Lecture 18 - Hypersensitivity Part 1

Hypersensitivity

is when the immune system has an exaggerated response to an antigen (something it thinks is harmful). This overreaction can cause anything from mild tissue damage to even death.

How many types of Hypersensitivity are there?

4 types

Type I Hypersensitivity

• Allergy: IgE-mediated

• Involves Mast cells, basophils, eosinophils

• Degranulation; inflammatory effects

  • These cells degranulate → release histamine & inflammatory mediators.

Type II Hypersensitivity

• Involves IgG or IgM antibodies; Antibodies bind to antigens on host cells (your own cells)

This causes the cells to be:

• Antibody-mediated cytotoxicity

  • Antibodies cause cell death/damage

• Complement-mediated death or cell dysfunction

  • Antibodies trigger the complement system → cell pops/dies.

Type III Hypersensitivity

• IgG or IgM antibodies bind to Soluble Antigen (Antigens that float freely in blood or body fluids)

• These form Immune Complexes (Antigen-Antibody clumps)

• When too many complexes form, the Immune complexes settle (deposit) in tissues

• Complement is then activated

• Results in Inflammatory response: tissue damage

Type IV Hypersensitivity

• T-cell mediated

  • (Not antibody-based — this is the only hypersensitivity type that’s purely cellular.)

• Often Th1 activating Macrophages; Sometimes it may be Cytotoxic T Cells (Tc)

  • Inflammatory response

  • Symptoms manifest in days

    • “Delayed-type Hypersensitivity”

      • That’s why its called DTH because it takes a few days to develop

Type I Hypersensitivity - Allergies

• Inducing antigens = Allergens

  • “Allergens” are the things that trigger the allergic response

Type I Hypersensitivity - Allergy Symptoms

• Mild: Hay Fever, Hives, Allergic Asthma, GI disturbances

• Deadly: Anaphylaxis

• Onset: Minutes

Type I Hypersensitivity reactions are

immediate allergic reactions caused by IgE antibodies

Type I Hypersensitivity - Causes

Caused by the inordinate IgE response to allergens

• Caused by a person making too much IgE against harmless antigens

• Genetics and Environment

Type I Hypersensitivity - Genetic Factors

Some people are genetically prone to allergies

• Atopy - inherited predispositions to develop allergies

  • Runs in families

Genes involved:

• HLA Alleles

• Th2 Cytokines

• Epithelial lining integrity

  • Leaky skin/mucosa lets allergens enter more easily (like eczema patients)

Type I Hypersensitivity - Environmental Factors

• Protection (Reduce allergy risk)

  • Early infections - train the immune system to be balanced

  • Daycare/Siblings - more germs early = stronger immune regulation

  • Farms - high microbial exposure = fewer allergies (hygiene hypothesis)

• Predisposition:

  • Repeated antibiotics early - disrupts microbiome = less immune training

  • RSV infections - linked to asthma later

Sensitization Phase

first exposure to allergen, this is when the immune system becomes “primed” to react later and no symptoms have happened yet

Type I Hypersensitivity - Sensitization

• Step 1: Antigen-presenting cells (APCs) in skin/mucosa process and present allergen

  • Langerhans cells, a type of DC subset in skin

• Step 2: APCs present the allergen to T cells

  • They travel to lymph nodes and present allergen peptides to naive T cells

  • The T cells differentiate into Th2 cells (this is characteristic of allergies)

• Step 3: Th2 cytokines drive IgE production

  • Th2 cells release IL-4 and IL-13

  • Results in Class-switching to IgE production

• Step 4: IgE bind to Fc receptors

  • FcεRI = high-affinity IgE Fc receptor

  • Found in large numbers on mast cells, basophils

  • Can bind low concentrations of IgE

  • Binding extends half-life of IgE

• Fab region free to bind allergen (secondary response)

• Step 5: Mast cells which are the main effector cells are found in the mucosal tissues and capillaries, which are packed with histamine-containing granules are the main cells that cause allergic reactions once IgE is bound

Activation Phase

subsequent exposure to the same allergen, this is when symptoms actually occur

Type I Hypersensitivity - Activation

• Step 1: IgE cross-linking with allergen

  • Allergen binds to 2 IgE molecules at once (this is called cross-linking)

  • Cross-linking is the trigger for mast cell activation

• Step 2: Rapid mast cell degranulation

  • Mast cells release histamine = “Primary Mediator”

  • Other primary mediators:

    • Eosinophil, Neutrophil chemotactic factors

    • Proteases, Heparin

• Step 3: Different effects at respective sites

• Histamine causes:

  • Skin (Hives, swelling, itching), GI (vomiting, diarrhea, cramps), Respiratory (wheezing)

• Effects typically last 30-60 minutes

Late-phase Response

after the immediate reaction (histamine, minutes) the body has a second wave of inflammation. This response is stronger, last longer, and causes tissue damage.

Type I Hypersensitivity - Late-phase Response

• Step 1: Secondary mediators - these are newly made chemicals (not stored in granules_

  • Prostaglandins, leukotrienes, cytokines

• Step 2: Effects: 6-8 hours later

  • After the initial histamine response ends, the body ramps up a second wave of inflammation

• Step 3: Potent cell response

  • Brings many inflammatory cells into the tissue

• Infiltration of affected tissue

  • Eosinophils, Neutrophils, Mast cells, Basophils

  • Th2 cells, Macrophages

    • These cells travel into the affected tissue and make the inflammation stronger

• Step 4: Results in cells prolong response = tissue damage

Type I hypersensitivity- Manifestations

affected by Route (inhaled, ingested, injected, skin contact), Dose, Type of allergen

Rhinitis (“Hay Fever”)

• Route: Inhaled allergens in eyes

  • Examples: pollen, dust mites, pet dander

• Sneezing, runny nose, congestion, etc.

• Itchy, water eyes

Allergic Asthma

• Route: Inhaled allergens reaching the lower respiratory tract

• Recurrent episodes of obstruction of airflow

  • Bronchial smooth muscle constriction

  • Edema (swelling), mucus

• Breathlessness, cough/sputum

Food Allergy

• Route: ingested allergens

  • Examples: peanuts, shellfish, eggs

• Cramping vomiting, diarrhea

• If the allergen enters the bloodstream:

  • Skin reactions (hives)

  • Lungs (respiratory reactions)

  • Possible Anaphylaxis

Skin Manifestations

• Hives: “wheal-and-flare” reaction

  • Itching, redness, swelling

    • Caused by Vasodilation (widening of blood vessels)

• Mast cells are abundant in the skin and symptoms appear within minutes

• Angioedma

  • Same mechanism as hives, but in deeper dermal layers

  • Swelling of the lips, eyelids, hands, etc.

• Atopic eczema

  • Red, thickened, scaly skin

Anaphylaxis

• Systemic, multi-organ reaction, can be deadly

• May involve:

  • Airway constriction

    • Bronchospasm, laryngeal edema (throat swelling)

  • Skin, GI effects (Hives, vomiting/diarrhea)

  • Severe drop in blood pressure (causes anaphylactic shock)

Type I Hypersensitivity - Treatments

avoiding allergens, using medications like antihistamines and bronchodilators, treating anaphylaxis with epinephrine, blocking IgE with monoclonal antibodies, and building long-term tolerance with allergy immunotherapy

Drugs/Medications

depends on severity and type of reaction

• Hay fever, hives, rhinitis

  • Antihistamines and decongestants

• Asthma

  • Antihistamines and bronchodilators

  • Severe: leukotriene blockers, corticosteriords

• Anaphylaxis (life-threatening)

  • Epinephrine - rapid and powerful vasoconstrictor

Monoclonal Antibodies vs IgE (Biological Therapy)

• Binds free IgE in the blood

• Prevents/blocks IgE from binding to FcεRI

  • Results in fewer activated mast cells = fewer reactions

• Has been used for severe asthma

Allergy Immunotherapy (“Allergy Shots”)

• Gradually increasing doses of allergen over time

  • Build up tolerance

  • Months to years

• Effects: Th1, Treg cell response

  • Th1 response counters Th2 response

  • Treg response down-regulates Th2 response

  • IgG (from Th1 response) neutralizes allergen before allergen binds to IgE

• Has been used for asthma, rhinitis

Type I hypersensitivity- Testing

Direct skin testing and Immunoassays

Type I Hypersensitivity- Direct Skin Testing

• Small dose of allergen into skin

• Rapid results; large panel (tests many allergens at once)

• Results in 15-20 minutes

  • Positive = Wheal-and-flare (Raise bump from swelling and surrounding redness)

Direct Skin Testing - False Negatives

• Test shows no reaction even though the person is allergic

• Causes: Taking antihistamines, improper reagent storage/technique

Direct Skin Testing - False Positives

• Test shows a reaction even though the person is NOT allergic

• Reaction to other components of injections, trauma

Type I Hypersensitivity- Immunoassays (e.g., ELISA)

• Assess total IgE levels

• Assess allergen-specific IgE levels

  • measures IgE directed against a specific allergen and helps determine exact trigegrs

Type II Hypersensitivity

occurs when IgG or IgM antibodies bind to antigens on the host cell surface (surface of the body’s own cells) causing those cells to be damaged or destroyed

• Antibody-mediated cytotoxicity

Type II Hypersensitivity - Outcomes

• 1. Cell death via Classical complement pathway - MAC

  • IgG or IgM activates complement

  • Complement cascade leads to the Membrane Attack Complex (MAC)

  • MAC forms pores = cell lysis and death

• 2. Opsonization/phagocytosis

  • Ig, Complement binding

  • Receptors to each phagocytes

  • Phagocytes bind → engulf and destroy the opsonized cells.

  • Antibody-dependent cell-mediated cytotoxicity

    • When IgG coats a target cell, NK cells bind and release toxic granules → cell death.

  • 3. Inhibition or increase of cell function

    • Some autoimmune diseases

Transfusion Reactions

occur when a patient receives blood with RBC antigens that their antibodies recognize as foreign. Because antibodies bind directly to RBC surfaces, this is a classic Type II hypersensitivity

Type II Hypersensitivity - Transfusion Reactions

• Reaction vs various blood group antigens

  • ABO, others

    • ABO reactions: usually IgM, may also be IgG

• Some antibodies made naturally (cross-reactive with microbe carbs)

• Some antibodies made after exposure to cells with the antigen

Incompatible Blood Transfusion

• Wide range of effects

• From undetectable RBC loss to rapid, massive hemolysis

  • The patients antibodies bind donor RBC antigens = complement activation = RBC destruction

• Factors:

  • Amount of specific antibody present in patient

  • Number of RBCs received; amount of antigen on RBC (How much donor RBCs)

  • Degree of complement activation (how strong)

  • Others

Acute Hemolytic Reactions

Cause:

• Pre-formed IgM antibodies (usually against ABO antigens)

• These rapidly activate the classical complement pathway → MAC-mediated lysis

• Minutes-hours (within a day)

Results:

• Release of

  • Cytokines

  • Clotting factors

  • Vasoreactive substances

Can lead to:

• Disseminated intravascular coagulation

• Kidney, circulatory system failure

Delayed Hemolytic Reactions

• Within a few weeks of transfusion

Cause:

• Memory (IgG) response to antigens previously seen

  • Usually certain non-ABO antigens

Mechanism:

• IgG-coated RBCs are removed by macrophages in the spleen or liver

  • Extravascular hemolysis (less complement action)

• Less severe than acute reaction

  • IgG does not activate complement as efficiently as IgM

  • Hemolysis happens gradually in spleen/liver