Hypersensitivity reactions

 

Introduction:

Immunologic mechanisms of tissue damage (immunopathology):

Exaggerated immune response may result in reactions harmful to the host i.e. immunopathology. This may occur due to:

  • An overactive immune response that produces more damage than it prevents as in hypersensitivity reactions and graft rejection.
  • Failure of appropriate recognition as in autoimmune diseases.

 

Hypersensitivity reactions

Classification:

Gell & Coomb’s classification:

Type I: immediate (anaphylactic) hypersenstivity.

Type II: cytotoxic or cytolytic reactions.

Type III: immune complex mediated reactions

Type IV:  delayed type hypersensitivity reactions (DTH).

Type I - Hypersensitivity:

(Immediate, Anaphylactic, IgE-mediated)

Definition:

When an antigen (allergen) reacts with IgE fixed on mast cells and basophils (produced by previous exposure), it results in degranulation and release of chemical mediators which lead to disease manifestations which may be localized (atopy) or systemic (anaphylaxis).

Pathogenesis:

  1. Allergens include:
  • Inhalants g. Pollens, fungal spores, animal dander, dust, mites etc… Ingestants e.g. milk, fish, egg, chocolate strawberries etc….
  • Contactantsg. wool, nylon etc...
  • Injectants including drugs e.g. penicillins, serum injections e.g. antitetanic sera, anesthesia or insect venom.
  1. On first exposure to an allergen:
  • APCs mainly DCs and macrophages capture the antigen, process it and present its epitopes to TH2 which is activated and produce IL-4 that in turn stimulates class switching of B cells to produce IgE.
  • IgE is cytotropic (i.e. tissue fixing) it binds to receptor for Fc portion of IgE (FcERI) on basophils and mast cells.

 

III. On re-exposure to the same antigen:

  • It causes cross linking of bound IgE which leads to mast cell activation, degranulation and release of its mediators.
  • Mediators derived from mast cells fall into 3 classes:
  1. Preformed mediators:

These mediators are stored in the granules and include histamine.

  1. Newly synthesized mediators:

They include leukotrienes, prostaglandins and platlet activating factor (PAF).

  1. Cytokines:

Secreted by activated mast cells (and basophiles) e.g TNF, IL-3, IL-4, IL-5 and chemokines. TH2 recruited to the site of reaction also secrete cytokines.

  • Preformed mediators (histamine) mediate the immediate manifestations of hypersensitivity:

* Contraction of smooth muscles leading to bronchospasm.

* Increased mucus secretion.

* Vasodilatation and increased vascular permeability leading to edema & hypotension.

* Also histamine is responsible for wheal and flare reaction that occurs 15-20 minutes following intradermal injection of an allergen.

  • Newly synthesized mediators and cytokines mediate a late phase inflammatory reaction that occurs 2-4 hours after exposure, reaches maximum severity within 24 hours then it subsides gradually. They mediate this inflammatory reaction via:

* Recruitment of inflammatory cells (granulocytes and TH2) to the site of reaction.

* Increasing IgE production.

* Activation of eosinophiles.

* Tissue damage.

Clinical Types:

  1. Anaphylaxis:
  • It is the systemic form of type I hypersensitivity reactions that occurs on exposure to an allergen to which the body is previously sensitized.
  • The allergens are usually injectants including drugs e.g. penicillins, serum injections e.g. antitetanic sera, anesthesia or insect venom.
  • It manifests as shock due to sudden decrease of blood pressure, respiratory distress due to bronchospasm, cyanosis, edema…etc.
  • The condition is rapidly treated with corticosteroid injection (life saving), epinephrine and antihistamincs.
  1. Atopy:
  • It is the localized form of type I hypersensitivity reactions that affects one organ on exposure to an allergen that induces production of specific IgE.
  • These allergens are usually environmental proteins and chemicals i.e. inhalants, ingestants and contactants.
  • There is strong familial predisposition to development of atopy. This predisposition is genetically determined. Atopic individuals produce high levels of IgE in response to environmental allergens compared to normal individuals who produce mainly IgG and little IgE.
  • Atopy manifests in different ways depending on the site of antigen antibody reaction:

* Urticaria: skin rash and subcutaneous edema.

* Rhinitis (Hey fever): rhinorrhea, congestion, nasal obstruction.

*Asthma: bronchial constriction, edema, increased mucus secretion.

* Conjunctivitis in the eyes.

Diagnosis:

  1. In case of anaphylaxis, diagnosis is clinical to allow immediate life saving treatment.
  2. In case of atopy, diagnosis is established by:
  3. History taking to determine the allergen involved.
  4. Skin tests which are performed by intradermal injection by different groups of allergens. Wheal and flare reaction (erythema) occurs 15-20 minutes at the site of allergen to which the individual is allergic.
  5. Determination of total serum IgE (high in atopic patients) by radioimmunosorbent test (RIST).
  6. Determination of specific serum IgE to different allergens using radioallergosorbent test (RAST).
  7. Provocation tests in case of food allergies.

Management:

  1. Avoidance of the specific allergen responsible for the condition.
  2. Hyposensitization: It is a form of immunotherapy which is done by subcutaneously injecting gradual increasing doses of an extract of the allergen, this leads to:
  3. Induction of regulatory T cells that switches the immune response from TH2 to TH1 reducing IgE production.
  4. Stimulation of blocking IgG antibody production that binds to the allergen preventing its combination with IgE fixed to the cells.
  5. Induction of T cell tolerance.
  6. Drug therapy:

* Drugs are used to:

  • Inhibit mast cell degranulation.
  • Antagonize the effects of mast cell mediators.
  • Reduce inflammation.

 

* These drugs include:

  • Corticosteroids, epinephrine, antihistamincs and theophylline.
  • Sodium chromoglycate that stabilize mast cells and reduce degranulation.
  • β- adrenergic agonists are bronchial dilators that relax smooth muscles in airways e.g. terbutaline.
  • Montelukast (singular 10) is specific receptor antagonist that blocks the effects of leukotrienes. It reduces airway inflammation in asthma.
  • Omalizumzb is a humanized monoclonal anti IgE antibody that binds to IgE preventing its binding to Fc receptors on mast cells. It prevents both immediate and late phases of asthma.
  • IL-4 and IL-5 antagonists are under trials.

Type II hypersensitivity
(Cytotoxic or Cytolytic reactions)

Definition:

It is the type of hypersensitivity that occurs when IgM or IgG react with an antigen on cell surface (whether this antigen is a part of cell membrane or it is a circulating antigen or hapten that attaches to the cell membrane), leading to lysis of the cells due to complement fixation, opsonization or antibody dependent cellular cytotoxicity (ADCC).

Pathogenesis (mechanism of cytolysis):

* Antibodies are formed against cellular antigens e.g. RBCs surface antigens.

* These antibodies can cause cell lysis due to:

a-  Complement activation and fixation to the antigen antibody complex on the cell surface causes formation of membrane attack unit (C5b6789).

b-  Opsonization: antibody (opsonin) bound to cell surface antigen leads to enhancement of phagocytosis of target cells.

c-  ADCC: antibody coated cells (tumor cells, graft cells or infected cells) can be killed by cells that possess Fc receptors i.e. NK, macrophages and PMNLs.

Clinical conditions (types) due to cytotoxic reactions:

  1. Heteroreactive: e.g.
  2. Transfusion reactions due to incompatible blood transfusion.
  3. Hemolytic disease of newborn due to Rh incompatibility.
  4. Drug reaction: drug acts as a hapten that attaches to cell surface leading to antibody production that leads to cell lysis e.g.

Drug induced haemolytic anemia: penicillin, quinidins, phenacetin.

Drug induced thrombocytopenia: quinines.

  1. In graft rejection cytotoxic reactions are one of the mechanisms of tissue damage. In hyper acute graft rejection the recipient has already preformed antibodies to the graft. Rejection occurs within 2 hours.
  2. Autoreactive: e.g.
  3. In many autoimmune diseases e.g. autoimmune hemolytic anaemia, ITP, nephrotoxic nephritis, hashimoto’s thyroiditis, and mysthenia gravis
  4. Non cytotoxic type II hypersensitivity is detected in Graves's disease which is a form of thyroditis where antibodies are produced against TSH surface receptors. These antibodies do not destroy the cells but mimic the action of TSH leading to cell stimulation and over production of thyroid hormones.

Type III (Immune complex hypersensitivity)

Definition:

  • It is the type of hypersensitivity that occurs due to binding of complement fixing antibodies (IgM or IgG) to soluble antigens forming immune complex of a certain size that escape phagocytosis and become deposited in tissues on the basement membrane of blood vessels leading to tissue injury.
  • Normally large immune complexes are rapidly eliminated with in minutes mainly by kupffer cells in the liver. However small complexes (due to low affinity antibodies as those formed to auto-antigens) require hours to several days for their removal. Circulation of high levels of these immune complexes will overwhelm the ability of phagocytic system to remove them and the excess complexes then deposit in various tissues.

Mechanism of Tissue Injury:

The immune complex triggers a variety of inflammatory processes:

1-  Complement activation that leads to release of anaphylatoxins (C3a, C5a) which stimulates degranulation of mast cells and basophiles with release of vasoactive amines (e.g. histamine). These increase vascular permeability and help deposition of immune complex on the basement membrane.

2-  Complement activation leads to attraction of neutrophils by C5a (i.e. chemotaxis) that release their lysosomal enzymes leading to tissue damage and intensify the inflammatory process.

3-  Platelets aggregate that leads to release of vasoactive amines and formation of microthrombi that cause local ischemia.

Clinical conditions (types) due to immune complexes:

Diseases produced by immune complexes are those in which the antigen persists without being eliminated as in:

  • Exposure to large amount of the antigen.
  • Repeated exposure to the antigen.
  • Persistent chronic infection.
  • Autoimmunity to self components.
  1. Heteroreactive:
  2. Localized: e.g.
  3. Arthus reaction:
  • Local immune complex deposition phenomenon that occurs due to repeated injection of the same antigen subcutaneously.
  • After 2-3 injections, local reaction occurs in the form of edema, erythema and necrosis.
  • Immune complexes are deposited in small blood vessels leading to vasculitis, microthrombi formation, vascular occlusion and necrosis.
  • This reaction occurs in diabetic patients receiving repeated injections of SC insulin.
  1. Post-streptococcal glomerulonephritis.
  2. Allergic alveolitis:

It occurs due to deposition of immune complexes in the lungs after repeated inhalation of the antigen e.g. dust (farmer's lung).

  1. Certain infections in which the antigen is persistently produced as in chronic HBV infection, HIV infection and leprosy.

II- Systemic: e.g.

  1. Serum sickness:
  • Systemic immune complex deposition phenomenon that occurs due to I.V injection of large dose of foreign antisera to diphtheria, snake venom etc…or drugs as penicillins or sulphonamides.
  • Antigen is slowly cleared from the circulation while antibody production starts leading to the formation of soluble immune complexes.
  • Immune complexes are deposited in different parts of the body leading to disease manifestations (heart ® infarction, skin ® rash & erythema, joints ® arthritis, kidney ®N.) that occurs nearly 10 days following the injection.
  • The disease is self limited and the patient recovers gradually as the immune complexes are eliminated. Corticosteroids enhance the recovery.
  1. Vasculitis that causes hemorrhage & necrosis.
  2. B) Autoreactive:

Endogenous antigen antibody complexes are involved in the pathogenesis of several autoimmune diseases e.g. rheumatoid arthritis, SLE

Diagnosis:

It is established by detection of Immune complex:

  1. In tissues:
  • Biopsy stained with fluorescein labeled anti C3, anti IgG or IgM.
  1. In blood:
  • Decreased C3 level.
  • Precipitation of immune complexes and determination of the amount of IgG in the precipitate.
  • Estimation of binding of immune complexes to C1q, rheumatoid factor or Raji cells (a human lymphblastoid cell line that binds immune complexes through C3 receptors).
  • Sera containing immune complexes may form cryoprecipitate at 4°C.

Management:

  • Stop the allergenic drugs.
  • Suppression of immune response by steroids.
  • Removal of immune complexes by plasmapharesis or exchange transfusion.

Type IV hypersenstivity

(Cell Mediated / Delayed Type
Hypersensitivity DTH)

Definition:

  • DTH reactions are initiated due to activation of specifically sensitized T cells (memory T cells) reacting with specific antigen leading to production of cytokines that attract and activate monocyte/macrophages & lymphocytes leading to cellular infiltration and tissue damage.
  • This response is delayed i.e. occurs hours or days after contact with the antigen and often lasts for days.

Mechanism (pathogenesis):

After initial sensitization of T cells, memory cells are formed that when recognize the specific antigen they cause tissue injury either by triggering DTH or by direct killing of target cells by CD8 T cells as follow:

  • TH1 cells become stimulated to release cytokines (IFN-g, IL-2, GM CSF and TNF-b).
  • These cytokines attract lymphocytes, activate macrophages (IFN-g) and activate TC leading to cell infiltration (mononuclear cell infiltrate) after 24-48 hrs.
  • Tissue damage is due to:
  1. Products of activated macrophages (hydrolytic enzymes, reactive oxygen intermediates, nitric oxide) & pro-inflammatory cytokines (IL-1, IL-6 & TNF).
  2. TC direct killing effect.
  • Chronic DTH usually leads to fibrosis due to secretion of cytokines & growth factors by the macrophages.

Clinical conditions (types) due to DTH:

  1. Heteroreactive:
  2. Skin tests:

Principle:

DTH to antigens of microorganisms occurs in many infectious diseases and can be used as an aid for diagnosis.

Examples:

  • Tuberculin test for tuberculosis:

I.D. injection of PPD to previously sensitized person (by exposure or BCG vaccine) leads to induration & redness ³ 10 mm that occurs after 48-72 hrs (mononuclear cell infiltration).

  • Brucillin test for brucellosis.
  • Lepromin test in leprosy.
  • Feri's test in lymphogranuloma venereum.
  • Candidin test in candida.
  1. Contact dermatitis:

That occurs due to chemicals, drugs or metals. These substances enter the skin in small molecules acting as haptens that when bind to tissue proteins become immunogenic leading to inflammatory reactions in the form of eczema, rash or vascular eruptions.

  1. Graft rejection: inflammation & necrosis of the organ.
  2. Chronic granulomatous infections: as TB, leprosy.
  • The persistence of antigen in the tissues leads to local DTH reaction in the form of granuloma (localized mononuclear cell infiltration).
  • Systemic manifestations also occur due to cytokines secreted from the macrophages (IL-1, IL-6 and TNF-a).
  1. Autoreactive:

As thyroiditis, insulin dependent diabetes milletus (T cells destroy insulin secreting beta cells) and ulcerative clolitis.