Comprehensive Study Guide on Hypersensitivity Types I-IV

Overview of Hypersensitivity and Immunopathology

This lecture introduces the concept of hypersensitivity, which represents immune responses capable of causing injury and disease if not tightly controlled. While previous lectures explored the power and formation of immune responses, hypersensitivity focuses on inappropriate responses that deviate from beneficial protection.

Core Definition of Hypersensitivity

Hypersensitivity is defined as an undesirable immune response produced by an otherwise "normal and happy and fully functioning immune system." These reactions can occur in response to normal foreign antigens (which should be reacted to but become damaging when uncontrolled) or self-antigens (resulting in autoimmune conditions). Essential characteristics include:

• Host Sensitization: In most cases, a "pre-sensitized host" is required for a hypersensitivity reaction to occur.

• Classification: Reactions are categorized into four groups (Type I through Type IV) based on the mechanisms involved and the time they take to manifest.

Type I Hypersensitivity: Immediate Hypersensitivity

Type I is also known as immediate hypersensitivity or the classic allergic response. It is mediated by $IgE$ antibodies and involves mast cells, basophils, and eosinophils.

Terminology and Statistics

• Atopy (or Atopy): A clinical term for allergy; they are synonymous.

• Allergen: Any substance that triggers an allergic reaction.

• Prevalence: Allergic diseases are highly frequent in the community and can be triggered by ingestion (food), inhalation, physical contact, stings, or medications.

The Hygiene Hypothesis

This hypothesis explains the increasing prevalence of allergies in Western countries. It suggests an inverse relationship between the incidence of parasitic disease (helminths and protozoans) and the prevalence of allergy:

• Mechanism: The $IgE$-mediated anti-parasite response is no longer "educated" because parasites are less common due to sanitized food/water, personal hygiene, and medicine.

• Outcome: Without a parasitic target, this arm of the immune system inappropriately targets harmless allergens.

Mechanisms of Type I Reactions

Any allergic reaction requires a sensitization process upon the first exposure. Subsequent exposures trigger clinical symptoms.

The Sensitization Process

1. First Exposure: An allergen (e.g., respiratory) enters the airway and is taken up by local Antigen Presenting Cells (APCs).

2. T-cell Polarization: Peptides are presented to T-cells, which inappropriately differentiate into $Th2$ cells.

3. $IL-4$ Release: $Th2$ cells produce $IL-4$, which signals B-cells to switch to $IgE$ production.

4. Mast Cell Priming: $IgE$ binds to $Fc\epsilon$ receptors on mast cells. These mast cells are now "primed" for later encounters.

Reaction Phases

• Immediate Response (Minutes): Cross-linking of $IgE$ on mast cells leads to degranulation, releasing pre-formed mediators like histamines and proteases. This causes sneezing, coughing, itching, and reddened skin.

• Late-Phase Reaction (Minutes to Hours): Release of lipid mediators (prostaglandins and leukotrienes) causes vasorelaxation and vasodilation, resulting in fluid influx and swelling.

• Delayed Late-Phase (Hours to Days): Transcriptional activation of cytokine genes ($IL-4$, $IL-13$) perpetuates inflammation.

Clinical Manifestations and Diagnosis of Type I

Symptoms

Allery can affect multiple body systems:

• Skin/Mucous Membranes: Eczema, hives, itching, swelling.

• Respiratory: Hay fever, itchy eyes, earaches.

• Digestive: Diarrhea, constipation, vomiting, "gurping."

• Nervous System: Migraines (e.g., from smelling flowers), headaches, hyperactivity, lethargy.

• Anaphylaxis: The most severe form involves multiple organ systems. It leads to circulatory collapse from a drop in blood pressure (hypotension) and shock. It is treated with Adrenaline (Epinephrine).

Diagnostic Tools

• Skin Prick Test: A positive reaction is indicated by the development of a "wheal" on the skin within approximately $20$ minutes.

• Blood Tests: Measuring total $IgE$ can be misleading as levels do not always correlate with symptom severity.

• MCT (Mast Cell Tryptase): An enzyme measured in blood following an allergic reaction.

• RAST/CAP RAST/ImmunoCAP: Tests designed to measure antigen-specific $IgE$.

Asthma: Chronic Allergic Airway Inflammation

Asthma is a chronic inflammatory condition involving mast cells, eosinophils, and T-lymphocytes. Symptoms include recurrent wheezing and breathlessness due to airflow limitation.

Airway Remodeling

Chronic, uncontrolled inflammation leads to permanent structural changes:

• Generation of thick layers of smooth muscle cells.

• Infiltration of inflammatory cells (T-cells) into interstitial spaces.

• Formation of sub-epithelial scar tissue (fibrosis).

• Excessive mucus production that can block the airway completely.

Type II Hypersensitivity: Antibody-Mediated Disease

Type II reactions are mediated by $IgG$ (and sometimes $IgM$) antibodies directed against cell surface or tissue antigens.

Mechanisms of Injury

• Complement/Fc Mediated Inflammation: Antibodies bind to tissues, activating complement and recruiting neutrophils.

• Opsonization and Phagocytosis: Cells are marked for destruction by macrophages.

• ADCC: Natural Killer (NK) cells target the antibody-coated cells.

• Abnormal Physiologic Responses: Antibodies mimic hormones or block receptors without causing direct tissue injury (e.g., activating or switching off cellular pathways).

Examples

• Penicillin Allergy: Penicillin binds to cell surface receptors (acting as a hapten). B-cells create antibodies against the penicillin-receptor complex, leading to hemolysis or tissue damage.

• Graves' Disease: Antibodies target the Thyroid Stimulating Hormone (TSH) receptor, over-activating the thyroid and causing excess hormone production.

• Myasthenia Gravis: Antibodies block acetylcholine receptors at the neuromuscular junction, leading to muscle activation problems.

Type III Hypersensitivity: Immune Complex-Mediated Disease

This occurs when large complexes of antigen and antibody ($IgG$) are not cleared efficiently by the spleen and liver.

Pathology

• Deposition: Complexes deposit in blood vessels, joints (knees, ankles, hands), and lungs.

• Inflammation: The $Fc$ regions of the deposited antibodies activate complement and neutrophils, which release proteases and reactive oxygen species (ROS).

• Consequences: This results in vasculitis (blood vessel inflammation), hemorrhage, or thrombosis (clots).

Examples

• Systemic Lupus Erythematosus (SLE).

• Polyarteritis nodosa.

• Serum Sickness: Occurs when high concentrations of foreign sera (e.g., horse serum anti-venom) result in widespread complex formation.

Type IV Hypersensitivity: Cell-Mediated/Delayed Hypersensitivity

Type IV is distinct because it is not mediated by antibodies. It is driven by inappropriately activated T-cells, primarily $CD4+$ ($Th1$) and sometimes $CD8+$.

Characteristics

• Delayed Timing: Called "delayed" because cell-mediated responses take longer to develop than antibody-mediated ones.

• Localization: Responses tend to be highly localized to the area of antigen concentration.

Examples and Mechanisms

• Contact Dermatitis (e.g., Nickel Allergy): Nickel ions are taken up by DCs and presented to T-cells. T-cells proliferate and home back to the site of the piercing/contact, causing localized tissue damage.

• Graft Rejection: T-cells attack foreign tissue.

• Autoimmune Diseases: Type 1 Diabetes (targeting beta cells in the pancreas), Multiple Sclerosis (targeting myelin proteins in the CNS), Crohn's disease, and Rheumatoid Arthritis.

Epitope Spreading

In chronic Type IV reactions, diseases amplify over time through "epitope spreading." As initial T-cell responses cause tissue damage, internal antigens (which were previously hidden or tolerized) are revealed. These "new" antigens are picked up by APCs, stimulating additional T-cell populations and exacerbating the inflammatory response.