Hypersensitivity Reactions Types Notes

Hypersensitivity Reactions (Immunologic Tissue Injury)

Hypersensitivity is defined as an exaggerated or inappropriate immune response that is associated with the onset of adverse effects on the body.

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It is a reaction in response to an endogenous or exogenous antigen that manifests clinically as a form of immunologic tissue injury.

Many instances of hypersensitivity reactions are genetically determined or are associated with certain HLA types.

Based on underlying immune mechanisms, hypersensitivity reactions are of 4 types:

1. Type I: Anaphylactic (or atopic) hypersensitivity
2. Type II: Antibody-mediated cytotoxic hypersensitivity
3. Type III: Immune complex-mediated hypersensitivity
4. Type IV: Delayed (cell-mediated) hypersensitivity

Depending upon the speed of onset, duration, and type of the immune response (humoral or cell-mediated), 4 types of hypersensitivity reactions are grouped into either immediate or delayed types:

• Immediate type: in which on administration of antigen, the reaction occurs immediately (within seconds to minutes). Immune response in this type is mediated largely by humoral antibodies (B cell-mediated). Immediate type of hypersensitivity reactions include types I, II and
• Delayed type: In which the reaction is slower in onset and develops within 24 – 48 hours and the effect is prolonged. It is mediated by the cellular response (T cell-mediated) and it includes Type IV reaction.

Etiology, pathogenesis, and examples of immunologic tissue injury by 4 types of hypersensitivity reactions are discussed below and are summarised in the table

1. Type I: Anaphylactic (Atopic) 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 (anaphylaxis is the opposite of prophylaxis). The reaction appears within 15-30 minutes of exposure to antigen. In some instances, there is a second late-phase reaction occurring after 2-24 hours, for example, Allergic rhinitis.

Etiology:

Type I reaction is mediated by humoral antibodies of IgE type or reagin antibodies in response to antigen. The following factors have been considered responsible:

• Genetic basis:   There is evidence that the ability to respond to antigens and produce IgE are both linked to genetic basis. For example, there is a 50% chance that a child born to both parents allergic to an antigen may have a similar allergy.
• Further support to this hypothesis comes from observations of high levels of IgE in hypersensitive individuals and low levels of suppressor T cells that control the immune response in persons with certain HLA types (in particular HLAB8).
• Environmental pollutants:  Environmental pollutants increase mucosal permeability and thus allow increased entry of allergens into the body, which in turn leads to raised IgE levels.
• Concomitant factors:  Besides allergic response, type I reaction may be linked to the simultaneous occurrence of certain viral infections of the upper respiratory tract in a susceptible individual.

Pathogenesis:

Type I reaction includes participation by B lymphocytes and plasma cells, mast cells and basophils, neutrophils, and eosinophils. The underlying mechanism is as follows :

• During first contact of the host with an allergen, antigen-presenting cells (i.e. dendritic cells) present the allergen to naive CD4+ T helper cells which are activated and generate an excessive response by cytokine-producing TH2 cells.
• This results in the high production of several cytokines (IL-4, IL-5, IL-13) which act on B cells and plasma cells, stimulating excessive synthesis of IgE antibodies selectively.

Comparative features of 4 types of hypersensitivity reactions: 

• IgE antibodies so formed bind to the Fc receptors present abundantly 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 second contact with the same antigen, IgE antibodies on the surface of basophils and mast cells are so firmly bound to Fc receptors that it sets in cell damage to mast cells and basophils — membrane lysis, the influx of sodium and water, followed by their degranulation.
• On degranulation, preformed granules are released from mast cells and basophils which contain important chemicals and enzymes acting as mediators of immediate hypersensitivity— biogenic amines (histamine, serotonin, 5-HT), chemotactic factors of anaphylaxis (for neutrophils and eosinophils), enzymes (proteases, hydrolases, proteoglycans such as heparin and chondroitin sulfate).
• On activation, other inflammatory mediators that are synthesized de novo at the site and released are leukotrienes (C4 and D4), prostaglandins (thromboxane A2, prostaglandin D2, and E2), platelet-activating factor (PAF), and certain cytokines (TNF, IL-1, IL-4).
• The effects of released preformed granules as well as those agents synthesized on activation  are:
  • Increased vascular permeability:
    1. Smooth muscle contraction
    2. Increased nasal and lacrimal secretions
    3. Early vasoconstriction followed by vasodilatation
    4. Increased gastric secretion
    5. Shock, and
    6. 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:

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 that may incite local or systemic type I reactions are as under:

Systemic anaphylaxis:

• Administration of antisera, for example, Anti-tetanus serum (ATS).
• Administration of drugs, for example, Penicillin.
• Sting by a wasp or bee.

The clinical features of systemic anaphylaxis include itching, erythema, contraction of respiratory bronchioles, diarrhea, pulmonary edema, pulmonary hemorrhage, shock, and death.

Local anaphylaxis:

• Hay fever (seasonal allergic rhinitis) due to pollen sensitization of conjunctiva and nasal passages.
• Bronchial asthma due to allergy to inhaled allergens like house dust.
• Food allergy to ingested allergens like fish, cow’s milk, eggs, etc.
• Cutaneous anaphylaxis due to contact of antigen with skin characterized by urticaria, wheal, and flare.
• Angioedema is an autosomal dominant inherited disorder characterized by laryngeal Oedema, and edema of eyelids, lips, tongue, and trunk.

2. Type II: Antibody-Mediated (Cytotoxic) Hypersensitivity:

Type II or antibody-mediated reaction is a humoral response by antibodies that attack cell surface antigens on the specific cells and tissues and cause lysis of target cells. The antibodies so formed may be against normal cells and tissues (autoantibodies) or against exogenous antigens ( for example, Drug metabolites, and microbial products).

Etiology And Pathogenesis:

In general, type II reactions have participation by the complement system, tissue macrophages, platelets, natural killer cells, neutrophils, and eosinophils while the main antibodies are IgG and IgM class. In different settings, separate mechanisms are involved

• Opsonization and phagocytosis:
  • Target cells coated with IgG and IgM antibodies on their surface activate the classic pathway of the complement system which generates opsonins, C3b, and C4b.
  • Phagocytes possess receptors on their surface for specific products: Fc receptors for recognition and binding of IgG antibodies coated on the surface of the target cell, and receptors for binding C3b and C4b opsonins. The net result is the destruction of the target cell.
  • Antigen-antibody complex also activates the complement system and generates a membrane attack complex (C5b-C9) that attacks and destroys the target cell directly.
  • The destroyed target cells are phagocytosed by macrophages.
• Antibody-dependent cellular cytotoxicity
  • Antibodies may be deposited on fixed tissue sites such as the basement membrane or extracellular matrix of the cell.
  • This triggers complement activation with the generation of activation products, C3b and C5a) that are associated with the recruitment of polymorphs and monocytes.
  • Activation of monocytes, polymorphs, and NK cells releases lysosomal enzymes such as proteases causing destruction of a target cell and its components for example, In glomerulonephritis.
• Antibody-mediated cellular dysfunction:
  • In this mechanism, antibodies against cell surface receptors cause disruption of cellular function rather than causing cell injury or inflammation.
  • The disruption in function may cause impairment or may be stimulatory. For example, in myasthenia gravis, there is a formation of antibodies against acetylcholine receptors in the skeletal muscle that block the neuromuscular junction and cause weakness of the affected muscle.
  • On the contrary, in Graves disease, there is the formation of stimulatory antibodies against TSH and hence hyperthyroidism.

Examples Of Type II Reaction:

Examples of type II reactions are mainly on blood cells and some other body cells and tissues.

Cytotoxic antibodies to blood cells: 

These are more common. Some examples are as under:

• Autoimmune hemolytic anemia in which the red cell injury is brought about by autoantibodies reacting with antigens present on the red cell membrane. Antiglobulin test (direct
• Coombs’ test) is employed to detect the antibody on the red cell surface (page 326).
• Transfusion reactions due to incompatible or mismatched blood transfusion.
• Hemolytic disease of the newborn (erythroblastosis fetal) in which the fetal red cells are destroyed by maternal antibodies crossing the placenta.
• Immune thrombocytopenic purpura (ITP) is the immunologic destruction of platelets by autoantibodies reacting with surface components of normal platelets.
• Leucopenia with agranulocytosis may be caused by autoantibodies to leucocytes causing their destruction.
• Drug-induced cytotoxic antibodies are formed in response to the 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 the destruction of cells.

Cytotoxic antibodies to tissue components: 

• Cellular injury may be brought about by autoantibodies reacting with some components of tissue cells in certain diseases.
• In 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 male sterility, the anti-sperm antibody is formed which reacts with spermatozoa and causes
  impaired motility as well as cellular injury.
• In type 1 diabetes mellitus, islet cell autoantibodies are formed which react against islet cell tissue.
• In pernicious anemia, there is the formation of antibodies against intrinsic factors which results in abnormal erythropoiesis and anemia.
• In a hyperacute rejection reaction, antibodies are formed against the donor antigen.
• In some forms of glomerulonephritis, antibody-mediated cell injury is responsible.
• In Goodpasture syndrome, there is the formation of antibodies against renal glomeruli and lung alveoli which result in nephritis and pulmonary hemorrhages.
• In rheumatic heart disease, antibodies against streptococcal antigen cause the main manifestations of carditis and arthritis.
• In pemphigus vulgaris, bullae on the skin are formed due to antibodies against epidermal cadherin (at the intercellular junctions of epidermal cells).

3. Type III: Immune Complex-Mediated Hypersensitivity:

Type III reactions result from the deposition of antigen-antibody complexes on tissues, which is followed by activation of the complement system and inflammatory reaction, resulting in cell injury.

Etiology And Pathogenesis:

Type III reaction is not tissue-specific and occurs when antigen-antibody complexes are formed in circulation, and less often locally in situ. The antigen may be in an exogenous or endogenous agent:

• Exogenous antigens These include:
  • Low-grade microbial infection with bacteria or viruses stimulates a somewhat weak antibody response.
  • Extrinsic environmental antigens inhaled into the lungs, for example, Antigens derived from molds, plants, or animals.
• Endogenous antigens:
  • In this, there is the formation of immune complexes by autoantibodies against self-antigens for example, Against nucleus or immunoglobulin.
  • Type III reaction has participation by IgG and IgM antibodies, neutrophils, mast cells, and complement.
  • Regardless of the type of antigen, the pathogenic mechanism of type III immunologic cell injury depends upon whether immune complexes are formed in circulation or are locally formed in situ

Circulating Immune Complex-Mediated Cell Injury:

• Immune complexes are formed in circulation by the interaction of soluble or insoluble antigens and soluble antibodies.
• Generally, larger immune complexes have an excess of antibodies and are readily removed by the mononuclear phagocyte system. However, small and intermediate-sized immune complexes have an excess of antigens and cause maximum damage by getting deposited in tissues.
• The preferred site of deposits of circulating immune complexes is the tissues where blood is being filtered continuously, for example, Kidneys in the formation of urine, heart, serosal surfaces, and small blood vessels.
• Immune complexes deposited in the tissues incite inflammatory reactions by complement activation in a similar way as in type II reactions.
• In view of selective tissues where immune complexes are deposited, manifestations of nephritis, arthritis, vasculitis, etc occur.

Local Immune Complex-Mediated Cell Injury:

Less often, there may be local immune complex formation, often in the skin, causing tissue injury. This localized immune complex-mediated tissue injury is called the Arthus reaction.

In the initial description of the Arthus reaction, an injection of antigen into an already immunized rabbit having abundant circulating antibodies caused a localized reaction followed by the occurrence of tissue necrosis within 3-8 hours. The mechanism of local immune complex-mediated injury is as under:

• If an individual who is already immunized and has abundant circulating antibodies against a particular antigen, is given an intracutaneous injection of the same antigen, there is the entry of antigen into the vessel wall which then combines with circulating antibody and forms a local immune complex.
• The most common site for such formation of such local immune complexes is the skin where there is edema, hemorrhage, and tissue necrosis within a few hours.

Examples Of Type III Reaction:

• Immune complex glomerulonephritis in which the antigen may be glomerular basement membrane (GBM) or exogenous agents ( for example, Streptococcal antigen) for example, Post-streptococcal
  glomerulonephritis.
• SLE in which there is a nuclear antigen (DNA, RNA) and there is the formation of anti-nuclear and anti-DNA autoantibodies.
• Rheumatoid arthritis in which there is a nuclear antigen.
• Farmer’s lung in which actinomycetes-contaminated hay acts as an antigen.
• Polyarteritis nodosa having hepatitis B antigen and occurrence of systemic vasculitis.

• Drug-induced vasculitis in which the drug acts as an antigen.
• Reactive arthritis in which bacterial antigens.
• Serum sickness in response to various foreign protein antigens.
• Arthus reaction is an example of a localized immune complex disease presenting with cutaneous vasculitis.

4. Type Iv: Delayed (Cell-Mediated) Hypersensitivity:

Type IV reaction or delayed type hypersensitivity (DTH) is tissue injury by T cell-mediated immune response without the formation of antibodies (contrary to type I, II, and III) and is a slow and prolonged response. The reaction occurs about 24-48 hours after exposure to antigen and the effect is prolonged which may last up to 14 days.

Etiology And Pathogenesis:

Type IV reaction involves the role of mast cells and basophils, macrophages, and T cells (both CD4+ and CD8+). The antigen may be exogenous ( for example, Mycobacteria, viruses, fungi, etc) or endogenous agent ( for example, Nucleus, collagen, myelin, etc).

The mechanism of type IV reaction may be a classic delayed hypersensitivity mediated by CD4+ T cells or CD8+ T cell-mediated direct cytolysis:

• Classic DTH (Mediated by CD4+ T Cells): Classically, DTH occurs in response to several microbial agents for example, Mycobacteria, Viruses, Fungi, etc.
• Intradermal injection of purified protein derivative (PPD) represents the prototype example of DTH:
  • On first exposure (i.e. immunization for tuberculosis and exposure to tubercular antigen), naive CD4+ T cells recognize antigen on antigen-presenting dendritic cells.
  • These cells express cytokine IL-12 that differentiates naive CD4+ T cells into TH1 and TH17 cell types. Some of these TH1 cells remain as memory T cells for years.
  • If this individual who is previously exposed to tubercular antigen and has some degree of cell-mediated immunity, is given intracutaneous injection of PPD, memory T cells interact with antigen on antigen-presenting cells and get activated.
  • On activation, several proinflammatory cytokines are produced (IL-12, IL-2, IFN-γ, TNF-α), each with a distinct role. However, IFN-γ is most significant and causes the activation of macrophages and transforms them into epithelioid cells.
  • In such a previously antigen-exposed person, the cutaneous response occurs after a delay of about 24-48 hours after PPD injection, hence it is called DTH.
• Direct CD8+ T Cell-Mediated Cytolysis:
  • In this mechanism, sensitized CD8+ T (cytotoxic T cells) cells kill the antigen-bearing target cells directly:
  • The antigen is recognized by CD8+ T cells and produces mediators: perforins, granzymes, and other proteins.
  • Perforins drill holes into the target cell membrane while granzymes are proteolytic and cleave caspases, causing cell death by apoptosis.
  • CD8+ T cells also express cytokine IFN-γ causing inflammatory reactions in some examples of DTH.

Examples Of Type IV Reaction:

Reaction against mycobacterial infection for example, Tuberculin reaction, granulomatous reaction in tuberculosis, leprosy. Reaction against virally infected cells.

• Reaction against organ transplantation, for example, Transplant rejection, graft versus host reaction. Contact dermatitis on exposure to certain chemicals, plants, metals, etc.
• Rheumatoid arthritis has collagen as a self-antigen. Multiple sclerosis with myelin protein as self-antigen. Inflammatory bowel disease may either have self-antigen or enteric bacteria. Hypersensitivity Reactions (Immunologic Tissue Injury) Hypersensitivity reactions are an exaggerated or inappropriate immune response that is associated with the onset of adverse effects on the body.
• There are 4 types of hypersensitivity which are grouped into two categories: immediate (type I, II, and III) and delayed-type (type IV). Type I hypersensitivity is 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. It is mediated by humoral antibodies of IgE type for which mast cells and basophils play a key role. Type II is an antibody-mediated reaction is a reaction by humoral antibodies that attack cell surface antigens on the specific cells and tissues and cause lysis of target cells.
• Type II reaction is tissue-specific and occurs after antibodies (IgG or IgM) bind to tissue-specific antigens, most often on blood cells. Type III reactions result from the deposition of antigen-antibody complexes on tissues, which is followed by activation of the complement system and inflammatory reaction and tissue injury. Antigen in type II reaction may be an exogenous or endogenous agent.
• Type IV or delayed hypersensitivity is tissue injury by T cell-mediated immune response without the formation of antibodies. The reaction occurs about 24 – 48 hours (delayed) after exposure to antigen and the response is prolonged.