Continuing Education Activity

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, resulting in cellular destruction, functional loss, or damage to tissues. Damage can occur through multiple mechanisms. This activity defines the involved pathogenic mechanisms, the clinical presentations, evaluation, and management of common forms of type II hypersensitivity reactions and highlights the role of the interprofessional team in the care of these patients.

Objectives:

• Describe the immune pathogenesis of type II hypersensitivity reactions.
• Review the evaluation of the most common forms of type II hypersensitivity reactions.
• Outline the various treatment options for the most common forms of type II hypersensitivity reaction.
• Summarize the importance of collaboration and communication amongst the interprofessional team to enhance the care of patients with a type II hypersensitivity reaction.

Introduction

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, resulting in cellular destruction, functional loss, or tissue damage. Damage can occur 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]

Etiology

The type II hypersensitivity reaction develops in response to cell surface modifications 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 alters 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 self-antigens.[4]

Epidemiology

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 we can identify high-risk populations with advancing genetic studies in the future.[5] Epidemiology also varies according to the underlying cause of type II hypersensitivity reaction, such as in the case of hemolytic disease of the newborn; despite advanced immunoprophylaxis, an estimated 1 to 3 in 1000 Rh-negative women still develop alloimmunization today.[6]

Pathophysiology

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, III, and IV 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).[7]

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 target cell's surface, particularly IgG antibodies. 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.[8]

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.[8]

Antibodies can also bind to the target cell resulting in complement pathway activation and formation of the membrane attack complex involving complement components C5b6789. The membrane attack complex creates a channel to induce the 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.[9]

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 primarily 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.[10]

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.[11]

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 the 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.[12]

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.[13]

Histopathology

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.[14] 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.[15] 

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.[16] 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.[17]

History and Physical

History and physical examination findings differ based on the disease category presented. With type II hypersensitivity reactions, during the history taking, the patient might report repeated blood transfusions, blood group or rhesus incompatibility, or a history of recent drug intake. The patient might clinically present with features of autoimmunity, e.g., immune thrombocytopenia (characterized by bleeding disorders), autoimmune hemolytic anemia (characterized by jaundice), and other blood dyscrasias (autoimmune neutropenia).[33][34] I

n myasthenia gravis, the patient could have symptoms suggestive of generalized muscle weakness with difficulty in mobilizing, eating, speech, and carrying out routine activities.[18]

Evaluation

The evaluation of this form of immediate hypersensitivity reaction depends on the nature of the inciting factor and a combination of clinical presentations and investigative data to establish a proper diagnosis.

Surveying an antibody immune-mediated reaction represents the key feature considering the history and examination. One of the most common examples of type II hypersensitivity is the one following drug intake in patients with drug-induced lupus. In this type, anti-red blood cell or anti-dsDNA antibodies are produced as a result of a drug attaching to red blood cells resulting in drug-induced systemic lupus erythematosus (SLE).

The evaluation includes the following: Complete blood cell count surveying hemoglobin (autoimmune hemolytic anemia), red blood cell count, neutrophils, lymphocytes, and platelets for cytopenias, and an assessment of immunoglobulins with a quantitative assay for IgG, IgM, and IgE depending on the type of hypersensitivity reaction. Animals, plants, food, and environmental pollutants can be used in skin prick tests, and a radioallergosorbent test (RAST for IgE) can be done.[19] Drug allergies can also be detected through intradermal tests, such as hypersensitivity to ceftriaxone and carbamazepine.[20][21][20] 

The detection of autoantibodies can be assessed in systemic autoimmune diseases like SLE and rheumatoid arthritis (RA). Autoantibodies can also be done against specific organs, e.g., autoantibody against islet cells in diabetes mellitus, thyroid-stimulating hormone (TSH) receptor antibody to differentiate it from other causes of thyrotoxicosis, and acetylcholine receptor antibody test (highly specific for myasthenia gravis).[22][23]

Treatment / Management

The treatment following diagnosis will depend on the treatment guidelines and recommendations for each disease subset. Avoidance of the inciting trigger in case of adverse drug events, hemolysis, or drug-induced autoimmune disease is very important. Management of cytopenias should be done according to a defined protocol. Systemic glucocorticoids represent another important intervention to suppress antibody response and prevent tissue damage.

Examples of Management Protocols

In the case of a drug-induced adverse event, drug-induced lupus, or cytopenias, the drug should be discontinued.

Antibiotic therapy should be started in cases with acute rheumatic fever to eradicate the carriage of group A streptococcus. Penicillin V and benzylpenicillin are primarily used for this purpose. Oral cephalosporins are used as an alternative therapy for penicillin-allergic patients. Symptomatic treatment of acute manifestations like arthritis (with NSAIDs), carditis (with aspirin or oral prednisone), and chorea (with diazepam) should be provided. Prevention of progression of cardiac damage by giving prophylaxis against future group A streptococcal infections should be done. Benzathine penicillin G is administered intramuscularly for prophylaxis.[24]

In immune-mediated thyrotoxicosis (Graves disease), antithyroid drugs, including propylthiouracil and methimazole, are started. Radioiodine ablation and surgical excision should also be considered. Glucocorticoids are used for ophthalmopathy.[25]

In myasthenia gravis, acetylcholinesterase inhibitors like pyridostigmine are started. Immunosuppressive therapy (like corticosteroids) is used for the patient's refractory to pyridostigmine therapy. Thymectomy is considered in patients refractory to drug therapy. Plasma exchange and intravenous immune globulin should be given in myasthenic crises.[26]

Differential Diagnosis

The differential diagnosis of type II hypersensitivity reactions largely depends on the presentation patterns specific to each disease category. In addition, knowledge of the other different types of hypersensitivity reactions and the clinical presentations of each is essential. 

The following are the most common examples:

• Hemolytic anemias
• Cytopenias (thrombocytopenia- neutropenia)
• Drug toxicities
• Autoimmune diseases
• Allergic reactions
• Infections[27]
• Endocrinopathies
• Neuromuscular disorders (congenital, familial, degenerative, inflammatory, iatrogenic, neoplastic, and autoimmune)[25][26][28]
• Valvular heart disease[27]

Prognosis

The prognosis of type II hypersensitivity reactions differs based on timely diagnosis, carefully considering the possible differential diagnoses. Additionally, it varies from one disease category to another. For instance, the overall prognosis of hemolytic disease of the newborn is good if identified and treated promptly. In the case of myasthenia gravis, most patients have a near-normal life span with the current treatment modalities. Fifty years ago, the mortality rate was around 50% to 80% in the myasthenic crisis, and now it has reduced substantially to 4.47%.[29]

Complications

If left untreated, patients may develop tissue or organ damage, which depends on the clinical presentation, e.g., cytopenias might contribute to infections, bleeding tendencies, and severe anemias. Acute rheumatic fever may lead to rheumatic heart disease with valvular lesions (stenosis and regurgitation).[30] Myasthenia crisis may prove fatal if not treated promptly with intubation and glucocorticoid therapy.[31]

Deterrence and Patient Education

Patients should be educated about the diagnosed disease and the importance of taking medications to avoid serious complications that can prove to be life-threatening. They should be advised to avoid taking new medications without checking with the medical provider. Patients with myasthenia gravis should be advised to comply with the treatment plan to ensure that the disease remains well controlled.[32]

Enhancing Healthcare Team Outcomes

Type II hypersensitivity reactions require close collaboration and communication amongst the interprofessional team involving clinicians (MDs, DOs, NPs, and PAs), immunologists, nurses, pharmacists, and laboratory staff. This will provide a patient-centered approach, improve outcomes and patient safety, and enhance team performance. In the case of drug allergy, the pharmacist should check the patient's medication record, and the nursing staff should be vigilant and should have the patient clarify any prior allergic reaction to drugs.[33] 

Nurses can serve as patient contact points and coordinate activities between interprofessional team members. All persons on the care team must be able to communicate with any other team member in the event of any concerns or changes in patient status. All interventions and observations must be documented in the patient's health record by every team member so everyone has access to the same updated information regarding the case. This interprofessional approach will help drive the best possible patient outcomes with the fewest adverse events. [Level 5]