Types of Hypersensitivity

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All allergic and autoimmune diseases develop on the ground of various types of hypersensitivity of the immune system.

Hypersensitivity means the excessive immune reaction against some antigens or allergens.


There are two basic types of hypersensitivity: immediate and delayed.


  • Immediate type of hypersensitivity depends largely on the humoral immune response followed by the synthesis of antibodies of different classes. After contact with an antigen, this type of reaction evolves rapidly and even instantly, from several seconds (in the case of anaphylactic shock) to 12-24 hours (urticaria), in typical cases, in about 30 minutes. The mechanisms of immediate hypersensitivity are the basis of various kinds of immunopathological reactions (anaphylactic, cytotoxic, immune complex-mediated, anti-receptor stimulatory and blocking reactions). Manifestations that develop 4-12 hours or even later after the onset of antigen exposure are considered to be “late” immediate-type reactions.
  • Delayed type of hypersensitivity evolves in 24-72 h after antigenic challenge. Delayed hypersensitivity is mainly maintained by the cooperation of antigen-specific T cells, dendritic cells and phagocytes. It’s a cell-mediated type of hypersensitivity. Well known immunologists P.G.H. Gell and R. Coombs has proposed a classification of different types of hypersensitivity reactions. This division was based on distinct immune mechanisms essential to certain types of immunopathology.

According to Gell and Coombs, five predominant types of immunopathological reactions were defined:

Type I Hypersensitivity– anaphylactic hypersensitivity [Type 1 Hypersensitivity]

Type II Hypersensitivity– cytotoxic hypersensitivity [Type 2 Hypersensitivity]

Type III Hypersensitivity– immune complex-mediated hypersensitivity [Type 3 Hypersensitivity]

Type IV Hypersensitivity– cell-mediated or delayed hypersensitivity [Type 4 Hypersensitivity]

Type V Hypersensitivity– stimulatory and blocking (receptor-mediated) hypersensitivity [Type 5 Hypersensitivity]

Types of Hypersensitivity
Types of hypersensitivity
Source: Grepmed

Type I Hypersensitivity– anaphylactic hypersensitivity [Type 1 Hypersensitivity]


Most allergic diseases develop according to the first type of hypersensitivity reactions (anaphylactic shock, atopic bronchial asthma, urticaria, angioneurotic edema, pollinoses, allergic rhynitis, insect allergy, food allergy, etc.). These reactions, on the other hand, are almost negligible in autoimmune disease pathogenesis.

Types of Hypersensitivity
Type-1-Hypersensitivity

Type II Hypersensitivity– cytotoxic hypersensitivity(Type 2 Hypersensitivity)


The reactions of the second type result from the antibody recognition of cell-bound antigens. Antibodies engaged in these reactions are probably class IgM and IgG. As the immune complex on the cell membrane has been formed, the classical pathway activation complement is initiated. Membrane attack complex destroys target cells that cause tissue damage. These cytotoxic reactions can be triggered by different autoantigens, bacterial antigens, chemical substances and drugs adsorbed on the cell surface.

Another pathway of cytotoxic hypersensitivity is provided by killer cells and phagocytes – antibody-dependent cell-mediated cytotoxicity – ADCC. It is exhibited by phagocytic myeloid cells (polymorphs and monocytes) and by natural killer cells (NK) with Fc receptors for Ig molecules. The contact between the effector and the target cells via the immune complex triggers the release of cytotoxic molecules from leukocytes, thereby promoting target lyses.

A large number of autoimmune processes are evoked by a cytotoxic mechanism. It is prevalent in various diseases affecting blood cells (autoimmune hemolytic anemia, aplastic anemia, agranulocytosis, thrombocytopenic purpura or Werlhof’s disease, etc where blood cells are destroyed by antibody-mediated lyses.

Type-II-Cytotoxic-Hypersensitivity

Type III Hypersensitivity– immune complex-mediated hypersensitivity [Type 3 Hypersensitivity]


Solutionary immune complexes are responsible for these immunopathological reactions. Immune complex formation is a common event within the immune response, but in some cases, redundant amounts of immune complexes are not seized by phagocytes. These immune complexes are present in the bloodstream. After a period of circulation, the capillary vessels are attached to the endothelium. Ag-Ab aggregates form deposits under the basal vascular membrane.

Settled immune complexes are capable of activating both the classical and alternative pathways of the complement system. The activation of the complement promotes endovascular inflammation (autoimmune vasculitis). Complementary activation products inhibit cell migration by increasing vasculitis. Tissues and organs with a rich capillary net are highly susceptible to complex immune damage (lungs, kidneys, skin, synovial and connective tissue).

Examples of autoimmune diseases caused by immune complex-mediated hypersensitivity include systemic lupus erythematosus (SLE), rheumathoid arthritis (RA), autoimmune glomerulonephritis, serum disease and many others.

The primary antigen, which causes immune inflammation in SLE, is a protein-DNA complex. Immune complexes settle in different organs (kidneys, lungs, etc.) Complement fixation and further activation of immune cells result in tissue inflammation leading to deep organ dysfunction. Severe glomerulonephritis (‘lupus-nephritis’) is the most dangerous in SLE.

Joint inflammation in rheumatoid arthritis is caused by a complex immune attachment to sinovial tissue and cartilage. Primary autoantigen epitopes in RA are located in the Fc portion of the patient’s IgG, which is autoantigenic due to abnormal glycosylation. Autoantibody (so-called “rheumatoid factor”) usually binds the IgM class to own IgG molecules, resulting in complement activation and immune cell involvement.

After repeated injections of large quantities of foreign proteins or drugs, serum sickness is created. The antigen is slowly removed from circulation and therefore triggers the generation of specific antibodies. It may occur during intensive treatment of life-threatening diseases (diphtheria, botulism, tetanus, etc.) with xenogenic horse antitoxic sera. The reaction is followed by fever, vasculitis, hives, arthralgia and kidney damage. Serum disease appears to be more common in current situations in the case of beta-lactam antibiotic therapy.

Type-III-Immune-Complex-Hypersensitivity

Type IV Hypersensitivity– cell-mediated or delayed hypersensitivity [Type 4 Hypersensitivity]


In many diseases of distinct aetiology (contact dermatitis, multiple sclerosis, metal ion allergy, sarcoidosis and the large number of infections, tuberculosis, leprosy, brucellosis, tularemia, Lyme disease, etc.), delayed hypersensitivity is observed.

Reactions mediated by cells are mainly stimulated by Th1 cells. The reactions are produced within 1-3 days of exposure to the antigen. IL-2 and γ-interferon are secreted by Th1, involving macrophages and dendritic cells in the reaction. They produce pro-inflammatory cytokines (IL-1, IL-6, IL-12, IL-18, alpha-TNF, presumably) that promote chronic productive inflammation. The proliferation of connective tissue limits the spread of the pathogen forming chronic granuloma at the inflammation site. In different infections, where slow cell allergic reactions evolve, assessment of delayed-type hypersensitivity is useful. It is essential for mentioned above tuberculosis, leprosy, brucellosis, as well as for syphilis, tularemia, glanders, actinomycosis and some other disorders.

The development of delayed hypersensitivity is dependent on the structure of bacterial antigenics. Some bacterial antigens (e.g., components of the cell wall) primarily activate Th1 and macrophages that promote infectious allergies mediated by cells. The long incubation period with unclear manifestations characterises these diseases. At that stage, different laboratory methods, including skin tests, are used to diagnose such disorders. Delayed hypersensitivity to infectious antigens (allergens) is evaluated by skin tests for laboratory diagnosis of infectious pathology. Generally, the latter is injected intracutaneously.

Tuberculin Mantoux tuberculosis (tuberculin skin test or TST) is a well-known example of skin test disease diagnosis. In order to estimate patient hypersensitivity to M, tuberculin is an infectious allergen. About tuberculosis. After continuous cultivation of bacteria in the liquid nutrient medium, R.Koch obtained it through filtration of the old Mycobacterium tuberculosis culture. It was initially applied for the treatment of tuberculosis, but without success. Nevertheless, it was shown to be quite appropriate for diagnosing tuberculosis. It was further purified to derive protein fractions for this purpose (tuberculin PPD or purified protein derivative).

Skin induration and redness develop when a small amount of tuberculin is injected into the skin of a patient previously exposed to Mycobacterium tuberculosis, reaching a peak in 24-72 hours. The skin and subcutaneous tissues are colonised by mononuclear cells. A positive skin test indicates that M.tuberculosis has infected the individual. The explanation of the test is not very simple because the reaction is influenced by various conditions (previous BCG vaccination and chemotherapy, patient anamnesis, conditions of immune status, etc.). However a change from negative to positive in the skin test implies recent infection and possible current tuberculosis activity. A positive response to the skin test helps the diagnosis to help control the treatment of tuberculosis.

In leprosy, a positive lepromin skin test indicates a non-suppressed cell-mediated immune tuberculoid form of the disease, whereas a negative test corresponds to lepromatous leprosy with severe cell-mediated immunity inhibition. Brucellosis (Burnet test with brucellin) and tularemia laboratory diagnosis (skin test with tularin) are successfully applied in skin tests. A positive delayed-type skin test with a specific microbial antigen supports the diagnosis of the corresponding infection in systemic mycotic and certain protozoan infections (histoplasmosis, blastomycosis, toxoplasmosis, etc.) In many viral infections (herpes simplex, mumps, etc.), cell-mediated hypersensitivity develops as well.

Type-IV-Cell-Mediated-Hypersensitivity

Type V Hypersensitivity– stimulatory and blocking (receptor-mediated) hypersensitivity [Type 5 Hypersensitivity]


Autoantibodies against the membrane receptors of the host cells are produced in certain pathological cases. These antibodies can modulate the function of the receptor to activate or repress cellular activity. Hypersensitivity mediated by receptors is sometimes referred to as a special type II type or cytotoxic hypersensitivity. However, it became important to separate them into the specific type of hypersensitivity (type V), taking into account the specific mechanisms and manifestations of stimulatory and blocking reactions. The bright example of the function stimulating autoantibody is the development of Graves disease. Antibodies are known to play a major role in the pathogenesis of the long-acting thyroid stimulator (LATS-factor).

The autoantibody of the IgG class that binds to thyroid-stimulating hormone (thyrotropin) receptors on thyroid gland cells has been proven to be the LATS factor. Autoantibody stimulates the receptors and initiates the production by thyrocytes of uncontrolled thyroid hormone. Thyroid gland hyperfunction contributes to the patient’s hyperthyroidism.

For the neuronal disorder Myasthenia gravis, the opposite action of autoantibodies, the cell receptor block, is essential. In that case, within the neuromuscular synapse, autoantibodies hinder the transmission of impulses. These antibodies on the post-synaptic muscle membrane bind to the acetylcholine receptor, thereby impairing its activity. With poor disease prognosis, receptor inactivation promotes progressing muscular weakness.