I remembered one day we have oral immunology test with Dr Ali, everyone was busy with the notes and trembling their fingers trying to memorize the notes. The topic that we prayed that it wouldn't ask by him was hypersensitivity and autoimmunity. It was funny, because we only understand Type 1 (at that time) and hoping type 2,3 and 4 will not come out. Now I decided to post immunology hypersensivity for home revision.
Ps: I am still giggling to myself! haha
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Hypersensitivity Type 1
Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause a range of symptoms from minor inconvenience to death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 - 12 hours).
Urticaria (bee sting)
conjuctivitis
Immediate hypersensitivity is mediated by IgE. The primary cellular component in this hypersensitivity is the mast cell or basophil. The reaction is amplified and/or modified by platelets, neutrophils and eosinophils. A biopsy of the reaction site demonstrates mainly mast cells and eosinophils.
The mechanism of reaction involves preferential production of IgE, in response to certain antigens (often called allergens). The precise mechanism as to why some individuals are more prone to type-I hypersensitivity is not clear. However, it has been shown that such individuals preferentially produce more of TH2 cells that secrete IL-4, IL-5 and IL-13 which in turn favor IgE class switch. IgE has very high affinity for its receptor (Fcε; CD23) on mast cells and basophils.
Cross-linking of IgE and allergens (substance enhance allergic reaction)
Such cross-linking leads to rapid degranulation (60-300 secs) of the mast cells and the release of primary inflammatory mediators stored in the granules. These mediators cause all the normal consequences of an acute inflammatory reaction - increased vascular permeability, smooth muscle contraction, granulocyte chaemotaxis and extravasation etc.
Mast cell activation via Fc epsilonRI also leads to the production of two other type of mediators. These secondary mediators, unlike the stored granule contents, must be synthesised de novo and comprise arachadonic acid metabolites (prostaglandins and leukotrienes) and proteins (cytokines and enzymes).
| Primary mediators |
| Histamine | | Vascular permeability, sm contraction |
| Serotonin | | vascular permeability, sm contraction |
| ECF-A | | eosinophil chaemotaxis |
| NCF-A | | neutrophil chaemotaxis |
| proteases | | mucus secretion, connective tissue degradation |
| Secondary mediators |
| Leukotrienes | | vascular permeability, sm contraction |
| Prostaglandins | | vasodilation, sm contraction, platelet activation |
| Bradykinin | | vascular permeability, sm contraction |
| Cytokines | | numerous effects inc. activation of vascular endothelium, eosinophil recruitment and activation |
Allergens
Numerous ideas have been put forward as to what property might distinguish antigens which stimulate a sufficient IgE response to generate type I hypersensitivity (allergens) from those antigens which rarely or never do so. However no common property has yet been discerned. below is a list of common allergens.
Systemic Anaphylaxis
The consequences of a generalised reaction are potentially fatal. Ingestion of nuts or seafood, insect bites (venom), and drug injection may all cause life-threatening reactions in highly sensitised individuals. Death in such cases is due to systemic release of vasoactive mediators leading to general vasodilation and smooth muscle contraction resulting in sudden loss of blood pressure, massive oedema and severe bronchiole constriction (systemic anaphylaxis).
Hypersensitivity Type 2
Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity.
Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement. Phagocytes and NK cells may also play a role. Type 2 is also known as autoimmunity as it attack self-antigen of the cell.
The Fab portion of the antibody binds to epitopes on the "foreign" cell. The NK cell then binds to the Fc portion of the antibody. The NK cell is then able to contact the cell and release pore-forming proteins called perforins, proteolytic enzymes called granzymes, and chemokines. Granzymes pass through the pores and activate the enzymes that lead to apoptosis of the infected cell by means of destruction of its structural cytoskeleton proteins and by chromosomal degradation. As a result, the cell breaks into fragments that are subsequently removed by phagocytes. Perforins can also sometimes result in cell lysis.
ADCC (Antibody dependent cell cytotoxicity)-induced by NK cell during cell apoptosis
Apoptosis occurs when certain granzymes activate a group of protease enzymes called caspases that destroy the protein structural scaffolding of the cell, degrade the cell's nucleoprotein, and activate enzymes that degrade the cell's DNA. As a result, the infected cell breaks into membrane-bound fragments that are subsequently removed by phagocytes. If very large numbers of perforins are inserted into the plasma membrane of the infected cell, this can result in a weakening of the membrane and lead to cell lysis rather than apoptosis. An advantage to killing infected cells by apoptosis is that the cell's contents, including viable virus particles and mediators of inflammation, are not released as they are during cell lysis.
The lesion contains antibody, complement and neutrophils. Diagnostic tests include detection of circulating antibody against the tissues involved and the presence of antibody and complement in the lesion (biopsy) by immunofluorescence. The staining pattern is normally smooth and linear, such as that seen in Goodpasture's nephritis (renal and lung basement membrane) (figure 3A) and pemphigus (skin intercellular protein, desmosome)
Mechanism of Hypersensitivity Type 2
Hypersensitivity Type 3
Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganisms.
Serum sickness (arthus reaction)
The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is caused by platelets and neutrophils. The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process.
It is now thought that this form of hypersensitivity has a lot in common with type I except that the antibody involved is IgG and therefore not prebound to mast cells, so that only preformed complexes can bind to the low affinity FcgammaRIII.
Watch Type 3 hypersensitivity animation
Large quantities of soluble antigen-antibody complexes form in the blood and are not completely removed by macrophages. These antigen-antibody complexes lodge in the capillaries between the endothelial cells and the basement membrane. The antigen-antibody complexes activate the classical complement pathway and complement proteins and antigen-antibody complexes attract leukocytes to the area. The leukocytes then discharge their killing agents and promote massive inflammation. This leads to tissue death and hemorrhage. This is also example of autoimmunity.
The Arthus reaction
The Arthus reaction is the name given to a local type III hypersensitivity reaction. It is easy to demonstrate experimentally by subcutaneous injection of any soluble antigen for which the host has a significant IgG titre. Because the FcgammaRIII is a low affinity receptor and because the threshold for activation via this receptor is considerably higher than for the IgE receptor the reaction is slow compared with a type I reaction, typically maximal at 4-8hrs, and consequently more diffuse. The condition extrinsic allergic alveolitis occurs when inhaled antigen complexes with specific IgG in the alveoli, triggering a type III reaction in the lung, for example in 'pigeon fanciers lung' where the antigen is pigeon proteins inhaled via dried faeces. Complement is not required for the Arthus reaction, but may modify the symptoms.
Systemic reaction of type 3 hypersensitivity
The presence of sufficient quantities of soluble antigen in circulation to produce a condition of antigen excess leads to the formation of small antigen-antibody complexes which are soluble and poorly cleared. In the normal animal these complexes fix complement but experiments in animals genetically deficient in C3 or C4 have shown that complement is not required for pathology to be observed following antibody-antigen complex challenge. The major pathology is due to complex deposition which seems to be exacerbated by increased vascular permeability caused by mast cell activation via FcgammaRIII. The deposited immune complexes trigger neutrophils to discharge their granule contents with consequent damage to the surrounding endothelium and basement membranes. The complexes may be deposited in a variety of sites such as skin, kidney and joints. Common examples of generalised type III reactions are post-infection complications such as arthritis and glomerulonephritis.
Type 4 hypersensitivity
Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The classical example of this hypersensitivity is tuberculin (Montoux) reaction which peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by induration and erythema (abnormal redness and inflammation of skin)
Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, etc.) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy, chemicals, heavy metals, etc.) in which the lesions are more papular. Type IV hypersensitivity can be classified into three categories depending on the time of onset and clinical and histological presentation
Table 3 - Delayed hypersensitivity reactions |
Type | Reaction time | Clinical appearance | Histology | Antigen and site |
contact | 48-72 hr | eczema | lymphocytes, followed by macrophages; edema of epidermis | epidermal ( organic chemicals, poison ivy, heavy metals, etc.) |
tuberculin | 48-72 hr | local induration | lymphocytes, monocytes, macrophages | intradermal (tuberculin, lepromin, etc.) |
granuloma | 21-28 days | hardening | macrophages, epitheloid and giant cells, fibrosis | persistent antigen or foreign body presence (tuberculosis, leprosy, etc.) |
This is the only class of hypersensitive reactions to be triggered by antigen-specific T cells. Delayed type hypersensitivity results when an antigen presenting cell, typically a tissue dendritic cell which has picked up antigen, processed it and displayed appropriate peptide fragments bound to class II MHC is contacted by an antigen specific TH1 cell patrolling the tissue. The resulting activation of the T cell produces cytokines such as chemokines for macrophages, other T cells and, to a lesser extent, neutrophils as well as TNFbeta and IFNgamma. The consequences are a cellular infiltrate in which mononuclear cells (T cells and macrophages) tend to predominate. It is usually maximal in 48-72 hours.
The problem which this explanation faces is the rarity of antigen-specific T cells. Despite the fact that "memory T cells", unlike naive T cells, do circulate through tissues, there is some doubt that a single T cell could initiate the event. The answer to this conundrum may lie in the recent observations that at least some Type IV reactions absolutely require the presence of 'natural' IgM antibody for initiation. Due to the nature and kinetics of the reaction it is still believed that activation of memory TH1 cells is primarily responsible for propagating the reponse, but initiation may require IgM and probably also complement. One theory is that limited IgM-antigen complexes in local capilliaries may lead to a limiting, localised complement activation within the vessel activating the vascular endothelium and thus recruiting inflammatory cells including memory T cells.
The classical example of delayed type hypersensitivity is in tuberculosis.The tuberculosis skin test is a test used to determine if someone has developed an immune response to the bacterium that causes tuberculosis (TB). The tuberculin skin test is based on the fact that infection with M. tuberculosis bacterium produces a delayed-type hypersensitivity skin reaction to certain components of the bacterium. The components of the organism are contained in extracts of culture filtrates and are the core elements of the classic tuberculin PPD (also known as purified protein derivative).
This PPD material is used for skin testing for tuberculosis. Reaction in the skin to tuberculin PPD begins when specialized immune cells, called T cells, which have been sensitized by prior infection, are recruited by the immune system to the skin site where they release chemical messengers called lymphokines. These lymphokines induce induration (a hard, raised area with clearly defined margins at and around the injection site) through local vasodilation (expansion of the diameter of blood vessels) leading to fluid deposition known as edema, fibrin deposition, and recruitment of other types of inflammatory cells to the area. An incubation period of two to 12 weeks is usually necessary after exposure to the TB bacteria in order for the PPD test to be positive.
Result Interpretation
A tuberculin reaction is classified as positive based on the diameter of the induration in conjunction with certain patient-specific risk factors. In a healthy person whose immune system is normal, induration greater than or equal to 15 mm is considered a positive skin test. If blisters are present (vesiculation), the test is also considered positive.
Positive test tuberculin: 18mm
Summary of type 4 hypersensitivity
1. Antigen is injected into the subcut tissue and processed by local APC
2. A Th1 effector cell recognizes antigen and releases cytokines which act on vascular epithelium
3. Recruitment of T cells, phagocytes fluid and protein to site of antigen injection causes visible lesion
TH1 Influence of immune response
Sources: Microbiology and immunology online; Univ of south carolina school of medicine; http;//www.-immuno-path.cam.ac.uk, The adaptive immune system; faculty.ccbcmd.edu, tuberculosis skin test medicine.net.com
