SUMMARY
Hypersensitivity Types and Their Mechanisms
| Feature | Type I | Type II | Type III | Type IV |
|---|---|---|---|---|
| Immune Reactant | IgE | IgG or IgM | IgG and IgM | T cells |
| Antigen Form | Soluble antigen | Cell-bound antigen | Soluble antigen | Soluble or cell-bound antigen |
| Mechanism of Activation | Allergen-specific IgE antibodies bind to mast cells via their Fc receptor. When the specific allergen binds to the IgE, cross-linking of IgE induces degranulation of mast cells. | IgG or IgM antibody binds to cellular antigen, leading to complement activation and cell lysis. IgG can also mediate ADCC with cytotoxic T cells, natural killer cells, macrophages, and neutrophils. | Antigen-antibody complexes are deposited in tissues. Complement activation provides inflammatory mediators and recruits neutrophils. Enzymes released from neutrophils damage tissue. | TH1 cells secrete cytokines, which activate macrophages and cytotoxic T cells. |
| Examples of Hypersensitivity Reactions | Local and systemic anaphylaxis, seasonal hay fever, food allergies, and drug allergies. | Red blood cell destruction after transfusion with mismatched blood types or during hemolytic disease of the newborn. | Post-streptococcal glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. | Contact dermatitis, type 1 diabetes mellitus, and multiple sclerosis. |
Type I Hypersensitivity
Type 1 Hypersensitivity
The rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen.
It is commonly referred to as allergy.
Stage of Sensitization or Priming:
- There is entry of the antigen inside the body for the first time where it is captured by the antigen presenting cells and presented to the T cell which then differentiates into TH2 cell.
- The TH2 cell releases mediators like IL-3, IL-4, and IL-5. IL-4 causes activation of B cells.
- Activated B cells are responsible for release of IgE whereas IL-5 is responsible for activating the eosinophils.
- The secreted IgE then binds to mast cells in the circulation because of the presence of Fc receptors on the mast cells.
Subsequent Exposures
The subsequent exposure to the same antigen causes the features in two phases.
- In the initial phase (within minutes of antigen exposure), there is release of preformed mediators of the mast cell due to their degranulation causing the release of histamine, proteases, and chemotactic factors. Histamine causes vasodilation, bronchoconstriction, and increased permeability.
- Late phase (2-24 hours after antigen exposure) is marked by the release of secondary mediators from the mast cells that include prostaglandins, leukotrienes, cytokines, and platelet activating factor (PAF).
🔹 The clinical features are usually seen during the second time antigen exposure subsequent to sensitization or priming.
🔹 The cell critical in the pathogenesis is the mast cell whereas TH2 also plays an important role in the pathogenesis.
🔹 Histamine is responsible for the early clinical features because it is a preformed mediator. PAF is the major mediator of the late phase reaction.
🔹 IgE is the most important antibody to cause type 1 hypersensitivity reactions.
🔹 IL-4 is responsible for the secretion of IgE from the B cells and IL-5 is the most potent eosinophil activating cytokine known.
Examples of Type 1 Hypersensitivity
| Localized Hypersensitivity (Atopy) | Systemic Hypersensitivity (Anaphylaxis) |
|---|---|
|
Anaphylaxis due to:
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Type II Hypersensitivity
Type 2 Hypersensitivity (Cytotoxic)
Type II hypersensitivity is mediated by antibodies directed toward endogenous or exogenous specific antigens present on cell surfaces or extracellular matrix.
Immune reactions categorized as type II hypersensitivities, or cytotoxic hypersensitivities, are mediated by IgG and IgM antibodies binding to cell-surface antigens or matrix-associated antigens on basement membranes.
Mechanism
These antibodies can either:
- Activate complement, resulting in an inflammatory response and lysis of the targeted cells.
- Be involved in antibody-dependent cell-mediated cytotoxicity (ADCC) with cytotoxic T cells.
Effector Mechanisms for this Reaction:
- Opsonisation and Complement- and Fc Receptor-Mediated Phagocytosis.
- Complement and Fc Receptor-Mediated Inflammation.
- Antibody-mediated cellular dysfunction.
Examples of Type 2 Hypersensitivity Reaction
| Mechanism | Examples |
|---|---|
|
Opsonization and Complement- and Fc Receptor-Mediated Phagocytosis |
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Complement and Fc Receptor-Mediated Inflammation |
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Antibody-mediated cellular dysfunction |
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The Examples of Type 2 Hypersensitivity Reaction:
My Blood Group Is Rh Positive
- My – Myasthenia gravis
- Blood – Blood transfusion reactions
- Group – Goodpasture syndrome and Graves’ disease
- Is – Insulin-resistant diabetes, ITP
- R – Rheumatic fever
- h – Hyperacute graft rejection
- Positive – Pernicious anemia and Pemphigus vulgaris
Type III Hypersensitivity
Type 3 Hypersensitivity (Immune Complex Mediated)
In this type of hypersensitivity, the deposition of antigen-antibody complexes in tissues occurs, leading to disease.
Mediator: IgG, IgM
There are two types of reactions in this category:
- Arthus reaction (localized)
- Serum Sickness (generalized)
Pathogenesis
Phase I – Immune Complex Formation
- Formation of antibody occurs about 5 days after introduction of the antigen.
- The small or intermediate immune complexes are most pathogenic, whereas the large complexes are rapidly removed by the macrophages.
Phase II – Immune Complex Deposition
- In this phase, immune complexes get deposited in the glomeruli, joints, skin, heart, serosal surfaces, and blood vessels.
Phase III
- Immune complex-mediated inflammation appears 10 days after antigen administration.
- Results in the development of vasculitis, glomerulonephritis, and arthritis.
- Activates the intrinsic pathway of the coagulation system and microthrombi formation, leading to tissue ischemia and necrosis.
- The blood vessels show intense neutrophilic infiltration and necrotizing vasculitis, resulting in fibrinoid necrosis.
Examples of Type 3 Hypersensitivity
| Localized Hypersensitivity | Systemic Hypersensitivity |
|---|---|
| Arthus reaction | SLE |
| Farmer’s lung |
|
| Hypersensitivity pneumonitis | Post-streptococcal glomerulonephritis |
| Polyarteritis nodosa | Serum sickness |
Examples of Type 3 Hypersensitivity
The mnemonic for Type 3 Hypersensitivity is:
SHARP
- S: Serum sickness, Schick test, and Systemic Lupus Erythematosus (SLE)
- H: Hypersensitivity pneumonitis and Henoch-Schönlein Purpura
- A: Arthus reaction
- R: Reactive arthritis and Rheumatoid arthritis, Raji assay
- P: Polyarteritis nodosa (PAN) and Post-streptococcal glomerulonephritis (PSGN)
Type IV Hypersensitivity
Type 4 Hypersensitivity (Delayed Hypersensitivity)
The cell-mediated type of hypersensitivity is initiated by antigen-activated (sensitized) T lymphocytes.
It is a slow and prolonged response and includes:
- The delayed type hypersensitivity reactions mediated by CD4+ T cells
- Direct cell cytotoxicity mediated by CD8+ T cells
Pathogenesis
1. The delayed type hypersensitivity reactions mediated by CD4+ T cells
- Antigen is captured by the APCs and presented to the T cell, which then differentiates into TH1 cell.
- The sensitized TH1 cells enter the circulation and remain in the memory pool of the body.
- On re-exposure, cytokines like TNF-α, lymphotoxin, IFN-γ, IL-2, and IL-12 are released.
- The activated macrophages give rise to epithelioid cells, leading to the formation of a granuloma.
2. Pathogenesis of T cell mediated cytotoxicity (CD8+ T cells)
- Cytotoxic T lymphocytes (CTL) destroy antigen-bearing target cells, such as tumor cells, virus-infected cells, and allogenic tissue during graft rejection.
Examples of Type IV Hypersensitivity
| Examples | Examples |
|---|---|
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Type V Hypersensitivity: Not an Acceptable Classification
Type V Hypersensitivity
Type V hypersensitivity is not officially recognized as a separate category within the Gell and Coombs classification of hypersensitivity reactions. Instead, it is considered a subtype of Type II hypersensitivity.
Key Features of Type V Hypersensitivity
- Antibodies target specific receptors on cells instead of destroying them.
- Can lead to either stimulation (overactivity) or blocking (inhibition) of receptor function.
- It is commonly linked with autoimmune diseases.
Examples of Type V Hypersensitivity
- Graves’ disease: Autoantibodies stimulate the thyroid-stimulating hormone (TSH) receptor, causing hyperthyroidism.
- Myasthenia gravis: Autoantibodies block acetylcholine receptors at the neuromuscular junction, leading to muscle weakness.
Some sources incorrectly describe Type V as **antibody-dependent cell-mediated cytotoxicity (ADCC)**, but ADCC is a mechanism seen in Type II hypersensitivity.
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