Hypersensitivity: Types and Immune Responses

• Hypersensitivity occurs when the immune system is a bit "extra" and results in undesirable outcomes.

Hypersensitivity Overview

• Hypersensitivity is an abnormal physiological response to external or internal triggers/antigens
• Immune cells recognise the trigger as foreign, leading to a reaction and damage
• Hypersensitivity results in allergies and autoimmune diseases

Gell and Coombs Classification for Hypersensitivity Types

• There are 4 types of hypersensitivity reactions
• It is based on the types of antigens and immune responses.
• Type I is IgE-Mediated Hypersensitivity
• Type II is IgG-Mediated Cytotoxic Hypersensitivity
• Type III is Immune Complex-Mediated Hypersensitivity
• Type IV is Cell-Mediated Hypersensitivity
• Immunoglobulin-mediated reactions are immediate, occurring within 24 hours
• Cell-mediated reactions are delayed, typically occurring after more than 12 hours

Immune Response

• The immune response begins with an antigen being recognised as non-self
• Presented to T cells or directly attached to B cells
• Receptors undergo change through rearrangement of genes
• Cells are activated to respond to the specific antigen

Immune cell types

• T helper cells (CD4+) are divided into classes (Effector and Memory) which include:
• Effector T cells (TH1, TH2, TH17)
• Memory T cells differentiate into effector cells on secondary exposure
• Regulatory T cells play a role in tolerance

Types of T helper cells

• TH1 cells produce IFN-ү and IL-2, promote cell-mediated immune response, and involve cytotoxic cells and macrophages
• TH2 cells produce IL-4 and IL-13
• TH2 cells induce B cells to produce antigen-specific IgE

B cells

• Internalise antigens
• Major Histocompatibility Complex C (MHC) class II antigen processing pathway is processing pathway
• MHC class II molecules present antigenic peptide on B cell surface to TH2 cell (T cell receptor)
• Interaction requires cell ligands to interact, activating signalling cascade
• Interaction is essential in switching from IgM to IgE in the presence of IL-4 and IL-13

Type I Reactions

• Allergic Reaction
• IgE-mediated
• Manifestations include: skin issues, nose issues, eye issues, lung issues, systemic issues
• Anaphylactoid reactions are similar but not IgE-mediated
• Skin: urticaria, allergic dermatitis, angioedema
• Nose: rhinitis, hayfever
• Eyes: allergic conjunctivitis
• Lungs: bronchospasm, atopic asthma
• Systemic: anaphylaxis (hypotension and airway compromise)

Phase 1 of Type 1 Reaction: Antigen/allergen exposure

• Usually inhaled, ingested, or via skin contact
• All allergens processed presented by antigen-presenting cells These travel to lymph nodes, prime naïve T helper cells
• It can differentiate into TH1/2/17 cells
• Differentiation is dependent on antigen and cytokine environment
• Interleukins favour differentiation favours eosinophil production, recruitment and mast cell activation

Phase 2 of Type 1 Reaction: Re-exposure to allergen

• Antigen-specific IgE binds to high-affinity IgE receptors on mast cells and basophils
• Allergen binds to and crosslinks bound IgE antibodies
• Release of chemical mediators (preformed, newly-synthesized) and cytokines

Mediators of Allergic Response (Preformed)

• Histamine acts on H1 and H2 receptors causing contraction of smooth muscles and vasodilation/vasopermeability, enhanced mucous production, and pruritus
• Tryptase is released from mast cells and degrades allergens, plays a role in the airway, and is a good marker of mast cell activation
• Proteoglycans are also preformed mediators

Mediators of Allergic Response (Newly formed)

• Leukotrienes are neutrophil chemotaxis and activation, vascular permeability, and potent bronchoconstrictors
• Prostaglandins and Thromboxane A2
• Platelet activating factor and Adenosine are newly formed mediators
• Bradykinin causes hypotension
• Cytokines include IL-4, IL-5, IL-6, IL-9, IL-13, and TNFα as newly formed mediators

Allergic response symptoms

• Mediators are responsible for signs and symptoms of an allergic response

Length of phases in allergic response

• Immediate phase within minutes that brings eosinophilia and basophils
• Late-phase occurs hours later and has redness/swelling of skin, nasal discharge, airway narrowing, sneezing, and wheezing, which usually resolves within 24–72 hours
• Chronic allergic inflammation can result from chronic/repeated exposure, leading to eosinophils, Tissue damage and increased levels of IgE

Type I Allergy testing

• Serum tryptase can differentiate anaphylaxis from other causes of shock/reaction if tested soon after reaction
• Serum IgE does not always correlate with clinical symptoms
• Eosinophils are raised in atopic individuals
• Serum antigen-specific IgE levels are specific to foods, bees, and environmental allergies
• False positive results can occur with skin prick tests for allergic rhinoconjunctivitis, allergic asthma, food allergies, venom allergies, and penicillin drug allergies as outpatient setting

Type I Allergy Management

• Management for life threatening anaphylaxis with Epinephrine (Adrenaline)
• Remove causative agent if applicable
• Treat depending on symptoms/system affected:
• Avoid triggers
• Antihistamines (H1 receptor antagonists as needed/daily)
• Corticosteroids (inhaled, nasal, topical, short-course)
• Leukotriene-receptor antagonists block mediator effects as needed

Immunotherapy for Type I sensitivities

• Subcutaneous and sublingual immunotherapy (SCIT, SLIT) is recommended for certain allergies
• It promotes increased IgG and decreased IgE production

Type 2 Hypersensitivity

• Mediated by antibodies binding directly to antigens on the surface of tissue
• This results in cell destruction
• Mediated by IgG and IgM
• Involves the complement and macrophages/other cytotoxic cells

Antibody Mechanisms in the Pathogenesis of Autoimmune Hemolytic Anemia (AIHA)

• Involves antibody to target cells which are recognised as foreign target cells
• Process in this pathogenesis include:
• Opsonising of a target cell which makes phagocytosis more likely
• Activates complement, causing opsonisation or phagocytosis
• Activates the membrane attack complex (MAC)
• Activates natural killer cells and cytotoxic killing by being antibody-dependent

Type 2 Hypersensitivity Reactions

• Activate complement cascade, drawing neutrophils and inflammation to the site (chemotaxis)
• Example is Goodpasture syndrome
• Foreign-produced antibodies that react to self-tissues activate complement and cell damage
• In autoimmune disease autoantibodies bind to receptors stimulating the receptor like Grave's disease
• Myaesthenia gravis occurs when autoantibodies bind to receptors blocking them

Abnormal antibody production Triggers

• Immune system should have self-awareness
• Foreign antigens structurally look like self-antigens
• Altered epitopes or bound self-antigens that are recognised as foreign
• Breakdown in tolerance to self-antigens
• There is genetic predisposition to this, but can also be caused by drugs

Testing and Management of Type 2 Hypersensitivity

• Based on history and examination
• Blood tests for autoantibodies
• Biopsy of the effected site
• Treatment includes:
• Removing trigger if applicable
• Removing antibodies
• Suppress immune response with with corticosteroids, immunosuppressants/immunomodulators, “biologics" - monoclonal antibodies
• Remove target organ
• Block the effects with blocking agents

Type III Hypersensitivity Reactions

• Immune complexes form and precipitate in vessels or glomeruli
• Initiate classical complement pathway

Type III Clinical Presentation

• Clinical features, tests, and treatment
• Usually present 1-2 weeks after Ag exposure (delayed)
• Presents as serum sickness-fever, rash, sore, swollen, and joint paint
• System involvement depends on the antigen/illness, but generally, skin, kidney, and joint involvement are most common

Type III APSGN

• Affects children with cola-coloured urine, oedema (swelling around eyes), and hypertension weeks after throat or skin infection

Type III Diagnosis and Management

• Investigation depends on clinical presentation/illness
• Complement levels (C3 C4)
• Urine with cells, blood, protein
• Biopsy with skin showing leukocytoclastic vasculitis
• Treatment, if applicable, removes the agents and suppress inflammation (steroids; supportive
• Always test/treat HIV

Type IV Hypersensitivity Reaction

• Delayed type appearing 48-72 hours after antigen exposure which is inflammatory
• Mediated by T cells, cell-mediated immunity
• Responsible for transplant rejection and immunity to intracellular pathogens
• Contact dermatitis and TB reactions

Type IV Diagnostic Tests

• Tests depend on clinical presentation
• Test and administer antibiotics as needed
• Avoid infection if possible and use anti relievers if contracted