HC27: Mechanisms of hypersensitivity reactions

Immunopathology

There are 3 types of immunopathology:

• Immunodeficiency: an ineffective immune response
• Hypersensitivity: an overactive immune response
• Autoimmunity: an inappropriate reaction to self-antigens

A common feature is loss of (self)tolerance and lack of control of the immune response resulting in (chronic) inflammation.

Inflammation:

Inflammation is a protective response aimed to eliminate cause of injury, clear damaged tissue and initiate repair. Classical signs of inflammation are:

• Pain
• Heat
• Redness
• Swelling

Chronic inflammation contributes to a wide variety of diseases like cancer, diabetes and Alzheimer.

Hypersensitivity:

Characteristics of hypersensitivity reactions are:

• Undesirable reactions of the normal immune system in pre-sensitized hosts
  • The reaction is not abnormal
  • Pre-sensitized hosts → there has been contact with the antigen before
• Mechanisms are similar to those operative in the normal immune response
• Abnormal because of the exaggerated or otherwise inappropriate form resulting in tissue injury

There is a classification that distinguishes hypersensitivity reactions in 4 types:

• Type I reactions: immediate hypersensitivity
• Type II reactions: antibody-mediated diseases
• Type III reactions: immune-complex mediated diseases
• Type IV reactions: T-cell mediated diseases

Type I, II and III reactions are mediated by antibodies → the reactions are immediate. Type IV reactions are mediated by T-cells → the reactions are delayed.

Type I hypersensitivity

Examples:

Type I hypersensitivity is IgE-mediated. Examples are:

• Atopic rhinitis
  • For example seasonal hayfever
• Atopic conjunctivitis
• Atopic asthma
  • Allergy and bronchial hyperresponsiveness
• Atopic dermatitis
• Food allergy
• Systemic anaphylaxis

Atopy:

Atopy is the predisposition to make IgE antibodies that specifically target innocent substances in the environment.

Process:

In case of IgE-mediated hypersensitivity (type I), 3 particles are involved:

• IgE
• Eosinophils
• Mast cells

IgE-mediated hypersensitivity has 2 phases:

• Allergic sensitization
  1. A dendritic cell phagocytoses an allergen
  2. The dendritic cell presents a fragment of the pathogen to a Th0-lymphocyte
  3. The Th0-lymphocyte evolves to a Th2-lymphocyte
  4. The Th2-lymphocyte starts to produce IL-4 and IL-13 → B-cells differentiate to plasma cells and class-switch to the production of IgE
• Symptomatic phase
  1. Dendritic cells present antigens to memory Th2-cells → release IL-4, IL-5 and IL-13 → results in characterizing symptoms
     • IL-4 and IL-13 activate the epithelia → mucus production and fibroblast activation
     • IL-5 produces and activates eosinophils in the bone marrow
  2. Sensitization has already taken place → the allergen binds to mast cells with high affinity IgE-receptors
  3. Activation of mast cells results in cross-linking of IgE-receptors → 2 receptors bind 1 antigen
     • Degranulation of the mast cell → histamine and protease release
       • There molecules are already present → reactions occur immediately
     • De novo-synthesis and secretion of lipid mediators in the mast cell
       • Important for continuation of the inflammatory reaction
  4. Vasodilatation → increased vascular permeability → contraction of smooth muscle cells → chemotaxis of leukocytes

Because of the interplay of all the immune cells locally, they all produce mediators that keep the inflammation going → the inflammation is in a chronic state. Even if there is no contact with allergens, the inflammation is still there → it’s keeping itself in balance.

Asthma:

Asthma is an allergy of atopy in most patients, characterized by airway hyperresponsiveness related to mast cells degranulating.

The larger parts of the respiratory tract contain smooth muscle cells. In case of asthma, these cells need less stimulation to contract → leads to shortness of breath. There are acute and chronic responses:

• Acute responses: mediated by the release of histamine
  1. A mucosal mast cell captures the antigen
  2. Inflammatory mediators contract smooth muscle, increase mucus secretion by airway epithelium and increase blood vessel permeability
• Chronic response: mediated by cytokines and eosinophil products

The airways of asthma patients can be distinguished by:

• Thicker walls
• More smooth muscle
• More mucus
• Bigger mucus glands
• Presence of inflammation cells

The basal membrane, which contains lots of mucus glands, thickens → leads to mucus production. Hyperplasia and mucus production cause the airways become clogged.

Possible treatments for asthma are:

• Antihistamines
• Bronchodilators
  • b2-receptor agonists
• (Inhaled) corticosteroids
• Leukotriene inhibitors
• (Expensive) biologicals
  • Monoclonal antibodies that inhibit IgE
    • Prevents the mast cell from acquiring cell-surface IgE → cannot be activated through FceRI and its cell-surface expression is downregulated
    • Anti-IgE cross-links IgE bound to FceRI → activates mast cell degranulation --> inflammatory response
  • Monoclonal antibodies that inhibit Th2 cytokines such as IL-4, IL-5 and IL-13
    • Under clinical development
• Desensitization using subcutaneous or sublingual immunotherapy (SCIT)
  • Stimulation of regulatory T-cells

Which treatment is chosen depends on the severity of the asthma.

Autoimmune response

Type II, III and IV hypersensitivity reactions can be initiated by:

• An autoimmune response
• A response to exogenous antigens

An autoimmune response is an attack of healthy tissues by antibodies and effector T-cells → failure of self-tolerance.

Type II hypersensitivity

Type II hypersensitivity is antibody-mediated hypersensitivity. In this case, the antibodies IgG, IgM and IgA are directed against cell surface or extracellular matrix components. This causes:

• Activation of the complement system
• Interaction with FcR-bearing effector cells

Examples:

Examples of type II hypersensitivity are:

• Transfusion reactions
• Autoimmune haemolytic anaemia
• Haemolytic disease of the newborn
• Goodpasture’s syndrome
• Receptor targeting in Myasthenia gravis and Graves’ disease
  • Myasthenia gravis: the AChR is blocked
  • Graves’ disease: the TSH receptor is stimulated

Autoimmune haemolytic anaemia:

In case of haemolytic anaemia, erythrocytes are destroyed in an autoimmune reaction. This happens via 3 mechanisms:

1. Erythrocytes bind anti-erythrocyte autoantibodies
2. The 3 mechanisms are activated:

• FcR-expressing cells in the spleen → phagocytosis and erythrocyte destruction
• Complement fixation and CR1-expressing cells in the spleen → phagocytosis and erythrocyte destruction
• Complement activation and intravascular hemolysis → erythrocyte and lysis destruction

Penicillin:

Small-molecule drugs such as penicillin can bind to erythrocyte receptors, causing surface antigens to change. These antigens aren’t recognized by the body anymore → leads to the formation of antibodies against erythrocytes:

• Penicillin binds to bacterial transpeptidase and inactivates it
• Penicillin modifies proteins on human erythrocytes to create foreign epitopes

Haemolytic anaemia of the newborn:

Haemolytic anaemia of the newborn makes it possible for mother and child to have a different Rhesus factor. A Rhesus negative mother can have a Rhesus positive fetus:

1. The fetal erythrocyte is recognized by the mother as foreign because the mother only has erythrocytes without the Rhesus factor
2. B-cells are activated → primary immune response → IgM and low affinity IgG are secreted
3. A minor destruction of the fetal erythrocytes takes place due to the low level of IgG → the newborn is fairly healthy

In case this happens during the second pregnancy, there already is sensitization of the immune system:

1. Memory B-cells make a lot of high-affinity IgG immunoglobulins
2. IgG goes to the fetal circulation via the placenta
   • IgM cannot pass the placenta
3. A massive amount of fetal erythrocytes is destroyed → anemic newborn baby

This can be prevented from happening. Passive immunization with the anti-Rhesus D antigen IgG prevents hemolytic anemia of the newborn → the mother doesn’t produce any antibodies against the fetus and won’t be able to generate the memory response. Only IgG can pass the placenta and access the circulation of the fetus → the primary immune response isn’t a big issue, but the memory response is.

Type III hypersensitivity

Type III hypersensitivity is immune complex-mediated hypersensitivity. In this case, antibodies (IgG, IgM and IgA) form immune complexes against soluble components → the antigen persists and the clearance is insufficient. This results in a continued infection or autoimmune disease. Different cells are involved:

• IgG, IgM and IgA
• Complement system
• FcR-presenting effector cells

Examples:

Examples of type III hypersensitivity are:

• Systemic
  • Serum sickness
  • Systemic lupus erythematosus (SLE)
  • Rheumatoid arthritis
• Local
  • Arthus reaction
  • Extrinsic allergic alveolitis

There can be an acute or chronic reaction. Usually, the complexes are phagocytosed in the spleen or liver.

Extrinsic allergic alveolitis:

Extrinsic allergic alveolitis is a type III hypersensitivity response against soluble molecules that are inhaled. This causes sensitivity reactions in the lung. People are exposed to certain triggers → form immune complexes in the alveoli → get stuck and lead to local inflammation. Examples are:

• Farmer’s lung
• Bird-breeder’s lung
• Air-conditioner lung
• Compost lung
• Chemical worker’s lung

Type IV hypersensitivity

Type IV hypersensitivity is delayed hypersensitivity. Several cells are involved:

• Monocytes
• Macrophages
• CD4 T-cells
• CD8 T-cells
• Cytokines
  • IFN-g
  • TNF a

Examples:

Examples of type IV hypersensitivity are:

• Contact hypersensitivity
  • For example against nickel
• Sarcoidosis
• Lepra
• Tuberculosis

Process:

In case of type IV hypersensitivity, many cytokines are released:

1. An antigen is processed by tissue macrophages and stimulates Th1-cells
2. Cytokines are released
   • Chemokines → macrophage recruitment to the site of the antigen
   • IFN-g→ activates macrophages → increases release of inflammatory mediators
   • TNF-aand LT → local tissue destruction and increased expression of adhesion molecules on local blood vessels
   • IL-3/GM-CSF → monocyte production by bone marrow stem cells

Variations:

Because T-cells are part of the process, the response is slower → develops days after the exposure. Variations of delayed hypersensitivity are:

• Contact reactions
  • After 48-72 hours
• Tuberculin reactions
  • After 48-72 hours
• Granulomatous reactions
  • After 21-28 days

Mantoux reaction:

The Mantoux test is used to test for tuberculosis → it detects antibodies in the body:

1. Tuberculin is injected in the subcutaneous tissue
2. Tuberculin is picked up by macrophages
3. In case contact with TBC has taken place, pre-existing T-helper cells are activated
4. Pre-existing T-helper cells start to produce cytokines which act locally on the recruitment of more inflammatory cells

This process takes time → takes place after several days. Fault-positives can occur if one recently has been vaccinated against TBC.

Granulomatous reactions:

In case of granulomatous reactions, T-cells are chronically activated. The immune system tries to engulf the pathogen by creating multi-nucleated giant cells surrounded by a ring of T-cells → granulomas. A granuloma contains:

• Macrophages
• Epitheloid cells
  • Derived from activated macrophages
• Giant cells
  • Multi-nucleated → formed upon fusion of epitheloid cells
• Lymphocytes
• Fibrosis

Examples of granulomatous hypersensitivity are:

• Leprosy
• Tuberculosis
• Schistosomiasis
• Sarcoidosis
• Crohn’s disease