Overview
An introduction to the four types of Hypersensitivity reaction: what initiates each, how each is mediated, what the outcome is, and which conditions are associated with each. Types I to III are antibody mediated and type IV is cell mediated, and the four are ordered from fastest to slowest onset (minutes for type I through to about three days for type IV). The lecture works through type I allergy and its immediate and late phase components, atopy and the hygiene hypothesis, the overlap between hypersensitivity and autoimmunity, then the mechanisms and clinical examples of types II, III and IV, closing with two summary tables. Reference: Robbins 10th Ed, Pathologic Basis of Disease pp 205 to 215 (also cited as Diseases of the Immune System, Hypersensitivity pp 135 to 145).
Learning objectives
- Know what the four types of hypersensitivity reaction are.
- Understand how each type is initiated and mediated, and what the outcome is.
- Know the conditions associated with each type.
What hypersensitivity is
- Hypersensitivity is an inappropriate or exaggerated immune response against antigens or allergens. It includes both allergy and autoimmunity.
- It is a consequence of: reactions against self antigen; inappropriate reactions against microbes; reactions against environmental antigens.
- “Once a hypersensitivity reaction starts, it is difficult to control or terminate it.”
General characteristics
- Four types: I, II, III and IV.
- Types I to III are antibody mediated; type IV is cell mediated.
- Hypersensitivity occurs on the second and subsequent exposures to antigen. It does not occur following primary exposure to antigen.
The four types at a glance (fast onset to slow onset)
| Type | Initiating event | Onset |
|---|---|---|
| I (allergy) | Antibody mediated degranulation of mast cells and basophils; rapid | Minutes |
| II | Binding of antibody to a cell membrane or extracellular matrix | 1 day |
| III | Antibody binding to soluble molecules to form immune complexes | 1 to 2 days |
| IV | Attack by immune cells in the absence of antibody | 3 days |
This ordering slide is shown twice in the lecture, once as an introduction and once as a recap before type IV.
Type I hypersensitivity (allergy)
An allergen is a substance that causes an allergic reaction. Examples given:
- Small soluble proteins or glycoproteins, often proteases
- Dust mite faeces
- Food components: milk, nuts, eggs, fish
- Insect saliva
- Plant excretions
- Chemicals
- Drugs, for example penicillin
Sites of local anaphylaxis
Local type I reactions occur at defined sites: allergic rhinitis (nose and eyes), asthma (lungs), atopic eczema and urticaria (skin), food allergy (gut).
Mechanism
First encounter (primary immune response):
- Exposure to allergen, for example pollen, at a mucosal lining.
- Activation of TH2 cells and IgE class switching in B cells.
- IgE secreting B cells produce IgE.
- IgE binds to FcεRI on mast cells and basophils, so the antibody sits on the outside of the cell.
Second and subsequent exposures (secondary immune response):
- Allergen binds the IgE already bound to FcεR on mast cells and basophils.
- Cross-linking of FcεR by antigen generates a signal for degranulation.
- The mast cell is activated and releases mediators, which split into two arms: vasoactive amines and lipid mediators, and cytokines.
Two arms of the response
Immediate response, within minutes:
- Degranulation releases granule contents (histamine) and membrane phospholipids.
- Membrane phospholipids are converted to prostaglandins and leukotrienes, which act as chemotactic factors.
- Effects: vasodilation, vascular leakage, smooth muscle spasm.
- The Robbins pathway labels this the immediate hypersensitivity reaction, occurring minutes after repeat exposure and driven by vasoactive amines and lipid mediators.
Late phase reaction, within hours (2 to 8 hours after repeat exposure):
- Secreted cytokines TNF, IL-4, IL-5 and IL-13.
- These recruit eosinophils and neutrophils, causing tissue damage; IL-13 triggers epithelial mucus secretion.
- Effects: leukocyte infiltration, epithelial damage, bronchospasm.
Clinically, the manifestation curve shows an immediate peak shortly after allergen exposure and a late phase peak around 8 to 12 hours. A skin test shows an immediate wheal and a separate late phase reaction, both with localised swelling and erythema. Histology shows mast cell degranulation with oedema and vascular congestion in the immediate phase, and eosinophil infiltration in the late phase.
Factors released by eosinophils contribute to itching and bronchial irritability.
Atopy
Atopy is the genetic tendency to develop allergic diseases. Allergic individuals may have:
- Many more IgE molecules per mast cell
- High affinity Fc receptors for IgE on mast cells and basophils
- Higher IgE levels, greater than 1 µg/ml in serum
- Genetic predisposition: 80% have at least one affected parent
The hygiene hypothesis
- There is an inverse relationship between the incidence of infectious disease and that of allergic and autoimmune disease. Over 1950 to 2000, rheumatic fever, hepatitis A, measles, mumps and tuberculosis all declined, while Crohn’s disease, multiple sclerosis, type 1 diabetes and asthma all rose (Bach et al. 2002, N Engl J Med 347, 911).
- This is attributed to less exposure to parasitic, bacterial and viral infections early in life.
- The hypothesis was proposed in 1989: “we are too clean for our own good”.
- It is not well supported by scientists, although it is established in lay culture.
- It is considered important that we are exposed to a diverse range of organisms, not necessarily pathogenic, to train the immune system to react appropriately.
- The current key focus is the microbiome, diet, genetics and antibiotic use.
Hypersensitivity and autoimmunity
- Hypersensitivity describes the mechanisms by which the body reacts, or over-reacts, to certain stimuli.
- Most but not all hypersensitivity reactions are manifested in autoimmune disorders.
- Hypersensitivity types II to IV include autoimmune disorders.
Features of autoimmune disease:
- Breakdown of immunologic tolerance
- May be systemic, affecting tissues throughout the body, or localised to specific sites
- Presence of autoantibodies
- Lymphocyte, macrophage and plasma cell infiltration into lesions
- Presence of more than one autoimmune condition
- Female bias
- Occurs in families
- HLA associations, especially HLA-DR (for example rheumatoid arthritis) and HLA-B27 (for example ankylosing spondylitis)
- Lesions classified by hypersensitivity types II, III and IV
Type II hypersensitivity (antibody mediated, cytotoxic)
The principal mechanism of tissue injury is antibody mediated (cytotoxic). Antibodies are directed against target antigens on the surface of cells or on tissue components. Mnemonic used in the lecture: “II cy-two-toxic”.
Three mechanisms of tissue injury:
- Opsonisation and phagocytosis (complement and Fc receptor mediated). The target cell is opsonised with C3b and antibody, binds a phagocyte through the Fc receptor and the C3b receptor, and is engulfed and phagocytosed. Example: autoimmune haemolytic anaemia, where the antigen is red cell membrane protein, producing haemolysis and anaemia.
- Complement and Fc receptor mediated inflammation. Antibody bound to a cell or tissue surface engages Fc receptors and activates complement, generating C5a and C3a, which recruit and activate phagocytes; these release neutrophil enzymes and reactive oxygen intermediates, producing inflammation and tissue injury. Example: Sjögren’s syndrome.
- Antibody-mediated cellular dysfunction, with no necessary cell destruction. Example: Graves disease, where antibody against the TSH receptor binds and stimulates the receptor on thyroid epithelial cells, driving thyroid hormone production without the normal hormone trigger, causing hyperthyroidism. Example: myasthenia gravis, where antibody to the acetylcholine receptor binds ACh receptors on the muscle membrane and blocks acetylcholine released from the nerve ending from binding, causing muscle weakness and paralysis.
Clinical examples of type II
- Incompatible blood transfusions
- Hyperacute graft rejection
- Myasthenia gravis
- Graves disease
- Acute rheumatic fever
- Some drug hypersensitivities
ABO groups underlying transfusion reactions: group A carries the A antigen and anti-B antibodies in plasma; group B carries the B antigen and anti-A; group AB carries both A and B antigens and no antibodies; group O carries no antigen and both anti-A and anti-B.
Sjögren’s syndrome
- Destruction of exocrine glands; the lacrimal and salivary glands are affected, giving dry eyes and dry mouth.
- Prevalence 1 in 400 people.
- Common in older women, 50 years and over.
- Around 50 to 80% of patients have anti-nuclear antigens.
- Autoantibodies act via the Fc receptor and induction of apoptosis and inflammation (type II hypersensitivity).
- Infiltration of CD4 T cells and B cells, releasing cytokines, also contributes to inflammation.
Type III hypersensitivity (immune complex disease)
Mediated by immune complexes of antibody and antigen. They can form when there are high antigen and antibody concentrations at the same time. Mnemonic used in the lecture: “three is free”, for the free soluble antigen involved.
The pathology produced depends on where the complexes lodge:
- Vasculitis if in the vessels
- Glomerulonephritis if in the kidney
- Arthritis if in the joints
The three phases
- Immune complex formation. Antigen circulates in the vessel lumen; a B cell differentiates into a plasma cell which releases free antibody; free antibody binds circulating antigen to form antigen-antibody complexes within the vessel, near the endothelium.
- Immune complex deposition. Complexes are deposited on the vessel wall, with influx of neutrophils and complement activation. Neutrophils bind the antibody via the Fc receptor.
- Immune complex-mediated inflammation. Frustrated phagocytosis: neutrophils cannot ingest immune complexes stuck to the basement membrane, so they release lysosomal enzymes; there is platelet aggregation, and damage results from complement-mediated inflammation, producing vasculitis of the vessel wall.
Histology of immune complex vasculitis shows a dense inflammatory cell infiltrate surrounding the wall of a vessel in cross-section.
Systemic lupus erythematosus
- Common, 1 in 2500.
- Manifestations include nephritis, skin lesions and arthritis; the characteristic sign shown is a malar (butterfly) rash across the cheeks and nose.
- Can manifest at any age but normally arises in the 20s to 30s.
- Caused by autoantibodies which form immune complexes (type III hypersensitivity).
- Major autoantibodies are directed at nuclear antigens (ANAs).
- Disease is remitting and relapsing.
Type IV hypersensitivity (cell mediated)
A cell mediated response, with two main mechanisms.
1. Delayed type hypersensitivity (DTH)
- CD4 T cells produce cytokines which mediate inflammation.
- CD8 T cells also contribute through cytokine production.
- Takes 2 to 3 days to develop.
- Pathway: an antigen presenting cell presenting tissue antigen activates a CD4+ T cell, which produces cytokines; a CD8+ T cell recognising antigen on normal tissue cells also contributes cytokines; the cytokines cause inflammation, which leads to tissue injury of the normal tissue.
CD4-mediated examples:
- Crohn’s disease: chronic intestinal inflammation of the GI tract; CD4 T cell activation and granuloma formation.
- Rheumatoid arthritis: chronic arthritis; inflammation mediated by Th17 cytokines.
- Multiple sclerosis: demyelination of the CNS, paralysis; inflammation mediated by Th1 and Th17 cells.
- Tuberculosis: the Mantoux test is a DTH response; Th1 response and granuloma formation.
2. T cell-mediated cytolysis (direct cell cytotoxicity), CD8 mediated
- CD8+ cytotoxic T lymphocytes bind directly to normal tissue cells presenting the relevant antigen, killing them and producing tissue injury.
- Examples: type 1 diabetes, destruction of the β cells in the pancreas; Hashimoto’s thyroiditis, given on the slide as destruction of the thymus.
Granuloma formation (type IV)
- An antigen presenting cell processes antigen and releases IL-12.
- IL-12 activates a CD4+ TH1 cell.
- The TH1 cell produces IL-2 (acting back on itself), TNF (acting on blood vessels to recruit monocytes) and IFN-γ (acting on monocytes).
- Monocytes differentiate and organise into a granuloma: a central giant cell surrounded by epithelioid cells, with lymphocytes, macrophages and fibroblasts at the periphery.
Immediate (allergy) versus delayed type hypersensitivity
| Feature | Allergy | Type IV |
|---|---|---|
| Time to develop | 30 minutes | 48 to 72 hours |
| Central area appearance | Blister | Red induration |
| Peripheral area appearance | Red (flare) | Red |
| Palpation of central area | Soft | Hard |
| Main cell type | Mast cell (IgE) | Th cell |
Summary tables
By immune reactant and antigen (fastest to slowest)
| Immune reactant | Antigen | Effector mechanism | Examples | |
|---|---|---|---|---|
| Type I (ITH) | IgE | Soluble antigen | Antibody (Th2), mast cell activation | Allergic rhinitis, asthma, systemic anaphylaxis |
| Type II | IgG | Cell associated | Antibody, complement, phagocytes: opsonisation and phagocytosis | Autoimmune haemolytic anaemia |
| Type II | IgG | Cell or matrix associated | Antibody, complement, Fc receptor neutrophils: complement and inflammation | Sjögren’s syndrome |
| Type II | IgG | Cell-surface receptor | Antibody blocking function of the cell receptor | Myasthenia gravis, Graves disease |
| Type III | IgG | Soluble antigen | Antibody, complement, phagocytes: immune complex formation | Vasculitis, SLE |
| Type IV (DTH) | Th1 | Soluble antigen | Th1 cytokine release, macrophage activation, inflammation | Contact sensitivity, rheumatoid arthritis, MS, tuberculosis |
| Type IV | CTL | Cell-associated antigen | CD8 T cell mediated cytolysis | Type 1 diabetes, Hashimoto’s thyroiditis |
The first five columns are grouped as antibody mediated and the last two as cell mediated.
Mechanisms, lesions and prototypical disorders (Robbins)
| Type | Immune mechanism | Histopathologic lesions | Prototypical disorders |
|---|---|---|---|
| Immediate (I) | IgE production, immediate release of vasoactive amines and other mediators from mast cells, later recruitment of inflammatory cells | Vascular dilation, oedema, smooth muscle contraction, mucus production, tissue injury, inflammation | Anaphylaxis; allergies; bronchial asthma (atopic forms) |
| Antibody mediated (II) | IgG or IgM binds antigen on target cell or tissue, leading to phagocytosis or lysis by activated complement or Fc receptors, with leukocyte recruitment | Phagocytosis and lysis of cells; inflammation; in some diseases functional derangement without cell or tissue injury | Autoimmune haemolytic anaemia; Goodpasture syndrome |
| Immune complex mediated (III) | Deposition of antigen-antibody complexes, complement activation, leukocyte recruitment by complement products and Fc receptors, release of enzymes and other toxic molecules | Inflammation, necrotising vasculitis (fibrinoid necrosis) | SLE; some forms of glomerulonephritis; serum sickness; Arthus reaction |
| Cell mediated (IV) | Activated T lymphocytes cause (1) cytokine release, inflammation and macrophage activation, and (2) T cell-mediated cytotoxicity | Perivascular cellular infiltrates; oedema; granuloma formation; cell destruction | Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis |
Self-test
- Define hypersensitivity and state the three categories of stimulus it can arise against.
- Explain why a hypersensitivity reaction does not occur on first exposure to an antigen.
- List the four hypersensitivity types with the initiating event and typical onset time of each, and state which are antibody mediated.
- Describe the steps of a type I reaction from first allergen encounter through to mast cell degranulation.
- Distinguish the immediate response from the late phase reaction in type I hypersensitivity, in terms of mediators, timing and effects.
- Predict what would happen if an allergen could bind IgE on a mast cell but could not cross-link FcεR.
- List four features that predispose an individual to atopy, including the serum IgE threshold given.
- Explain the hygiene hypothesis and the epidemiological observation it was built on.
- List the features of autoimmune disease, including the two HLA associations given.
- Describe the three mechanisms of tissue injury in type II hypersensitivity, with a disease example of each.
- Distinguish the antibody mechanism in Graves disease from that in myasthenia gravis.
- Describe the three phases of type III hypersensitivity.
- Explain why the site of immune complex deposition determines the disease produced, and give three examples.
- A patient in her 20s presents with nephritis, arthritis and a rash across the cheeks and nose. What is the diagnosis, what hypersensitivity type is it, and what are the major autoantibodies directed against?
- Describe the two mechanisms of type IV hypersensitivity and name diseases associated with each.
- Describe the steps of granuloma formation, naming the cytokines involved and the cells of the finished granuloma.
- Distinguish an immediate allergic skin reaction from a type IV skin reaction on time to develop, appearance, palpation and main cell type.
- For each of the four types, state the immune reactant and the nature of the antigen it reacts against.
Answers
Reveal answers
- An inappropriate or exaggerated immune response against antigens or allergens, including allergy and autoimmunity. It arises against self antigen, inappropriately against microbes, or against environmental antigens.
- Hypersensitivity occurs only on second and subsequent exposures. The primary exposure sensitises (for example IgE production and binding to mast cells) but does not itself produce the reaction.
- Type I (allergy), antibody mediated degranulation of mast cells and basophils, minutes. Type II, binding of antibody to a cell membrane or extracellular matrix, 1 day. Type III, antibody binding to soluble molecules forming immune complexes, 1 to 2 days. Type IV, attack by immune cells in the absence of antibody, 3 days. Types I to III are antibody mediated; type IV is cell mediated.
- Allergen exposure at a mucosal lining activates TH2 cells and drives IgE class switching in B cells; IgE secreting B cells produce IgE; IgE binds FcεRI on mast cells and basophils. On repeat exposure the allergen binds the already bound IgE and cross-links FcεR, generating the signal for degranulation and mediator release.
- Immediate response, within minutes: degranulation releases histamine, and membrane phospholipids are converted to prostaglandins and leukotrienes acting as chemotactic factors, producing vasodilation, vascular leakage and smooth muscle spasm. Late phase, within hours (2 to 8 hours, clinically peaking around 8 to 12 hours): secreted cytokines TNF, IL-4, IL-5 and IL-13 recruit eosinophils and neutrophils and IL-13 triggers epithelial mucus secretion, producing leukocyte infiltration, epithelial damage and bronchospasm.
- No degranulation. Cross-linking of FcεR by antigen is the step that generates the degranulation signal, so binding alone would not release the mediators and neither the immediate nor the late phase response would follow.
- Many more IgE molecules per mast cell; high affinity Fc receptors for IgE on mast cells and basophils; serum IgE greater than 1 µg/ml; genetic predisposition, with 80% having at least one affected parent.
- Proposed in 1989 as “we are too clean for our own good”: there is an inverse relationship between the incidence of infectious disease and that of allergic and autoimmune disease, attributed to less exposure to parasitic, bacterial and viral infections early in life. The observation was that between 1950 and 2000, rheumatic fever, hepatitis A, measles, mumps and tuberculosis fell while Crohn’s disease, multiple sclerosis, type 1 diabetes and asthma rose. It is not well supported by scientists, though it is established in lay culture; exposure to a diverse range of organisms, not necessarily pathogenic, is thought important for training the immune system, and the microbiome, diet, genetics and antibiotic use are the current focus.
- Breakdown of immunologic tolerance; may be systemic or localised; autoantibodies present; lymphocyte, macrophage and plasma cell infiltration into lesions; more than one autoimmune condition present; female bias; occurs in families; HLA associations, especially HLA-DR (rheumatoid arthritis) and HLA-B27 (ankylosing spondylitis); lesions classified by hypersensitivity types II, III and IV.
- (1) Opsonisation and phagocytosis: the cell is coated with C3b and antibody, binds a phagocyte via Fc and C3b receptors and is engulfed, as in autoimmune haemolytic anaemia against red cell membrane proteins. (2) Complement and Fc receptor mediated inflammation: bound antibody activates complement, generating C5a and C3a which recruit phagocytes that release neutrophil enzymes and reactive oxygen intermediates, as in Sjögren’s syndrome. (3) Antibody-mediated cellular dysfunction, as in Graves disease and myasthenia gravis.
- In Graves disease the antibody against the TSH receptor stimulates the receptor on thyroid epithelial cells without the normal hormone trigger, driving thyroid hormone production and hyperthyroidism. In myasthenia gravis the antibody to the acetylcholine receptor inhibits binding of the neurotransmitter to its receptor on the muscle membrane, causing muscle weakness and paralysis.
- Phase I, immune complex formation: a plasma cell releases free antibody which binds circulating antigen in the vessel lumen, forming complexes near the endothelium. Phase II, deposition: complexes deposit on the vessel wall with neutrophil influx and complement activation, neutrophils binding antibody via the Fc receptor. Phase III, inflammation: frustrated phagocytosis, since neutrophils cannot ingest complexes stuck to the basement membrane, so they release lysosomal enzymes; with platelet aggregation and complement-mediated inflammation this produces vasculitis.
- The complexes cause disease wherever they lodge and trigger complement-mediated inflammation, so the affected tissue determines the clinical picture: vasculitis in vessels, glomerulonephritis in the kidney, arthritis in the joints.
- Systemic lupus erythematosus (malar or butterfly rash), a type III immune complex hypersensitivity; the major autoantibodies are directed at nuclear antigens (ANAs). It affects about 1 in 2500, usually arises in the 20s to 30s, and is remitting and relapsing.
- (1) Delayed type hypersensitivity: CD4 T cells activated by an antigen presenting cell produce cytokines that mediate inflammation and hence tissue injury, with CD8 T cells also contributing cytokines; it takes 2 to 3 days. Examples are Crohn’s disease (CD4 activation and granuloma formation), rheumatoid arthritis (Th17 cytokines), multiple sclerosis (Th1 and Th17 cells) and tuberculosis (Th1 response, granuloma formation, Mantoux test). (2) Direct cell cytotoxicity: CD8 cytotoxic T lymphocytes bind and kill tissue cells presenting the antigen. Examples are type 1 diabetes (destruction of pancreatic β cells) and Hashimoto’s thyroiditis (given on the slide as destruction of the thymus).
- An antigen presenting cell processes antigen and releases IL-12, which activates a CD4+ TH1 cell. The TH1 cell produces IL-2 acting back on itself, TNF acting on blood vessels to recruit monocytes, and IFN-γ acting on monocytes. The monocytes differentiate and organise into a granuloma with a central giant cell surrounded by epithelioid cells, and lymphocytes, macrophages and fibroblasts at the periphery.
- Allergy develops in about 30 minutes, with a blister centrally, a red flare peripherally, a soft centre on palpation, and mast cells (IgE) as the main cell type. Type IV develops in 48 to 72 hours, with red induration centrally, redness peripherally, a hard centre on palpation, and Th cells as the main cell type.
- Type I, IgE against soluble antigen. Type II, IgG against cell associated antigen, cell or matrix associated antigen, or a cell-surface receptor. Type III, IgG against soluble antigen. Type IV, Th1 cells against soluble antigen in DTH, and CTLs against cell-associated antigen in T cell-mediated cytolysis.