Hypersensitivity reactions

• Hypersensitivity is defined as an exaggerated or inappropriate state

of immune response with onset of adverse effects on the body.

• In this case the immune system is inadequately controlled , directed

against normally harmless antigens or inappropriately target host
tissues.

• Can be systematic or localized.

Pathologic immune responses may be directed against different types of antigens
and may result from various underlying abnormalities e.g. :

Autoimmunity: reactions against self antigens.

Reactions against microbes.

Reactions against environmental antigens.

In all of these conditions, tissue injury is mediated by the same mechanisms that
normally function to eliminate infectious pathogens, The problem in these
diseases is that the immune response is triggered and maintained inappropriately.
There are four types of reactions:

Type I- IgE mediated.

Type II-Antibody-Mediated.

Type III-Immune Complex-Mediated.

Type IV-Delayed-Type Hypersensitivity (DTH).

Type I: IgE - Mediated Hypersensitivity
• Type I hypersensitivity is defined as a state of rapidly
developing or anaphylactic type of immune response to an
antigen (i.e. allergen) to which the individual is previously
sensitized.

• The reaction appears within 15-30 minutes of exposure to

antigen.
• Susceptibility to immediate hypersensitivity reactions is genetically
determined.

• Allergens are antigens that can stimulate a type I

hypersensitivity response.

Allergens bind to IgE and trigger degranulation of chemical

mediators.
Pathogenesis
• Type I reaction includes participation by B lymphocytes and plasma cells, mast
cells and basophils, neutrophils and eosinophils.

• During the first contact of the host with the antigen, sensitization takes place.
In response to initial contact with antigen, circulating B lymphocytes get
activated and differentiate to form IgE-secreting plasma cells.

• IgE antibodies so formed bind to the Fc receptors present in plenty on the

surface of mast cells and basophils, which are the main effector cells of type I
reaction. Thus, these cells are now fully sensitized for the next event.
• During the second contact with the same antigen, IgE
antibodies on the surface of mast cells-basophils are so
firmly bound to Fc receptors that it sets in cell damage
membrane lysis, influx of sodium and water an
degranulation of mast cells-basophils.
• The released granules contain important chemicals and enzymes
with proinflammatory properties— histamine, serotonin,
vasoactive intestinal peptide (VIP), chemotactic factors of
anaphylaxis for neutrophils and eosinophils, leukotrienes B4 and
D4, prostaglandins (thromboxane A2 prostaglandin D2 and E2) and
platelet activating factor.
The effects of these agents are:
• Increased vascular permeability.

• Smooth muscle contraction.

• Early vasoconstriction followed by vasodilatation.

• Increased gastric secretion.

• Increased nasal and lacrimal secretions.

• Increased migration of eosinophils and neutrophils at the site of local injury

as well as their rise in blood (eosinophilia and neutrophilia).
Examples of type I reaction
• The manifestations of type I reaction may be variable in severity and
intensity.

• It may manifest as a local irritant (skin, nose, throat, lungs etc), or

sometimes may be severe and life-threatening anaphylaxis.

• Common allergens which may incite local or systemic type I reaction

are:
Localized anaphylaxis:
• i) Hay fever (seasonal allergic rhinitis) due to pollen sensitization of conjunctiva and
nasal passages.

• ii) Bronchial asthma due to allergy to inhaled allergens like house dust.

• iii) Food allergy to ingested allergens like fish, cow’s milk, eggs etc.

• iv) Cutaneous anaphylaxis due to contact of antigen with skin characterized by

urticaria, wheal and flare.

• v) Angioedema, characterized by laryngeal edema, edema of eyelids, lips, tongue and

trunk.
Systemic anaphylaxis:
• The clinical features of systemic anaphylaxis include:

• Itching, erythema, contraction of respiratory bronchioles, diarrhea,

pulmonary edema, pulmonary hemorrhage, shock and death.
Type II: Cytotoxic (Cytolytic) Reaction
• Type II or cytotoxic reaction is defined as reactions by
humoral antibodies that attack cell surface antigens on the
specific cells and tissues and cause lysis of target cells.
ETIOLOGY AND PATHOGENESIS
• The mechanism involved is as under:

• Opsonization and phagocytosis: When circulating cells, such as red

blood cells or platelets, are coated (opsonized) with autoantibodies,
with or without complement proteins, the cells become targets for
phagocytosis by neutrophils and macrophages. These phagocytes
express receptors for the Fc tails of IgG antibodies and for breakdown
products of the C3 complement protein, and use these receptors to
bind and ingest opsonized particles.
• Antigen-antibody complex also activates complement system and
exposes membrane attack complex (MAC) that attacks and destroys
the target cell.

• In some cases, antibodies directed against a host protein impair or

dysregulate important functions without directly causing cell injury
e.g in myasthenia gravis.
Examples of type II reaction
• Autoimmune hemolytic anemia in which the red cell injury is
brought about by autoantibodies reacting with antigens
present on red cell membrane. Antiglobulin test (direct
Coombs’ test) is employed to detect the antibody on red cell
surface.
• Transfusion reactions due to incompatible or mismatched blood
transfusion.

• Hemolytic disease of the newborn (erythroblastosis fetalis) in which

the fetal red cells are destroyed by maternal isoantibodies crossing
the placenta.
• Idiopathic thrombocytopenic purpura (ITP) is the immunologic
destruction of platelets by autoantibodies reacting with surface
components of normal platelets.

• Drug-induced cytotoxic antibodies are formed in response to

administration of certain drugs like penicillin, methyl dopa,
rifampicin etc. The drugs or their metabolites act as haptens binding
to the surface of blood cells to which the antibodies combine,
bringing about destruction of cells.
• Graves’ disease (primary hyperthyroidism), thyroid autoantibody is
formed which reacts with the TSH receptor to cause hyperfunction
and proliferation.

• In myasthenia gravis, antibody to acetylcholine receptors of skeletal

muscle is formed which blocks the neuromuscular transmission at
the motor end-plate, resulting in muscle weakness.
• In type 1 diabetes mellitus, islet cell autoantibodies are formed
which react against islet cell tissue.

• In hyperacute rejection reaction, antibodies are formed against

donor antigen.
Type III-Immune Complex-Mediated Hypersensitivity

• Type III reactions result from deposition of antigen-antibody

complexes on tissues, which is followed by activation of the
complement system and inflammatory reaction, resulting in
cell injury.
Pathogenesis
• It may be mentioned here that both type II and type III reactions have
antigen-antibody complex formation but the two can be
distinguished.

• Antigen in type II is tissue specific while in type III is not so; moreover
the mechanism of cell injury in type II is direct but in type III it is by
deposition of antigen-antibody complex on tissues and subsequent
sequence of cell injury takes place.
• Type III reaction has participation by IgG and IgM antibodies, neutrophils,
mast cells and complement.

• The sequence of underlying mechanism:

• i) Immune complexes are formed by interaction of soluble antibody and

antigen.

• ii) Immune complexes which fail to get removed from body fluid get
deposited into tissues.
• iii) Fc component of antibody links with complement and activates
classical pathway of complement resulting in formation of C3a, C5a
and membrane attack complex.

• iv) C3a stimulates release of histamine from mast cells and its
resultant effects of increased vascular permeability and edema.
• v) C5a releases pro inflammatory mediators and chemotactic agents
for neutrophils.

• vi) Accumulated neutrophils and macrophages in the tissue release

cytokines and result in tissue destruction.
Examples of type III reaction
• Immune complex glomerulonephritis in which the antigen may be
GBM or exogenous agents (e.g. Streptococcal antigen).

• Goodpasture syndrome having GBM as antigen.

• SLE in which there is formation of anti-nuclear and anti-DNA

autoantibodies.

• Rheumatoid arthritis.
• Farmer’s lung in which actinomycetes-contaminated hay
acts as antigen.

• Polyarteritis nodosa and Wegener’s granulomatosis with

anti neutrophil cytoplasmic antigen.

• Drug-induced vasculitis in which the drug acts as antigen.

• An experimental example is acute Arthus reaction which
occurs with cutaneous injection of foreign antigen into an
individual leading to a localized tissue and vascular damage.

• Severity can vary from mild swelling to redness to tissue

necrosis.
• Serum Sickness: type III hypersensitivity reaction that
develops when a foreign serum protein is intravenously
administered resulting in formation of large amounts antigen-
antibody complexes and the deposition in tissue. Clinically
manifested as arthritis, vasculitis, nephritis.
Type IV (T Cell–Mediated)Hypersensitivity
• Type IV or delayed hypersensitivity reaction is tissue injury by cell
mediated immune response without formation of antibodies
(contrary to type I, II and III) but is instead a slow and prolonged
response of specifically- sensitized T lymphocytes.
ETIOLOGY AND PATHOGENESIS
• The antigen is recognized by CD8+ T cells (cytotoxic T cells) and is processed by
antigen presenting cells.

• Antigen-presenting cells migrate to lymph node where antigen is presented to

helper T cells (CD4+ T cells).

• Helper T cells release cytokines that stimulate T cell proliferation and activate
macrophages.

• Activated T cells and macrophages release proinflammatory mediators and cause

cell destruction.
• It is important for host defense against intracellular pathogens.

• Two types of T cell reactions are capable of causing tissue injury and
disease:

• Cytokine-mediated inflammation: cytokines are produced mainly by

CD4+ T cells.

• Direct cell cytotoxicity: mediated by CD8+ T cells.

Cytokine-mediated inflammation

• Sensitization phase:

• Occurs during primary exposure.

• TH cells are activated by Ag presented together with class II MHC on

an appropriate APC, such as macrophages or Langerhan cell
(dendritic epidermal cell).

• Generally CD4+ cells of the TH1 subtype are activated during

sensitization.
Effector phase: occurs upon subsequent exposure to the Ag.

• T cells secrete a variety of cytokines and chemokines, which recruit

and activate macrophages.

• Macrophage activation promotes phagocytic activity and increased

concentration of lytic enzymes for more effective killing.

• Activated macrophages are also more effective in presenting Ag and

function as the primary effector cell.
Examples of type IV reaction
• Reaction against mycobacterial infection e.g. tuberculous reaction,
granulomatous reaction in tuberculosis, leprosy.

• Reaction against virally infected cells.

• Reaction against malignant cells in the body.

• Reaction against organ transplantation e.g. transplant rejection,

graft versus host reaction.