Type II Hypersensitivity Reaction

Etiology

Type II hypersensitivity reactions happen when IgG or IgM antibodies target antigens on cell surfaces or in the extracellular matrix. These antigens may be intrinsic self-antigens, altered self-antigens, or foreign substances, such as drug haptens. For instance, drugs such as penicillin, thiazides, cephalosporins, or methyldopa can attach to cell surfaces and create new antigenic sites.[5][6][7] Autoantibodies can also target functional receptors, such as the TSH receptor in Graves’ disease or the acetylcholine receptor, MuSK, and LRP4 in myasthenia gravis. When the immune system recognizes these structures as foreign, it breaks tolerance and produces autoantibodies against the body’s own tissues.[6]  Normally, tolerance prevents this response, but it can be lost through mechanisms like haptenization or molecular mimicry, where foreign molecules resemble the body’s own proteins. This loss of tolerance leads to the activation of autoreactive B cells, production of harmful antibodies, and tissue injury.[5][6]

Epidemiology

Epidemiological data regarding hypersensitivity reactions are scarce. One-third of the adverse reactions occurring due to drugs are hypersensitivity reactions. These hypersensitive reactions can prove to be lethal and also prolong hospitalizations. Genetic predisposing factors remain unexplored; however, this may change through advances in genetic studies in the future.[8] Epidemiology also varies according to the underlying cause of type II hypersensitivity reactions, as seen in the case of hemolytic disease of the fetus and newborn. Despite advanced immunoprophylaxis, an estimated 1 to 3 in 1000 Rh-negative women develop alloimmunization.[9]

Pathophysiology

Type II hypersensitivity reactions, as classified by Gell and Coombs, are antibody-mediated immune responses involving IgG or IgM directed against normal or modified self-antigens located on the cell surface or within the extracellular matrix.[10] These reactions occur following exposure to exogenous agents, such as drugs, transfused blood components, or pathogens, that modify self-antigens or introduce neoantigens. This leads to the breakdown of immune tolerance, the production of autoantibodies, and subsequent tissue injury through 3 principal mechanisms: cell destruction, inflammation, and functional disruption.[3]  

Direct Cytotoxicity and Phagocytosis

Antibodies opsonize, or mark for destruction, target cells by binding to self-antigens on the cell surface. Complement fixation and activation of the complement cascade follow, and in some cases, culminate in the formation of the membrane attack complex, comprising C5b to C9, which causes direct cell lysis, especially of anucleated cells, such as erythrocytes.[11] Alternatively, complement activation may yield C3b, which also effectively opsonizes the cell.[12] Opsonization facilitates phagocytosis by macrophages and neutrophils through Fcγ receptors and receptors that bind C3b.[12] In other scenarios, antibody-dependent cellular cytotoxicity (ADCC) induces cell lysis by utilizing Fc receptors on NK cells, macrophages, neutrophils, and eosinophils. Contact between these cells and the antibody-coated cell triggers the release of perforin and granzymes, leading to the induction of apoptosis. Clinically, these mechanisms underlie autoimmune hemolytic anemia, immune thrombocytopenia (ITP), hemolytic transfusion reactions, and erythroblastosis fetalis.  

Complement-Mediated Inflammation   

Autoantibodies may activate the classical complement pathway, generating the anaphylatoxins C3a and C5a, leading to the recruitment and activation of neutrophils. These effector cells release proteolytic enzymes and reactive oxygen species, damaging host tissues. This inflammatory pathway is exemplified by anti-glomerular basement disease (Goodpasture syndrome), where anti-collagen IV antibodies injure glomerular and alveolar basement membranes.[13] Similarly, antibodies against the streptococcal antigens M-protein and N-acetyl-beta-D-glucosamine (NABG) cross-react with cardiac myosin and lysoganglioside in the CNS through molecular mimicry in patients with acute rheumatic fever, triggering myocarditis and Sydenham chorea, respectively.[14] Cross-reactivity with synovial proteins triggers the recruitment of neutrophils and the release of inflammatory cytokines, resulting in a reversible migratory polyarthritis without long-term joint damage.

Cellular Functional Disruption   

In certain conditions, antibodies bind to receptors on target cells, altering their normal function without causing cell death or inflammation. This occurs in patients with Graves' disease, where autoantibodies stimulate the TSH receptor, resulting in uncontrolled thyroid hormone synthesis.[15] Conversely, in patients with myasthenia gravis, antibodies block acetylcholine receptors at the neuromuscular junction, thereby impairing synaptic transmission and causing fluctuating muscle weakness.[16] In patients with pemphigus vulgaris, IgG autoantibodies bind to desmogleins, disrupting the adhesion of keratinocytes and leading to a loss of cohesion between epidermal cells.  

Histopathology

Immunohistopathology of type II hypersensitivity reactions reveals antibody-mediated injury, accompanied by disease-specific findings. In Graves’ disease, thyroid tissue exhibits follicular hyperplasia, increased follicle/stroma ratio, intracellular colloid droplets, cell scalloping, and a patchy lymphocytic infiltration.[17] Rheumatic heart disease shows valvular inflammatory infiltrates and pathognomonic Aschoff bodies within the myocardium.[18] In anti-GBM disease, renal biopsy may demonstrate crescentic glomerulonephritis, and immunofluorescence reveals a characteristic linear deposition of IgG and C3 along the basement membrane.[19] Pemphigus vulgaris is characterized by suprabasal acantholysis with a “tombstone” appearance of basal cells, and direct immunofluorescence shows intercellular, fishnet-like IgG and C3 deposition.[20]  

History and Physical

The clinical manifestations of type II hypersensitivity reactions are closely tied to the underlying autoimmune or alloimmune condition. During history taking, patients may report multiple prior transfusions, Rh or ABO incompatibility, or recent drug exposure, notably to agents known to induce immune cytopenias, such as methyldopa, penicillins, or cephalosporins.[33][34] Presentation varies according to the affected hematologic or neuromuscular system.  

Immune Thrombocytopenia

Caused by autoantibodies against platelet antigens, bleeding typically occurs in the skin and mucus membranes in up to two-thirds of patients, often accompanied by petechiae, non-palpable purpura, and hemorrhagic blisters in the mouth, as well as severe bleeding in approximately 10%.[21]  

Autoimmune Hemolytic Anemia  

Patients with autoimmune hemolytic anemia have autoantibodies that bind to antigens on their RBCs, causing hemolysis. Defined as warm or cold depending on the temperature at which the responsible antibodies react, warm-type antibodies typically bind at 37 ° C, and affected patients generally present with weakness, fatigue, abdominal pain, fever, shortness of breath, dizziness, and pallor in addition to signs of hemolysis, including jaundice, icterus, and painless dark urine.[22] Patients affected by cold agglutination disease experience acrocyanosis, ulcerations, Raynaud phenomenon, livido reticularis, and pain when swallowing cold foods or liquids, along with fatigue and an increased incidence of venous thromboembolism.  

Autoimmune Neutropenia

Granulocyte-specific antibodies cause autoimmune neutropenia, also known as benign neutropenia. The diagnosis most commonly becomes apparent upon performing a CBC during an infection or for unrelated reasons. Most patients affected by this condition have a normal bone marrow reserve of neutrophils and therefore do not have an increased risk of infections. This condition is more common in patients of African, Sephardic Jewish, West Indian, Yemenite, Greek, and Arabic descent. However, in some individuals, it may be related to underlying diseases, such as hepatitis B, collagen vascular disease, immune thrombocytopenia, primary abnormalities of B or T lymphocytes or natural killer cells, a deficiency of regulatory T cells, or autoimmune hemolytic anemia.  

Myasthenia gravis

Characterized by fluctuating weakness affecting ocular, bulbar, and limb muscles, leading to diplopia, dysphagia, dysarthria, and fatigability during physical tasks.[23] See StatPearls' companion topic," Myasthenia Gravis," for an in-depth discussion of the clinical presentation as well as the evaluation and management of myasthenia gravis.  

Graves' Disease

Patients with Graves’ disease typically present with signs of increased metabolic and cardiovascular activity, including weight loss despite increased appetite, tachycardia, widened pulse pressure, increased contractility, and decreased peripheral vascular resistance.[24] Ocular findings are common, such as lid lag, stare, proptosis, periorbital edema, and extraocular muscle dysfunction.[25] Neurologic features include tremor, tremulousness, mood swings, behavioral disturbances, and, in children, neurodevelopmental delay. The skin is warm and smooth due to increased blood flow and reduced keratin, accompanied by frequent sweating resulting from heightened calorigenesis. Nail and hair changes, such as onycholysis (Plummer nails), brittle nails, and hair thinning, may occur, along with associated autoimmune conditions like vitiligo and alopecia areata. Additionally, a goiter is typically present. See StatPearls' companion topic, "Graves' Disease," for additional information regarding the clinical presentation, evaluation, and management of Graves' disease.  

Pemphigus Vulgaris

Pemphigus vulgaris typically presents with widespread flaccid blisters on normal or erythematous skin, along with painful mucocutaneous erosions. Mucosal involvement is common, especially in the oral cavity. The blisters rupture easily, leaving friable, bleeding erosions that cause significant discomfort.  

Acute Rheumatic Fever and Rheumatic Heart Disease

Acute rheumatic fever typically occurs 1 to 5 weeks after a Group A streptococcal pharyngitis infection. Patients commonly present with fever, fatigue, and migratory polyarthritis, typically affecting large joints. Carditis may manifest as tachycardia, a new murmur, pericardial rub, or evidence of heart failure. Sydenham chorea presents with involuntary movements, emotional lability, and muscle weakness. Skin findings include erythema marginatum, a faintly red, non-pruritic rash, and subcutaneous nodules over extensor surfaces. The presentation is variable, and diagnosis relies on the revised Jones criteria, which require evidence of a recent streptococcal infection, along with major and minor clinical features. See StatPearls’ companion topic, "Acute Rheumatic Fever," for further information regarding the diagnostic criteria and clinical presentation of acute rheumatic fever. 

Patients with rheumatic heart disease often develop valvulitis as a result of prior acute rheumatic fever, most commonly affecting the mitral valve and, in 20% to 30% of cases, the aortic valve. Clinical findings may include an apical holosystolic murmur of mitral regurgitation, an apical mid-diastolic rumble of mitral stenosis, and a basal early diastolic murmur of aortic regurgitation. Additional manifestations include dyspnea, atrial fibrillation, thromboembolic stroke, and pulmonary hypertension.  

Hemolytic Disease of the Fetus and Newborn

Maternal IgG antibodies can destroy fetal or neonatal RBCs in the setting of blood group incompatibility, most often involving the Rh system, as well as the ABO system and, less commonly, the Kell, Duffy, MNS, P, and Diego antigens. Hemolytic disease of the newborn can range from mild, self-limited hyperbilirubinemia to life-threatening anemia. ABO incompatibility typically presents with mild to moderate jaundice and unconjugated hyperbilirubinemia within the first 24 hours of life, sometimes accompanied by symptomatic anemia manifesting as lethargy, tachycardia, and poor feeding, but usually without circulatory collapse. In contrast, Rh incompatibility often causes more severe hemolysis, which may require transfusion, and in the most serious cases, can result in hydrops fetalis, characterized by diffuse edema, pleural and pericardial effusions, and ascites. See StatPearls' companion topic, "Hemolytic Disease of the Fetus and Newborn," for an in-depth discussion on hemolytic disease of the fetus and newborn.  

Anti-Glomerular Basement Membrane Disease

Patients with anti-GBM disease typically present with malaise, weight loss, fever, or arthralgia, which usually lasts for a few weeks. Additional symptoms include hemoptysis, shortness of breath, fatigue, hematuria, proteinuria, edema, and hypertension.

Drug-Induced Lupus

Drug-induced lupus, in which medications such as hydralazine or procainamide trigger the formation of autoantibodies, notably anti-dsDNA or anti-erythrocyte antibodies, results in systemic or hematologic involvement. The most common presenting symptoms of drug-induced lupus are fever, arthralgias, arthritis, myalgias, rash, and serositis. Affected patients may rarely experience the organ-threatening manifestations associated with traditional systemic lupus erythematosus. Symptoms onset may be soon after drug administration or manifest after years on the offending drug.

Evaluation

The diagnostic evaluation of type II hypersensitivity reactions relies on identifying the inciting factor and integrating clinical findings with targeted laboratory and imaging tests. The process begins with a thorough clinical history, including recent drug exposures, infections, transfusion history, and systemic symptoms. The following table provides a brief overview of the diagnostic evaluation of some of the more common illnesses caused by type II hypersensitivities (See Table 1: Disorders Caused by Antibody-Mediated Hypersensitivity and Key Diagnostic Tests).

 Table 1: Disorders Caused by Antibody-Mediated Hypersensitivity and Key Diagnostic Tests

Treatment / Management

Management of type II hypersensitivity reactions depends on the underlying immunopathological mechanism and the specific clinical syndrome. The first priority is elimination of the inciting agent, particularly in drug-induced cytopenias and transfusion reactions, where stopping the offending drug or blood transfusion often halts disease progression.[30] Patients with drug-induced lupus who continue to remain symptomatic, despite discontinuation of the offending drug, may temporarily require NSAIDs, hydroxychloroquine, systemic glucorticoids, topical corticosteroids, or systemic therapy such as methotrexate and mycophenolate mofetil. Additionally, clinicians can avoid sensitization with Rh immune globulin (RhIg) prophylaxis. Babies with hemolytic disease of the fetus and newborn may require a transfusion or exchange transfusion, phototherapy, IVIG, erythropoiesis-stimulating agents, based on their bilirubin level and severity of anemia.[31][32](B3)

Glucocorticoids are the mainstay of treatment in conditions such as autoimmune hemolytic anemia and immune thrombocytopenia. Rituximab is an effective second-line agent for steroid-refractory cases. Plasmapheresis, combined with glucocorticoids and an immunosuppressant such as cyclophosphamide, is the recommended treatment regimen for anti-GBM disease.[33][34] Rituximab and mycophenolate mofetil are alternative immunosuppressants in patients who are unable to tolerate rituximab.

Prevention, with prompt treatment of group A streptococcal infection and continuous antibiotic prophylaxis in patients with a known history of acute rheumatic fever, is the key to preventing primary or recurrent rheumatic heart disease. Penicillin eradicates group A Streptococcus, and clinicians use benzathine penicillin G or oral penicillin V for long-term prophylaxis. See StatPearls' companion topic, "Bacterial Pharyngitis," for an in-depth discussion of the presentation, diagnosis, and management of group A streptococcal pharyngitis. Current evidence does not support the use of glucocorticoids, aspirin, or other anti-inflammatory agents in the treatment of rheumatic heart disease. However, some experts will use glucocorticoids in patients with severe carditis and heart failure or impending surgery due to severe mitral regurgitation.[35](A1)

Atenolol, 25 to 50 mg, titrated to a pulse of 60 to 90 bpm, maximum 200 mg/d, is the drug of choice for symptom management for Graves' disease. Methimazole is first-line to reduce thyroid hormone synthesis, with radioactive iodine or thyroid surgery reserved for select cases. Steroids or teprotumumab, an IGF-1R antagonist, treat thyroid eye disease.[36] Some experts recommend selenium 100 mg bid for 6 months in patients with mild eye disease. However, the studies showing its benefits originated from areas with selenium insufficiency, and the effects in selenium-rich regions are unclear.[37] Rituximab, tocilizumab, and mycophenolate mofetil are potential alternatives in patients who fail steroids and teprotumumab. (A1)

Clinicians should be aware of the potential for medications such as fluoroquinolones, macrolides, and neuromuscular blocking agents to exacerbate myasthenia gravis. Pyridostigmine improves neuromuscular transmission and is first-line in patients with mild symptoms of myasthenia gravis. Biologics such as rozanolixizumab, IVIG, glucocorticoids, or plasma exchange are used in patients with refractory symptoms or myasthenic crisis. Thymectomy is beneficial in early-onset or thymoma-associated disease. Fc receptor antagonists, such as efgartigimod, and C5 inhibitors, such as eculizumab, represent novel targeted therapies for severe cases.[38]

Differential Diagnosis

The differential diagnosis of type II hypersensitivity reactions largely depends on the patient's clinical presentation. The following list contains potential alternative diagnoses to include in the differential:  

• Acid maltase deficiency;
• Acute glomerulonephritis with pulmonary hemorrhage;
• Allergic reactions;
• Amyotrophic lateral sclerosis;
• Botulism;
• Brainstem and motor cranial nerve pathologies;
• Chronic progressive ophthalmoplegia;
• Cirrhosis;
• Cytopenias;
• Cyclic neutropenia;
• Disseminated intravascular coagulation;
• Drug-induced ANCA vasculitis;
• Drug toxicities;
• Endocrinopathies;
• Erythrocyte membrane defects;
• Erythrocyte enzyme defects;
• Gilbert syndrome;
• Glucose-6-phosphate dehydrogenase deficiency;
• Guillain-Barré syndrome;
• Heparin-induced thrombocytopenia;
• Hemolytic anemias;
• Hemolytic uremic syndrome;
• Hypersplenism;
• IgA pemphigus;
• IgA vasculitis;
• Lambert-Eaton myasthenic syndrome;
• Lyme disease;
• Megakaryocytic aplasia;
• Mixed cryoglobulinemia syndrome;
• Myelodysplastic syndrome;
• Oculopharyngeal muscular dystrophy;
• Paraneoplastic pemphigus;
• Pemphigus foliaceus;
• Polymyositis;
• Progressive bulbar palsy;
• Pyruvate kinase deficiency;
• Severe congenital neutropenia;
• Subacute cutaneous lupus erythematosus;
• Systemic lupus erythematosus;
• Thrombotic thrombocytopenic purpura;
• Valvular heart disease; and
• Viral myocarditis.[36][38][39][40][41]

Prognosis

The prognosis of type II hypersensitivity reactions depends on the underlying cause, the organ system involved, and the speed at which clinicians initiate treatment. Drug-induced hemolytic anemia, thrombocytopenia, or agranulocytosis usually resolve once the causative medication is discontinued. Transfusion reactions may also improve with prompt recognition and intervention, though they carry a high mortality risk if treatment is delayed. In autoimmune conditions such as autoimmune hemolytic anemia, immune thrombocytopenia, anti-GBM disease, and myasthenia gravis, outcomes range from good with immunosuppressive therapy to guarded when end-organ damage occurs—for example, pulmonary hemorrhage or renal failure in anti-GBM disease. Myasthenic crisis, once associated with 50% to 80% mortality rate, now has a significantly lower mortality rate of about 4.5% with modern care.[42] Chronic illnesses like autoimmune hemolytic anemia and immune thrombocytopenia often relapse but generally respond well to treatment. Other antibody-mediated diseases, including rheumatic fever, Graves’ disease, and myasthenia gravis, can cause long-term complications but are typically manageable with appropriate therapy.

Complications

Patients with autoimmune and immune-mediated disorders may develop significant disease-related and treatment-related complications. If left untreated, type II hypersensitivity reactions can result in progressive tissue and organ damage or death, depending on the underlying clinical entity. In anti-GBM disease, significant risks include acute kidney injury progressing to acute renal failure or chronic kidney disease, pulmonary hemorrhage with anemia and respiratory compromise, hypertension, and pulmonary fibrosis. Treatment carries its own hazards, including cyclophosphamide-induced bone marrow suppression, cardiac toxicity, infertility, hepatotoxicity, hemorrhagic cystitis, and secondary malignancy; IVIG-associated anaphylaxis, renal injury, transfusion-related acute lung injury, or thromboembolic events; plasmapheresis-related hypotension, hypocalcemia, and infection; and corticosteroid-related complications such as osteoporosis, diabetes, infection, peptic ulcer disease, cataracts, and adrenal suppression.[43][44]

Autoimmune hemolytic anemia may lead to acute kidney injury from hemoglobinuria, high-output heart failure, pigment gallstones with biliary complications, venous thromboembolism, infection due to functional or surgical asplenia, and transfusion-related hemolysis or iron overload, with additional morbidity from glucocorticoids.[45] Though uncommon, patients with autoimmune neutropenia may experience recurrent bacterial infections and delayed wound healing. Treatment with granulocyte colony-stimulating factor may cause bone pain and, in rare cases, splenic rupture. Additionally, immunosuppressive therapy further increases infection risk, splenectomy predisposes patients to life-threatening encapsulated bacterial infections and thrombosis, and glucocorticoids may cause hyperglycemia, osteoporosis, cataracts, and adrenal suppression.[46] Hemolytic disease of the fetus and newborn may cause severe anemia, hydrops fetalis, intrauterine fetal demise, hyperbilirubinemia with kernicterus, hepatosplenomegaly, DIC, and long-term neurodevelopmental delays.[47] In immune thrombocytopenia, the primary concern is bleeding; however, treatment also carries risks, including adverse reactions to IVIG, infections, complications from corticosteroids and immunosuppressants, post-splenectomy infections and thrombosis, and thromboembolism or marrow fibrosis from thrombopoietin receptor agonists.[48][47]

Graves’ disease may cause atrial fibrillation, thromboembolism, angina, thyroid storm, heart failure, and vision-threatening thyroid eye disease, with added risks of agranulocytosis or hepatotoxicity from antithyroid drugs and surgical complications such as recurrent laryngeal nerve injury.[49][50] Myasthenia gravis can progress to respiratory failure, aspiration, malnutrition, and impaired communication due to dysphagia and dysarthria. Treatment may transiently worsen weakness and cause steroid-related adverse effects, cholinergic crisis, immunosuppressant-related cytopenias, infections, malignancy, or adverse effects related to IVIG and plasmapheresis.[51][52][53] Pemphigus vulgaris predisposes patients to secondary skin infections, fluid and electrolyte imbalances, malnutrition due to the mucosal disease, chronic scarring, and treatment-related immunosuppression.[54] Rheumatic heart disease results in chronic valvular stenosis or regurgitation (particularly mitral involvement), heart failure, atrial fibrillation and other arrhythmias, pulmonary hypertension, systemic embolization, and infective endocarditis.[55]