Hypersensitivity Reactions-define, Classify,and discuss in detail ; Type 1Hypersensitivity Reaction Discuss and examples; 2nd yr mbbs pathology answer in detail refer robbins
Reading File
Finding Sources
Finding Sources
Reading File
Finding Sources
Reading File
Reading File
Reading File
I now have enough content from Robbins to construct a comprehensive, detailed answer. Let me compile everything into a well-structured response.
Hypersensitivity Reactions
Based on Robbins & Kumar Basic Pathology (Robbins Pathology), 10th Edition
DEFINITION
Hypersensitivity refers to injurious immune reactions that cause tissue damage in the host. The term originates from the concept that persons who have already mounted an immune response to an antigen are "sensitized" to it, so that subsequent pathological or excessive reactions represent a hypersensitive state.
Normally, the immune system is tightly regulated to eradicate infecting organisms without serious injury to host tissues. However, immune responses may be:
- Inadequately controlled
- Directed against normally harmless antigens (e.g., pollens, food)
- Inappropriately targeted to host tissues (autoimmunity)
In such cases, the normally beneficial immune response becomes the cause of disease.
"Immune responses that normally are protective are also capable of causing tissue injury." - Robbins & Kumar Basic Pathology, p. 141
CAUSES OF HYPERSENSITIVITY REACTIONS
Pathological immune responses may be directed against three categories of antigens:
1. Reactions Against Self (Autoimmunity)
Normally the immune system does not react against its own antigens - this is called self-tolerance. When self-tolerance fails, reactions against one's own cells and tissues arise, called autoimmunity, causing autoimmune diseases (e.g., SLE, rheumatoid arthritis).
2. Reactions Against Microbes
- T-cell responses against persistent microbes (e.g., Mycobacterium tuberculosis) may lead to severe inflammation and granuloma formation
- Antibodies against microbial antigens may form immune complexes that deposit in tissues (e.g., post-infectious glomerulonephritis)
- Antibodies or T cells reactive with a microbe may cross-react with host tissue (e.g., rheumatic heart disease after streptococcal infection)
- SARS-CoV-2 can induce systemic inflammatory reactions causing significant morbidity in COVID-19
3. Reactions Against Environmental Antigens (Allergy)
In higher-income countries, 20% or more of the population is allergic to common environmental substances (pollens, animal dander, dust mites, drugs). These individuals are predisposed to making unusual immune responses to noninfectious, typically harmless antigens.
In all these conditions, tissue injury is caused by antibodies, effector T lymphocytes, macrophages, and eosinophils - the same mechanisms that normally eliminate pathogens. Because the stimuli (self-antigens, persistent microbes, environmental antigens) are difficult to eliminate, hypersensitivity diseases tend to be chronic, debilitating, and therapeutic challenges.
CLASSIFICATION OF HYPERSENSITIVITY REACTIONS
Hypersensitivity reactions are classified into four types based on the principal immune mechanism responsible for injury. Three are variations of antibody-mediated injury; one is T-cell mediated.
| Type | Name | Mechanism | Histopathology | Examples |
|---|---|---|---|---|
| I | Immediate (IgE-mediated) | Th2 cells, IgE antibodies, mast cell degranulation | Vascular dilation, edema, smooth muscle spasm, mucus secretion, tissue infiltration by eosinophils | Anaphylaxis, allergic asthma, hay fever, food allergy, urticaria |
| II | Antibody-mediated (IgG/IgM against cell/tissue antigens) | IgG/IgM bind to cell-surface or matrix antigens → phagocytosis, lysis, inflammation, abnormal physiologic responses | Phagocytosis and lysis of cells; inflammation; cellular dysfunction | Autoimmune hemolytic anemia, Goodpasture syndrome, myasthenia gravis, Graves disease |
| III | Immune complex-mediated | Antigen-antibody complexes deposit in vessels and tissues → complement activation → neutrophil recruitment | Neutrophilic infiltration, necrosis (vasculitis, glomerulonephritis, arthritis) | SLE, post-streptococcal glomerulonephritis, serum sickness, Arthus reaction |
| IV | T-cell mediated (Delayed-type) | CD4+ Th1/Th17 cells secrete cytokines → inflammation + macrophage/neutrophil activation; CD8+ CTLs kill host cells | Perivascular lymphocytic infiltration, macrophage activation, granuloma formation | Contact dermatitis, tuberculosis, multiple sclerosis, type 1 diabetes, rheumatoid arthritis |
(Table 5.2, Robbins & Kumar Basic Pathology)
TYPE I HYPERSENSITIVITY (IMMEDIATE HYPERSENSITIVITY)
DEFINITION
Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of an antigen with IgE antibody bound to the surface of mast cells (and basophils).
It is initiated by entry of an antigen called an allergen - because it triggers allergy. Many allergens are environmental substances against which some individuals are predisposed to mount Th2 and IgE responses.
The severity ranges from:
- Mild - seasonal rhinitis, hay fever
- Severe - bronchial asthma
- Fatal - anaphylaxis
SEQUENCE OF EVENTS (Pathogenesis)
Type I hypersensitivity follows a stereotypic sequence of cellular responses (Robbins Fig. 5.10):
STEP 1: Sensitization Phase - Activation of Th2 Cells and Production of IgE
First exposure to allergen:
- Only a subset of individuals exposed to environmental antigens make strong Th2 and IgE responses (genetically predisposed = atopic individuals)
- Th2 cells are activated and secrete key cytokines:
- IL-4 and IL-13 - stimulate allergen-specific B cells to undergo heavy-chain class switching to IgE
- IL-5 - activates eosinophils recruited to the reaction
- IL-13 - stimulates mucus secretion by epithelial cells
STEP 2: Sensitization of Mast Cells
- Produced IgE antibodies bind to high-affinity Fc receptors (FcεRI) on the surface of mast cells and basophils
- Mast cells are now "armed" (sensitized) with antigen-specific IgE
- At this stage, the individual is sensitized but has no symptoms yet
STEP 3: Activation (Re-exposure / Elicitation Phase)
Upon second (or subsequent) exposure to the SAME allergen:
- The allergen binds to and cross-links adjacent IgE molecules on the mast cell surface
- Cross-linking of FcεRI triggers mast cell activation and degranulation
STEP 4: Mast Cell Degranulation and Mediator Release
Mast cells release mediators in two waves:
A. PRIMARY (PREFORMED) MEDIATORS - Released immediately from granules
| Mediator | Actions |
|---|---|
| Histamine | Vasodilation, increased vascular permeability, bronchoconstriction, increased mucus secretion, itching |
| Tryptase | Marker of mast cell activation; cleaves proteins |
| Heparin | Anticoagulant; binds growth factors |
| Chondroitin sulfate | Structural |
| Eosinophil chemotactic factor | Recruits eosinophils |
| Neutrophil chemotactic factor | Recruits neutrophils |
B. SECONDARY (NEWLY SYNTHESIZED) MEDIATORS - Generated from membrane phospholipids
| Mediator | Source | Actions |
|---|---|---|
| Leukotrienes (LTC4, LTD4, LTE4) | Arachidonic acid via lipoxygenase | Most potent bronchoconstrictors known; increased vascular permeability; mucus hypersecretion |
| Leukotriene B4 (LTB4) | Arachidonic acid | Chemoattractant for neutrophils and eosinophils |
| Prostaglandin D2 (PGD2) | Arachidonic acid via COX | Intense bronchoconstriction, vasodilation |
| Platelet-activating factor (PAF) | Membrane phospholipids | Bronchoconstriction, platelet aggregation, vasodilation |
| Cytokines (TNF, IL-4, IL-5, IL-13) | Mast cells | Recruit and activate inflammatory cells; sustain Th2 response |
TWO PHASES OF TYPE I HYPERSENSITIVITY
Immediate Phase (0-30 minutes)
- Caused by preformed mediators (mainly histamine) released within seconds to minutes
- Features: vasodilation, increased vascular permeability, smooth muscle spasm
- Peak at 5-30 minutes, resolves within 60 minutes
- Clinical: flushing, itching, urticaria, bronchoconstriction
Late Phase Reaction (2-24 hours later)
- Driven by cytokines (IL-4, IL-5, IL-13, TNF) released by mast cells
- Characterized by recruitment of eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells
- Sustained tissue damage and inflammation
- Clinical: prolonged bronchoconstriction in asthma, prolonged swelling
The late-phase reaction is largely responsible for the chronic symptoms in allergic asthma.
ROLE OF EOSINOPHILS
IL-5 (from Th2 cells and mast cells) is a powerful eosinophil activator. Eosinophils:
- Are recruited to sites of Type I hypersensitivity
- Release major basic protein (MBP) and eosinophil cationic protein (ECP) - directly toxic to epithelial cells
- Produce leukotrienes and PAF, amplifying the reaction
- Cause much of the tissue damage in chronic allergic inflammation (e.g., airway remodeling in asthma)
DEVELOPMENT OF ALLERGIES (Atopy)
Not all individuals develop allergic reactions. The predisposition to mount Th2 and IgE responses is called atopy and is determined by:
- Genetic factors: Polygenic inheritance; HLA-associated; genes encoding IL-4, IL-5, IL-13 (chromosome 5q)
- Atopic triad: Family history of asthma + eczema (atopic dermatitis) + allergic rhinitis in the same individual
- Environment: The "hygiene hypothesis" proposes that reduced childhood exposure to infections shifts the immune balance toward Th2 responses, increasing atopy in developed countries
MAST CELLS - Key Effector Cell
Mast cells are found in connective tissues throughout the body, especially near blood vessels, nerves, and beneath epithelial surfaces (skin, respiratory tract, GI tract) - explaining the distribution of allergic symptoms.
Two types:
- Mucosal mast cells - found in lung and intestinal mucosa; tryptase+
- Connective tissue mast cells - found in skin and peritoneum; tryptase+ and chymase+
Basophils circulate in blood; they express FcεRI and behave similarly to mast cells.
CLINICAL AND PATHOLOGIC MANIFESTATIONS
1. Systemic Anaphylaxis (Most Severe - Life-threatening)
- Trigger: Bee venom, drugs (penicillin), foods (peanuts, shellfish), latex
- Mechanism: Massive systemic mast cell/basophil degranulation
- Features:
- Hypotension (distributive shock from vasodilation)
- Bronchospasm, laryngeal edema (airway obstruction)
- Urticaria, angioedema
- GI cramping, vomiting
- Treatment: Epinephrine (adrenaline) immediately - counteracts vasodilation, bronchospasm
2. Localized Anaphylaxis (Atopic Allergy)
| Disease | Allergen | Mechanism |
|---|---|---|
| Hay Fever (Allergic Rhinitis) | Pollens, dust mites, animal dander | IgE on nasal mast cells → histamine release → rhinorrhea, sneezing, nasal congestion |
| Allergic Asthma | Inhaled allergens | IgE on bronchial mast cells → bronchoconstriction, mucus hypersecretion, late-phase eosinophilic inflammation → airway remodeling |
| Atopic Dermatitis (Eczema) | Environmental antigens, food | Mast cell activation in skin → pruritus, erythema, vesicles |
| Urticaria (Hives) | Foods, drugs, insect stings | Cutaneous mast cell degranulation → wheal and flare |
| Angioedema | Various | Deeper dermal and submucosal swelling |
| Food Allergy | Peanuts, shellfish, milk, eggs | GI mast cells + systemic → vomiting, diarrhea, urticaria, anaphylaxis |
| Allergic Conjunctivitis | Pollens | IgE-mediated mast cell degranulation in conjunctiva → itching, lacrimation |
MORPHOLOGY (Histopathology)
- Vascular dilation and increased permeability (edema, wheal)
- Smooth muscle spasm (bronchospasm, GI cramping)
- Increased mucus secretion
- Tissue infiltration by eosinophils (key hallmark in allergic asthma - Charcot-Leyden crystals from eosinophil breakdown in sputum)
- In chronic asthma: airway remodeling - subepithelial fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia
DIAGNOSIS
- Skin prick test: Wheal and flare within 15-20 minutes = positive (IgE mediated)
- Serum total IgE: Elevated in atopic individuals
- Specific IgE (RAST/ImmunoCAP): Measures allergen-specific IgE in serum
- Serum tryptase: Elevated after anaphylaxis (confirms mast cell activation)
- Eosinophilia: On peripheral blood smear in chronic atopic disease
TREATMENT PRINCIPLES
| Drug | Mechanism | Use |
|---|---|---|
| Epinephrine | α1-agonist (vasoconstriction), β2-agonist (bronchodilation) | Anaphylaxis - first line |
| Antihistamines (H1 blockers) | Block histamine receptors | Urticaria, rhinitis |
| Corticosteroids | Reduce cytokine production, eosinophil recruitment | Asthma, severe allergic reactions |
| Cromolyn sodium | Stabilizes mast cell membranes | Prophylaxis in asthma |
| Leukotriene antagonists (Montelukast) | Block LTC4/LTD4 receptors | Asthma, allergic rhinitis |
| Anti-IgE (Omalizumab) | Binds free IgE, reduces FcεRI expression | Severe allergic asthma |
| Allergen immunotherapy (Desensitization) | Shift from Th2 to Th1, induce regulatory T cells, produce IgG blocking antibodies | Hay fever, insect venom allergy |
SUMMARY FLOWCHART OF TYPE I HYPERSENSITIVITY
FIRST EXPOSURE (Sensitization)
Allergen → APCs → Th2 cells
Th2 → IL-4/IL-13 → B cells → IgE production
IgE → binds FcεRI on MAST CELLS (no symptoms yet)
SECOND EXPOSURE (Elicitation)
Allergen cross-links IgE on mast cells
↓
MAST CELL DEGRANULATION
↓
Preformed mediators (HISTAMINE) → Immediate phase (minutes)
New mediators (LEUKOTRIENES, PGD2) → Sustained bronchoconstriction
Cytokines (IL-4, IL-5, TNF) → Late-phase reaction (hours)
↓
CLINICAL: Anaphylaxis / Asthma / Hay fever / Urticaria / Food allergy
Reference: Robbins & Kumar Basic Pathology, 10th Edition, Chapter 5: "Diseases of the Immune System" - Hypersensitivity: Immunologically Mediated Tissue Injury (pp. 141-149)
This is a shared conversation. Sign in to Orris to start your own chat.