IHD W5 - Allergy and Hypersensitivity

Definitions

Atopy: genetic predisposition to make IgE in response to allergen exposure

Atopic March: natural history of allergic diseases and how they develop/progress. The initial manifestation in infancy is followed by staggered development of additional manifestations later in life. 

Allergen: any antigen that can cause allergic reaction

Asthma: type of Type I IgE-Th2 driven immune response in the airways.

Non-IgE allergic diseases

Type II, III, IV Gell and Coombs

mediated by TH1 cells and cytotoxic CD8 cells

• Non-IgE drug dependent drug-induced hypersensitivity reactions in susceptible individuals occur by binding of the drug to the surface of circulating blood cells.

• Systemic disease caused by immune-complex formation can follow the administration of large quantities of poorly catabolised antigens.

Gell and Coombs Classification mechanisms

Pros	Cons
Only successful attempt to classify disease by mechanism Useful framework to describe and understand various diseases.	Not useful clinically Oversimplified - many diseases (particularly chronic) utilise multiple components of the immune system and don't fit into this  classification.

Type I, II and III similarities

reactions can be transferred by serum 

• Type IV does not involve antibodies and requires the transfer of antigen-specific Th1 clones that orchestrate macrophage response.

Type I immediate ‘allergic’ hypersensitivity - classic allergy

IgE dependent

atopic individuals produce IgE against environmental antigens (allergens)

IgE cross-links Fcε receptors on innate cell surface

granule content from innate cells are released (histamine, proteases, heparin, leukotrienes, prostaglandins, chemokine) - symptom inducing

Systemic exposure to Type I allergic response

catastrophic, systemic release of inflammatory mediators via IgE cross linking on peri-vascular mast cells which manifests as Anaphylactic Shock

Local exposure to Type I response

localised release of inflammatory mediators

• epidermal: Urticaria

• inhalation: Asthma

• ingestion: Diarrhoea

Type II mechanism

Cytotoxic response - mediated by IgM and IgG targeting membrane associated antigens

• etiology: hapten-carrier, molecular mimicry or idiopathic (unknown)

IgM/IgG binds to antigen on host tissue/cells which causes damage via 3 routes:

1. antibody-dependent cell mediated cytotoxicity (cellular destruction)

2. activation of classical complement and cell lysis (inflammation)

3. cellular dysfunction (blocking normal receptor function)
   

Type III mechanism

Immune complex deposition - Ab-Ag complexes form in circulation, and are deposited into susceptible tissues - may also form directly in the tissue (Arthus reaction)

• in healthy individuals, Ag-Ab complexes are soluble and removed by macrophages in the spleen/liver

etiology: antigens that can induce complexes are either endogenous or exogenous, Type III response occurs in cases where the antigen cannot be easily destroyed eg. autoimmunity

• immune complex deposition is a prominent feature of several autoimmune diseases

Type III damage

Damage by immune complexes:

• precipitate and deposit into tissues if clearance system becomes overwhelmed

• leads to complement activation and inflammatory cell recruitment

• may trigger release of inflammatory and vasoactive mediators 

• proteases may damage connective tissue - clots formation as immune complexes activate platelets

Particularly affects blood vessels and the kidney:

3 steps to damage:

• immune complex formation

• immune complex deposition

• inflammatory reaction - classical complement, macrophages, neutrophil recruitement

Type III reaction types

Systemic reaction - serum sickness

7-14 days post exposure

rash, fever, joint pain, lymph node enlargement, proteinuria

• vasculitis if in blood vessel

• glomerulnephirtis if in kidneys

• arthritis if in joints

Local reaction - Arthus reaction

acute, local, typically after vaccination or insect bite

high inflammatory reaction, induced by injection of an antigen in an individual with high levels of circulating antibodies specific to it

• swelling and localised bleeding at injection site

• also seen when boosters are administered in individuals with high antibody titres

Diagnosing and treating Type III

immune complexes in blood are fragile and hard to quantify

• can be detected in tissue biopsies - however this is not simple

relevant antibodies are observed and amount of complement activation is measured

• complement factors in the blood decrease in systemic conditions, as they are being used up in hypersensitivity III reactions

main therapy is avoidance where possible, corticosteroids and immunosuppression

Type IV mechanism

delayed type - not humoral, cell mediated, initiated by T cells

• required delay to develop

• characterised by recruitment of macrophages at inflammation site

• involves sensitisation and effector phases 

Type IV Phases - Sensitisation phase

initiation involves sensitisation by an antigen, initial exposure triggers production of a T cell response

• often CD4+ TH1 subset

Type IV Phases - Effector phase

induced by second exposure to sensitising Ag.

• induces production of TH1 inflammatory cytokines (IFNy, TNF-a, IL-2, IL-3 etc.) these rescue and help macrophage activation

Type IV management

avoidance where possible

immunosuppression via blocking T cell activation or ablate T cells with anti-lymphocyte antibodies

corticosteroids

Type I eitology and mechanism

Etiology: IgE mediated hypersensitivity may have evolved because of their protective roles against helminth worms and animal venoms

allergies initiated by an interaction between IgE and multivalent antigen

free circulating IgE is usually low in serum

global concern of allergy

postulated hypotheses for increasing allergy prevelance

• allergen exposure

• biodiversity (overuse of antibiotics on gut flora)

• immune and metabolic homeostasis

• diet

Allergen features

• proteins or glycoproteins (bind MHC)

• possess many antigenic sites (epitopes) per molecule

• often have intrinsic enzymatic properties (favour transition into body)

• may contain potential PAMPs, stimulating innate immunity

• may enter mucosal tissues at low concentrations, including IgE-stimulating Th2 response

• self protein homology

• seasonal or perennial

IgE and FCE receptors 

IgE cross-links FCE receptors on innate cell surfaces causing degranulation and release of symptom causing molecules

• IgE Abs are not themselves harmful

High affinity: FCEI - constitutively expressed on mast cells and basophils

Low affinity: FCEII - regulated IgE levels

proteins as allergen components - example Der p1

Der p 1 is a cysteine protease, a major house dust mite allergen, promoting IgE/Th2 response via protease activity

• disrupts epithelial barrier

• biased Th1/Th2 polarisation; triggers IL-6 and cleaves IL-2 - reduces inflammation and promotes Th2

excessive IgE: Der p 1 can cleave FCERII (low affinity) on B cells, regulation of IgE

cleave surfactant: reduced allergen clearance

Classic Th2 cytokine profile - in Type I response

IL-4: stimulates/maintains Th2 response B cell class switching

IL-5: recruitment and activation of eosinophils, primes basophils for histamine and leukotriene release

IL-9: stimulates proliferation of mast cells

IL-13: promotes mucus secretion, airway hyperesponsivness

Preformed (primary) Type I mediators

• histamine: smooth muscle contraction, increased vasopermeability/vasodilation, enhanced mucus production, pruritus ,gastric acid secretion

• proteases: eg. Tryptase, contributes to airway remodelling

• Proteoglycans: eg. Heparin, an anticoagulant

De novo synthesised mediators (secondary):

eicosanoids (leukotrienes/prostaglandins): bronchoconstriction, vascular permeability,vasoconstruction, vasodilation, inflammation

Platelet activating factor (PAF): vascular permeability, bronchoconstriction, chemotaxis, degranulation of eosinophils

bradykinin: vasoperability, vasodilation, hypotension, smooth muscle contraction, activation of arachnidonic acid metabolites.

Eicosanoids - bioactive lipids, role in inflammation

comprise prostanoid, leukotrienes (LTs), and lipoxins, which have pro- and anti-inflammatory effects in asthma

• potent, short half life, act locally

In asthma, NSAIDs inhibit COX enzymes, leading to reduced prostaglandins and LT overproduction

• LT overproduction can worsen asthma

Early and late phase allergic reaction - Type I

Type I hypersensitivities are characterised by both early and late phase responses: 

• Early response occurs within minutes of allergen exposure

• Late responses, hours later, result of recruited cells

• A third phase has been described involving basophils and fibroblasts

Late-phase response is caused by continued production of these histamine and lipid mediators, and by recruitment of lymphocytes and myeloid cells

Late phase reaction is mediated by Th2 cells and eosinophils

Late responses, hours later, as a result of recruited cells. 

• Cytokines released from mast cells increased expression of chemokines and cell adhesion molecules (CAMs) on endothelium facilitating influx of neutrophils, eosinophils and Th2 cells.

Eosinophils play a large role in late phase, recruiting neutrophils and degranulation.