Hypersensitivity and Allergy: Mechanisms, Types, and Clinical Implications

Hypersensitivity and Allergy

Introduction

Hypersensitivity refers to an exaggerated or inappropriate immune response to a harmless substance, termed an allergen. This immune response can result in tissue damage and clinical symptoms, distinguishing allergies from intolerances. Allergic diseases are increasingly prevalent, especially in industrialized nations, and pose significant economic and healthcare burdens.

• Definition: Allergy is when a harmless substance is perceived as a threat and triggers an immune response.

• Prevalence: Affects about one third of the population at some point; numbers are rising globally.

• Economic Impact: Allergies cost tens of billions of dollars annually in the USA.

Genetic and Environmental Factors

Both genetic predisposition and environmental exposures contribute to the development of allergies.

• Genetic Factors: Family history increases risk; random chance is 1 in 5, doubles with one parent, 60-80% with both.

• Genetic Predisposition: Atopy, MHC, Th2, and inflammatory molecules play roles.

• Environmental Factors: Exposure to allergens (proteins), processed foods, reduced nutrients (vitamin D, omega-3 fatty acids), pollution, and ingredients in cosmetics.

The Hygiene Hypothesis

This hypothesis suggests that reduced exposure to microbes and parasites in infancy, due to cleaner lifestyles, vaccines, and antibiotics, may increase allergy risk. Urban living is associated with higher allergy rates compared to rural environments.

Common Allergens and Symptoms

• Common Allergens: Pollen, dust mite proteins, moulds, foods (peanuts, tree nuts, milk, eggs), animal dander, insect stings, medicines.

• Symptoms: Sneezing, wheezing, sinus pain, runny nose, coughing, hives, swelling, itchy eyes/ears/lips/throat/mouth, shortness of breath, vomiting, diarrhoea, increased nasal/airway secretions.

Anaphylaxis

Anaphylaxis is a severe, multi-system allergic reaction that can be life-threatening. Speed of onset depends on route of exposure (minutes for IV, hours for ingestion).

• Skin/Mucosa: Urticaria, swelling, mucus secretion.

• Respiratory: Breathlessness, wheezing, stridor, cough.

• Cardiovascular: Lightheadedness, tachycardia, coronary artery spasm.

• Gastrointestinal: Abdominal pain, diarrhoea, vomiting.

• Other: Headaches, anxiety.

Diagnosis of Allergy

• Challenges: Superficial signs may not be specific; detailed investigations and medical tests are required.

• Specialist Assessment: Immunologists may use symptom diaries and targeted questions to identify triggers.

Inflammation in Allergy

Inflammation is central to allergic responses. Components and mechanisms of inflammation are targets for both established and experimental treatments.

Types of Hypersensitivity

Type I Hypersensitivity (Immediate/Allergic/Atopic)

Type I hypersensitivity is mediated by IgE antibodies and involves mast cells and basophils. It is responsible for most common allergic diseases, ranging from mild symptoms to anaphylactic shock.

• Priming Phase: Allergen exposure leads to activation of dendritic cells, Th2 differentiation, and IgE production.

• Effector Phase: Subsequent allergen exposure causes IgE cross-linking on mast cells/basophils, leading to degranulation and release of inflammatory mediators.

Mechanism of IgE-Mediated Response

• Allergen induces memory B cells and plasma cells.

• Th2 cytokines (IL-4, IL-13) drive IgE production.

• IgE binds Fc receptors (FcεRI) on mast cells and basophils.

• Second exposure triggers degranulation via cross-linking, intracellular Ca2+ increase, and protein kinase C activation.

Normal Function of IgE

• IgE is important in defense against helminths, recruiting eosinophils for parasite killing.

Effector Cells

• Mast Cells: Located in skin/mucosa, contain vasoactive amines (histamine), serine proteases, and produce leukotrienes, prostaglandins, cytokines, and chemokines.

• Eosinophils: Present in blood/mucosa, effective against parasites, recruited by IL-5.

• Basophils: Similar to mast cells, mainly in blood.

Clinical Manifestations

Syndrome	Common Allergens	Route of Entry	Response
Systemic anaphylaxis	Drugs, serum, venoms, peanuts	Intravenous (direct into blood)	Edema, vascular collapse, respiratory failure
Acute urticaria (local)	Animal hair, insect bites	Through skin	Wheal and flare
Seasonal rhinitis (hay fever)	Pollen	Inhalation	Edema of nasal mucosa, sneezing
Asthma	Dander, pollen, dust mite feces	Inhalation	Bronchial constriction, increased mucus
Food allergy	Shellfish, milk, eggs, fish, wheat	Oral	Vomiting, diarrhea, pruritus, anaphylaxis

Allergic Asthma

• Characterized by airway inflammation, mucus hypersecretion, smooth muscle hypertrophy, and tissue remodeling.

• Late phase involves additional mediators (IL-4, IL-5, IL-6, TNFα, ECF, PAF) and recruitment of inflammatory cells.

Immune Modulators and Treatments

Drug	Action
Antihistamines	Block H1/H2 receptors on target cells
Cromolyn sodium	Blocks Ca2+ influx into mast cells
Epinephrine	Promotes cAMP, counteracts mediator effects
Corticosteroids	Suppress inflammation
Leukotriene antagonists	Block leukotriene effects

Immunotherapy

• Allergen-specific immunotherapy (AIT): Induces immune tolerance via small, increasing doses of allergen.

• Desensitisation: Reduces symptoms, less medication needed; used for severe, persistent allergies.

• Omalizumab: Monoclonal antibody therapy for severe allergic asthma, blocks IgE binding to FcεRI.

Type II Hypersensitivity (Antibody-Mediated)

Type II hypersensitivity involves antibody-mediated cytotoxicity, where antibodies target antigens on cell surfaces, leading to cell destruction or altered function.

• Mechanisms: Opsonization, complement activation, phagocytosis, and cell lysis.

• Examples: Penicillin-induced hemolytic anemia (extrinsic antigen), hemolytic disease of the newborn (Rh incompatibility).

Type III Hypersensitivity (Immune Complex-Mediated)

Type III hypersensitivity is caused by immune complexes formed between antibodies and soluble antigens, which deposit in tissues and activate complement, leading to inflammation and tissue damage.

• Not tissue specific: Can affect multiple organs, commonly kidneys and joints.

• Examples: Serum sickness (extrinsic), systemic lupus erythematosus (intrinsic).

Type IV Hypersensitivity (T Cell-Mediated)

Type IV hypersensitivity is mediated by T cells rather than antibodies. It involves delayed-type reactions and is responsible for contact dermatitis and other cell-mediated immune responses.

• Examples: Reactions to formaldehyde, nickel, poison oak, and poison ivy.

Summary Table: Types of Hypersensitivity

Type	Mechanism	Examples
I (Immediate)	IgE, mast cells, basophils	Allergy, anaphylaxis, asthma
II (Antibody-mediated)	IgG/IgM, complement, phagocytes	Hemolytic anemia, Rh disease
III (Immune complex)	Immune complexes, complement	Serum sickness, SLE
IV (T cell-mediated)	T cells, macrophages	Contact dermatitis

Conclusion

Hypersensitivity reactions represent abnormal immune responses to harmless antigens, leading to a spectrum of clinical manifestations. Understanding the mechanisms, types, and treatments is essential for effective diagnosis and management in clinical microbiology and immunology.