetal RBCs leak into the mother.
  • Postpartum: Fetal RBCs survive long enough to elicit an IgG response.
  • Second pregnancy: Maternal anti-D antibodies cross the placenta and attack fetal RBCs of the second rhesus-positive fetus.
  • Newborns may present with self-limiting hemolytic anemia to hydrops fetalis (severe anemia, skin edema, ascites, pulmonary/pericardial effusion).

Autoimmune thrombocytopenic purpura

  • Phagocytes destroy sensitized platelets in the blood.
  • Increased bleeding risk: < 20,000/μL
  • Can have petechiae, purpura, epistaxis to severe hemorrhage

Acute rheumatic fever

  • Antibodies against the cell wall of Streptococcus also react with the myocardium.
  • Major manifestations: arthritis, carditis, Sydenham chorea, subcutaneous nodules, erythema marginatum

Goodpasture syndrome

  • Antibodies attack antigens in the basement membrane of alveoli (pulmonary hemorrhage) and kidneys (nephritis).
  • Initially presents with systemic complaints, followed by renal (hematuria) and pulmonary symptoms (dyspnea, hemoptysis, cough)

Graves’ disease

  • TSH-receptor antibodies stimulate the thyroid gland to produce free T4 and T3 without TSH.
  • Goiter, exophthalmos on exam with symptoms such as heat intolerance, anxiety, tremors, palpitations, weight loss.

Myasthenia gravis

  • Antibodies inhibit the binding of acetylcholine to the nicotinic acetylcholine receptor. 
  • Antibodies also activate complement-mediated receptor destruction.
  • Fluctuating muscle weakness, worse at the end of the day or after exercise (ptosis, diplopia, fatigable chewing, limb weakness)
  • Respiratory muscle weakness leads to respiratory failure (myasthenia crisis).
Mechanism of grave's disease and myasthenia gravis

Mechanism of Graves’ disease (left) and Myasthenia gravis (right), both caused by type II hypersensitivity mechanism.

Image by Lecturio.

Diagnosis and Management

Diagnosis and management vary depending on the manifestations, organ system involved, and severity of impairment produced by the reaction.

Transfusion reactions

  • Diagnosis: clinical; Coombs test
  • Management: cessation of transfusion, repeat of blood typing and crossmatching and supportive care (disseminated intravascular coagulation (DIC) work-up depending on severity of reaction)

Autoimmune hemolytic anemia

  • Diagnosis: hemolysis work-up; Coombs test
  • Management (first-line): glucocorticoids; treat the underlying condition
  • Refractory cases may require immunosuppressive drugs, splenectomy.

Pernicious anemia

  • Diagnosis: CBC, B12, folate level with confirmatory tests if with borderline levels
  • Management: B12 supplementation

Hemolytic disease of the fetus and newborn

  • Diagnosis: pregnancy history, maternal antibodies, ultrasound, fetal lab tests
  • Prevention: anti-RhD at 28 weeks’ gestation and within 72 hours of birth

Autoimmune thrombocytopenic purpura

  • Diagnosis: clinical with CBC, peripheral smear, HIV, hepatitis C, and other tests based on history
  • Goal of management: prevent clinically important bleeding
  • If with bleeding, management may include: platelet transfusion, intravenous immunoglobulin (IVIG), glucocorticoids

Acute rheumatic fever

  • Diagnosis: lab tests (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), antistreptolysin O (ASO)) with Jones criteria, echocardiogram
  • Management: antibiotics for Streptococcus and supportive care

Goodpasture syndrome

  • Diagnosis: clinical along with labs (antineutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (anti-GBM) Ab), renal biopsy
  • Management: plasmapheresis and immunosuppressive therapy

Graves’ disease

  • Diagnosis: TSH-receptor Ab confirms diagnosis; thyroid function tests
  • Management: symptom control (beta-blockers) and reduction of thyroid hormone synthesis (antithyroid drugs, radioiodine, or thyroidectomy)

Myasthenia gravis

  • Diagnosis: single-fiber electromyography (most sensitive) and immunologic studies
  • Management: pyridostigmine, immunotherapies, and thymectomy


  1. Brodsky, R.; Mentzer, W. (Ed.); Tirnauer, J. (Ed.). (2019). Diagnosis of hemolytic anemia. UpToDate. Retrieved Aug 17, 2020, from https://www.uptodate.com/contents/diagnosis-of-hemolytic-anemia-in-adults
  2. Davies, T.; Ross, D. & Mulder, J. (Eds.). (2019). Pathogenesis of Graves disease. UpToDate.  Retrieved Aug 18, 2020, from https://www.uptodate.com/contents/pathogenesis-of-graves-disease
  3. Bird, S.; Shefner, J. & Goddeau, R. (Eds.). (2020). Pathogenesis of Myasthenia gravis. UpToDate. Retrieved Aug 17, 2020, from https://www.uptodate.com/contents/pathogenesis-of-myasthenia-gravis
  4. Mak, T.; Saunders, M.; Jett, B. (2007). Primer to the Immune response. Elsevier.
  5. Pranay, K.; Sanghera, P.; Batuman, V. (Ed.). (2018). Goodpasture syndrome. Medscape. https://emedicine.medscape.com/article/240556-overview

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