Hypersensitivity refers to excessive, undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system.

Hypersensitivity reactions require a pre-sensitized (immune) state of the host. Hypersensitivity reactions can be divided into four types: type I, type II, type III and type IV, based on the mechanisms involved and time taken for the reaction. Frequently, a particular clinical condition (disease) may involve more than one type of reaction.

TYPE I HYPERSENSITIVITY Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticariaand 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). 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 (Fc; CD23) on mast cells and basophils. A subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances (figure 1). Cross-linking of IgE Fc-receptor is important in mast cell triggering. Mast cell degranulation is preceded by increased Ca++ influx, which is a crucial process; ionophores which increase cytoplasmic Ca++also promote degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress degranulation. The agents released from mast cells and their effects are listed in Table 1. Mast cells may be triggered by other stimuli such as exercise, emotional stress, chemicals (e.g., photographic developing medium, calcium ionophores, codeine, etc.),anaphylotoxins (e.g., C4a, C3a, C5a, etc.). These reactions, mediated by agents without IgE-allergen interaction, are not hypersensitivity reactions, although they produce the same symptoms.

Table 1. Pharmacologic Mediators of Immediate Hypersensitivity MEDIATOR Preformed mediators in granules histamine tryptase kininogenase ECF-A (tetrapeptides) bronchoconstriction, mucus secretion, vasodilatation, vascular permeability proteolysis kinins and vasodilatation, vascular permeability, edema attract eosinophil and neutrophils

Newly formed mediators leukotriene B4 leukotriene C4, D4 prostaglandins D2 PAF basophil attractant same as histamine but 1000x more potent edema and pain platelet aggregation and heparin release: microthrombi

The reaction is amplified by PAF (platelet activation factor) which causes platelet aggregation and release of histamine, heparin and vasoactive amines. Eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factors attract eosinophils and neutrophils, respectively, which release various hydrolytic enzymes that cause necrosis. Eosinophils may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E, although this role of eosinophils is now in question.

Cyclic nucleotides appear to play a significant role in the modulation of immediate hypersensitivity reaction, although their exact function is ill understood. Substances which alter cAMP and cGMP levels significantly alter the allergic symptoms. Thus, substances that increase intracellular cAMP seem to relieve allergic symptoms, particularly broncho-pulmonary ones, and are used therapeutically (Table 2). Conversely, agents which decrease cAMP or stimulate cGMP aggravate these allergic conditions.

Table 2 - Relationship between allergic symptoms and cyclic-nucleotides Lowering of cyclic-AMP stimulation of -adrenergic receptor (nor-epinephrin, phenyl-epinephrin) or blocking of -adrenergic receptor (propanolol) elevation of cyclic-GMP stimulation of -cholinergic receptor (acetyl choline, carbacol) WORSENING OF SYMPTOMS IMPROVEMENT OF SYMPTOMS elevation of cyclic-AMP stimulation of -adrenergic receptor (epinephrine, isoproterenol) blocking of -adrenergic receptor (phenoxybenzamine) inhibition of phosphodiesterase (theophylline) binding of histamine-2 or PGE to their receptors

Diagnostic tests for immediate hypersensitivity include skin (prick and intradermal) tests (fig. 1A), measurement of total IgE and specific IgE antibodies against the suspected allergens. Total IgE and specific IgE antibodies are measured by a modification of enzyme immunoassay (ELISA). Increased IgE levels are indicative of an atopic condition, although IgE may be elevated in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.). There appears to be a genetic predisposition for atopic diseases and there is evidence for HLA (A2) association. Symptomatic treatment is achieved with anti-histamines which block histamine receptors. Chromolyn sodium inhibits mast cell degranulation, probably, by inhibiting Ca++ influx. Late onset allergic symptoms, particularly bronchoconstriction which is mediated

by leukotrienes, are treated with leukotriene receptor blockers (Singulair, Accolate) or inhibitors of thecyclooxygenase pathway (Zileutoin). Symptomatic, although short term, relief from bronchoconstriction is provided by bronchodilators (inhalants) such as isoproterenol derivatives (Terbutaline, Albuterol). Thophylline elevates cAMP by inhibiting cAMP-phosphodiesterase and inhibits intracellular Ca++ release is also used to relieve bronchopulmonary symptoms. The use of IgG antibodies against the Fc portions of IgE that binds to mast cells has been approved for treatment of certain allergies, as it can block mast cell sensitization. Hyposensitization (immunotherapy or desensitization) is another treatment modality which is successful in a number of allergies, particularly to insect venoms and, to some extent, pollens. The mechanism is not clear, but there is a correlation between appearance of IgG (blocking) antibodies and relief from symptoms. Suppressor T cells that specifically inhibit IgE antibodies may play a role.

TYPE II HYPERSENSITIVITY Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are Figure 1A normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II close-up view of intradermal hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is skin test with multiple positive minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement (Figure 2). Phagocytes and K cells may also play a role. allergen responses
Bristol Biomedical Image Archive. Used with permission

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) (figure 3B). Treatment involves anti-inflammatory and immunosuppressive agents.

Figure 2. Type II cytotoxicity mechanism

TYPE III HYPERSENSITIVITY Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g., serum sickness) or Figure 3A may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), Immunofluorescent stain of lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be immunoglobulin G (IgG) the pathogenic mechanism of diseases caused by many microorganisms. showing linear pattern in

Goodpasture's syndrome
Bristol Biomedical Image Archive. Used with permission

Figure 3B Pemphigus vulgaris immunofluorescence Bristol

Biomedical Image Archive. Used with permission

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 (Figure 4). The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process. The affinity of antibody and size of immune complexes are important in production of disease and determining the tissue involved. Diagnosis involves examination of tissue biopsies for deposits of immunoglobulin and complement by immunofluorescence microscopy. The immunofluorescent staining in type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture's syndrome). The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (nephelometry) binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes anti-inflammatory agents.

TYPE IV HYPERSENSITIVITY Type IV hypersensitivity is also known as cell mediated or delayed type hypersensitivity. The classical example of this hypersensitivity is tuberculin (Montoux) reaction (figure 5) which peaks 48 hours after the injection of antigen (PPD or old tuberculin). The lesion is characterized by induration and erythema.

Figure 4. Mechanism of damage in immune complex hypersensitivity

Table 3 - Delayed hypersensitivity reactions Type Reaction time 48-72 hr Clinical appearance eczema local induration Histology lymphocytes, followed by macrophages; edema of epidermis lymphocytes, monocytes, macrophages Antigen and site epidermal ( organic chemicals, poison ivy, heavy metals, etc.) intradermal (tuberculin, lepromin, etc.)

contact Figure 5 Mantoux intradermal tuberculin skin test for

tuberculin

48-72 hr

tuberculosis granuloma

21-28 days

hardening

macrophages, epitheloid and giant cells, fibrosis

persistent antigen or foreign body presence (tuberculosis, leprosy, etc.)

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 (figure 6), 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). Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T cells (Tc) cause direct damage whereas helper T (TH1) cells secrete cytokines which activate cytotoxic T cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage (figure 4). The delayed hypersensitivity lesions mainly contain monocytes and a few T cells. Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, interleukin-2, interferongamma, TNF alpha/beta, etc. Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test (figure 5)) and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lympho-cytotoxicity and IL-2 production. Corticosteroids and other immunosuppressive agents are used in treatment.

Poison Ivy CDC

Figure 6

Table 5 - Comparison of Different Types of hypersensitivity characteristics antibody antigen type-I (anaphylactic) IgE exogenous type-II (cytotoxic) IgG, IgM cell surface type-III (immune complex) IgG, IgM soluble type-IV (delayed type) None tissues & organs

response time appearance histology transferred with

15-30 minutes weal & flare basophils and eosinophil antibody

minutes-hours lysis and necrosis antibody and complement antibody erythroblastosis

3-8 hours erythema and edema, necrosis complement and neutrophils antibody SLE, farmer's lung disease

48-72 hours erythema and induration monocytes and lymphocytes T-cells tuberculin test, poison ivy, granuloma

examples

allergic asthma, hay fever

fetalis, Goodpasture's nephritis

You have learned: Distinctions between different types of hypersensitivity. Mechanisms of immune-mediated damages. Examples of different types of hypersensitivity and overlap among them. Diagnostic test for hypersensitivity diseases and treatments.

http://pathmicro.med.sc.edu/ghaffar/hyper00.htm

Hypersensitivity
From Wikipedia, the free encyclopedia

Not to be confused with Sensory processing disorder#Hyposensitivities and hypersensitivities. This article is about the medical condition. For the music album, see Hypersensitive.

Hypersensitivity

Classification and external resources

ICD-10

T78.4

ICD-9

995.3

DiseasesDB

28827

MeSH

D006967

Hypersensitivity (also called hypersensitivity reaction) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. The four-group classification was expounded by P. H. G. Gell and Robin Coombs in 1963.[1]
Contents
[hide]

1 Coombs and Gell classification

1.1 Type V

2 References 3 External links

[edit]Coombs

and Gell classification

Comparison of hypersensitivity types

Type

Alternative names

Often mentioned disorders

Mediators

Atopy Anaphylaxis Asthma Autoimmune hemolytic anemia Thrombocytopenia Erythroblastosis fetalis Goodpasture's syndrome Membranous nephropathy Graves' disease *see type V explanation below Myasthenia Gravis *see type V explanation below Serum sickness Arthus reaction Rheumatoid arthritis Post streptococcal glomerulonephritis lupus Nephritis Systemic lupus erythematosus(SLE) Extrinsic allergic alveolitis(Hypersensitivity pneumonitis) Contact dermatitis Mantoux test Chronic transplant rejection Multiple sclerosis [4] Graves' disease IgM or IgG T-cells IgG (Complement) IgM or IgG (Complement) IgE and IgG4

Allergy (immediate)

II

Cytotoxic, antibody-dependent

III Immune complex disease

IV

Delayed-type hypersensitivity[2] [3](DTH), cell-mediated immune memory response, antibody-independent

Autoimmune disease, receptor mediated (see below)

 [edit]Type

Myasthenia Gravis

(Complement)

This is an additional type that is sometimes (often in the UK) used as a distinction from Type 2. [5] Instead of binding to cell surface components, the antibodies recognise and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signaling. Some clinical examples:

Graves' disease Myasthenia gravis

The use of Type 5 is rare. These conditions are more frequently classified as Type 2, though sometimes they are specifically segregated into their own subcategory of Type 2.

http://en.wikipedia.org/wiki/Hypersensitivity

Type IV hypersensitivity
From Wikipedia, the free encyclopedia

Type IV hypersensitivity

Classification and external resources

MeSH

D006968

Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response. CD4+ helper T cells recognize antigen in a complex with Class 2 major histocompatibility complex. The antigen-presenting cells in this case are macrophages that secrete IL-12, which stimulates the proliferation of further CD4+ Th1 cells. CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Th1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

[edit]Examples

Disease

Target antigen

Effects

Diabetes mellitus type 1

Pancreatic beta cell proteins (possibly insulin, Glutamate decarboxylase)

Insulitis Beta cell destruction Demyelinating disease Perivascular inflammation Paralysis Ocular lesions Chronic arthritis Destruction of articular cartilage and bone Neuritis Paralysis

Multiple sclerosis

Oligodendrocyte proteins (myelin basic protein, proteolipid protein)

Rheumatoid arthritis

Antigen in synovial membrane (possibly type II collagen)

Some peripheral neuropathies Schwann cell antigen

 Hashimoto's Thyroiditis Thyroglobulin antigen Crohn's disease Contact dermatitis Mantoux test* (diagnostic)
Unless else specified in boxes, then ref is: * - Mantoux test not taken from [1]

Hypothyroidism Hard goiter Follicular thymitis Chronic inflammation of ileum and colon Dermatitis with usually short-lived itching Skin induration indicates TB exposure

Unknown

Environmental chemicals, e.g. poison ivy, nickel Tuberculin

[1]

The pathophysiology of the Tuberculin reaction is explained thus: M. tuberculosis are engulfed by macrophages after being identified as foreign, but due to a self- preserving mechanism peculiar to TB it is able to block the fusion of the phagosome within which it is existing with the lysosome which would destroy it. So it can continue existing and replicating within the immune cell designed to destroy it. After several weeks, the immune system somehow [ mechanism as yet unexplained] ramps up and, on stimulation with IFN-gamma, the macrophages become capable of killing M. tuberculosis by forming phagolysosomes and nitric oxide radicals. However unfortunately the hyper-activated macrophages secrete TNF which recruits multiple monocytes into the battle. These cells differentiate into epithelioid histiocytes which wall off the infected cells, but at the cost of significant inflammation and local damage. Some other clinical examples:

Temporal arteritis Hashimoto's thyroiditis Symptoms of leprosy Symptoms of tuberculosis Coeliac disease Graft-versus-host disease[2] Chronic transplant rejection

http://en.wikipedia.org/wiki/Type_IV_hypersensitivity

Type III hypersensitivity

From Wikipedia, the free encyclopedia

Type III hypersensitivity

Classification and external resources

Immune complex

MeSH

D007105

Type III hypersensitivity occurs when antigen-antibody complexes that are not adequately cleared by innate immune cells accumulate, giving rise to an inflammatory response and attraction of leukocytes.

[edit]Presentation
Type III hypersensitivity occurs when there is little antibody and an excess of antigen, leading to small immune complexes being formed that do not fix complement and are not cleared from the circulation. It is characterized by solvent antigens that are not bound to cell surfaces (which is the case in type II hypersensitivity). When these antigens bind antibodies, immune complexes of different sizes form[1]. Large complexes can be cleared by macrophages but macrophages have difficulty in the disposal of small immune complexes. These immune complexes insert themselves into small blood vessels, joints, and glomeruli, causing symptoms. Unlike the free variant, a small immune complex bound to sites of deposition (like blood vessel walls) are far more capable of interacting with complement; these medium-sized complexes, formed in the slight excess of antigen, are viewed as being highly pathogenic[2].

Such depositions in tissues often induce an inflammatory response,[3] and can cause damage wherever they precipitate. The cause of damage is as a result of the action of cleaved complement anaphylotoxins C3a and C5a, which, respectively, mediate the induction of granule release from mast cells (from which histamine can cause urticaria), and recruitment of inflammatory cells into the tissue (mainly those with lysosomal action, leading to tissue damage through frustrated phagocytosis by PMNs and macrophages)[4].

Immune Complex Glomerulonephritis, as seen in Henoch-Schnlein purpura; this is an example of IgA involvement in a nephropathy

The reaction can take hours, days, or even weeks to develop, depending on whether or not there is immunlogic memory of the precipitating antigen. Typically, clinical features emerge a week following initial antigen challenge, when the deposited immune complexes can precipitate an inflammatory response. Because of the nature of the antibody aggregation, tissues that are associated with blood filtration at considerable osmotic and hydrostatic gradient (e.g. sites of urinary and synovial fluid formation, kidney glomeruli and joint tissues respectively) bear the brunt of the damage. Hence, vasculitis, glomerulonephritis and arthritisare commonly-associated conditions as a result of type III hypersensitivity responses[5]). As observed under methods of histopathology, acute necrotizing vasculitis within the affected tissues is observed concomitant to neutrophilic infiltration, along with notable eosinophilic deposition (fibrinoid necrosis). Often, immunofluorescence microscopy can be used to visualize the immune complexes
[6]

). Skin response to a hypersensitivity of this type is referred to as an Arthus reaction, and is characterized by local erythema and some

induration. Platelet aggregation, especially in microvasculature, can cause localized clot formation, leading to blotchy hemorrhages. This typifies the response to injection of foreign antigen sufficient to lead to the condition of serum sickness[7].

[edit]Examples
Some clinical examples:

Disease

Target antigen

Main effects

Systemic lupus erythematosus

Nuclear antigens

Nephritis Skin lesions

 Post-streptococcal glomerulonephritis Streptococcal cell wall antigens Polyarteritis nodosa Reactive arthritis Hepatitis B virus antigen Several bacterial antigens Serum sickness Various Arthus reaction Farmer's Lung HenochSchnlein purpura
Unless else specified in boxes, then ref is:
[8]

Arthritis Nephritis Systemic vasculitis Acute arthritis Arthritis Vasculitis Nephritis Cutaneous vasculitis Alveolar inflammation Purpura Glomerulonephritis

Various

Inhaled antigens (often mould or hay dust) Unknown, likely respiratory pathogen

http://en.wikipedia.org/wiki/Type_III_hypersensitivity

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 postinfection 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 contact tuberculin granuloma Reaction time 48-72 hr 48-72 hr 21-28 days Clinical appearance Histology eczema local induration hardening lymphocytes, followed by macrophages; edema of epidermis lymphocytes, monocytes, macrophages macrophages, epitheloid and giant cells, fibrosis Antigen and site epidermal ( organic chemicals, poison ivy, heavy metals,etc.) intradermal (tuberculin, lepromin, etc.) 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

http://drainameducci.blogspot.com/2011/08/hypersensitivity.html