HYPERSENSITIVITY
HYPERSENSITIVITY
undesirable (damaging, discomfort producing and sometimes fatal) reaction produced by the normal immune system
• hypersensitivity reactions require a pre-sensitized (immune) state of the host
HYPERSENSITIVITY
Hypersensitivity reactions can be divided into four types according to Gell and Coombs: • type I, • type II, • type III • type IV, based on: • time taken for the reaction • type of antygen • the mechanisms involved • clinical symptoms
Frequently, a particular clinical condition (disease) may involve more than one type of reaction.
TYPE I HYPERSENSITIVITY TYPE I HYPERSENSITIVITY
known also as immediate or anaphylactic hypersensitivity 15-30 minutes from the time of exposure,
although sometimes may have a delayed onset (10 - 12 h) symptoms depends on the place of antigen entrance and reaction appearance - weal & flare histology - basophils and eosinophils
TYPE I HYPERSENSITIVITY
ANTIGEN: is soluble exogenous e.g: Drugs (antibiotics) Foods (nuts, shellfish) Insect venoms pollens Antigens enter body by: Injection Ingestion Inhalation Absorption Induces antibody formation
Anaphylaxis Pathophysiology
IMMUNOGLOBULIN – IgE very high affinity for its receptor on mast cells and basophils = is homocytotropic
IMMUNE CELLs Mast cells In all subcutaneous/submucosal tissues, Including conjunctiva, upper/lower respiratory tracts, and gut Basophils Circulate in blood mechanisms: Subsequent exposure to the same allergen cross links the cell-bound IgE and triggers the release of various pharmacologically active substances degranulation is preceded by increased Ca++ influx. The reaction is amplified and/or modified by: platelets, neutrophils -which release various hydrolytic enzymes that cause necrosis eosinophils -may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E TYPE I HYPERSENSITIVITY
IMMUNE ANTIGEN MECHANISM antigen reenters body soluble attach to IgE on the surface of mast or basophil cells cross links the cell- EFFECT bound IgE IMMUNO vasodilation mast cell GLOBULINE degranulation - increased capillary permeability IgE releases: Histamine, smooth muscle homocytotropic binded with Leukotrienes, spasm basophiles, SRS-A, ECF, mast cells and others skin- reaction- weal & flare TYPE I HYPERSENSITIVITY Induction and effector mechanisms
Antigen enters body Antibodies produced Attach to surface of mast or basophil cells Mast cells become sensitized Second or subsequent contact with the allergen Anaphylaxis Attaches to antibodies on mast or basophil cells Mast cell degranulates, releases Histamine Leukotrienes Slow reacting substance of anaphylaxis (SRS-A) Eosinophil chemotactic factor (ECF) clinical effects
TYPE I HYPERSENSITIVITY Pharmacologic Mediators Preformed mediators in Newly formed mediators granules • leukotriene B4 • Histamine • basophil attractant • vasodilatation, • bronchoconstriction, • leukotriene C4, D4 • vascular permeability, mucus • same as histamine but 1000x secretion, more potent
• Tryptase • prostaglandins D2 • proteolysis • edema • pain
• Kininogenase • PAF • kinins • platelet aggregation • vasodilatation, • heparin release • vascular permeability, edema • microthrombi
• ECF-A(tetrapeptides) • attract eosinophil and neutrophils
TYPE I HYPERSENSITIVITY
biological effects Vasodilation Increased Capillary Permeability Smooth Muscle Spasm TYPE I HYPERSENSITIVITY biological effects VASODILATION
Decreased peripheral vascular resistance Hypotension Tachycardia Peripheral hypoperfusion TYPE I HYPERSENSITIVITY biological effects
Increased Capillary Permeability Tissue edema, urticaria (hives), itching Laryngeal edema Airway obstruction Respiratory distress Stridor (Awhistling sound when breathing) Fluid leakage from vascular space Hypovolemic shock (shock caused by severe blood or fluid loss) TYPE I HYPERSENSITIVITY biological effects Smooth Muscle Spasm GI Tract Spasm Nausea, vomiting Cramping, diarrhea Bronchospasm Respiratory distress “Tight Chest” Wheezing Bladder Spasm Urinary urgency Urinary incontinence
TYPE I HYPERSENSITIVITY CLINICAL MANIFESTATIONS: depends on place of antigen entrance and reaction skin -urticaria and eczema eyes -conjunctivitis,Hay fever nasopharynx -allergic rhinorrhea (persistent watery mucus discharge from the nose), gastrointestinal tract -gastroenteritis blood -anaphylactic shock bronchopulmonary -asthma may cause a range of symptoms from minor inconvenience to death
Urticaria
Anaphylaxis Systemic reaction of multiple organ systems to antigen-induced IgE-mediated immunulogic mediator release in previously sensitized individual limited or global Results in an acute allergic reaction with shortness of breath, rash, wheezing, hypotension. Atopy anaphlilatcic reactions of organisms with genetic predidpositions There appears to be a genetic predisposition for atopic diseases: high levels of IgE are produced there is evidence for HLA (A2) association
Anaphylactoid reaction 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
TYPE I HYPERSENSITIVITY
DIAGNOSTIC tests:
skin tests prick and intradermal BUT also in dermographism, (common types of urticaria in which the skin becomes raised and inflamed when stroked, scratched, rubbed, and sometimes even slapped), is NOT anaphylactoid reaction IgE level total IgE : - RIST, PRIST specific IgE antibodies against the suspected allergens –RAST, FAST, BUT increased IgE levels may be elevated in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.). eosinophiles in blood smear in nasal smear, BAL BUT increased eosinophiles amount may be elevated in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.). histamin, tryptase, leucotrienes level - only in researches - ELISA
Macrophages Eosinophils
BAL SMEAR BAL SMEAR OF ASTHMA PERSON OF HEALTHY PERSON
Eosinophils
BLOOD SMEAR BLOOD SMEAR OF HEALTHY PERSON OF ASTHMA PERSON EOSINOPHILIA Prick test
In the prick test, a few drops of the purified allergen are gently pricked on to the skin surface, usually the forearm. This test is usually done in order to identify allergies to pet dander, dust, pollen, foods or dust mites. Intradermal injections are done by injecting a small amount of allergen just beneath the skin surface. The test is done to assess allergies to drugs like penicillin or bee venom.
To ensure that the skin is reacting in the way it is supposed to, all skin allergy tests are also performed with proven allergens like histamine or glycerin. The majority of people do react to histamine and do not react to glycerin. If the skin does not react appropriately to these allergens then it most likely will not react to the other allergens. These results are interpreted as falsely negative. Skin „Prick test”
Interpretation of results The injection site is measured to look for the growth of wheal, a small swelling of the skin after 10 minutes.
• + – wheal diameter 2 mm - 5 mm • ++ – wheal diameter 5 mm - 1 cm with flare reaction • +++ – wheal with a severe flare reaction and characteristic „pseudopodia”
RAST - Radioallergosorbent Test is a blood test, which detect specific IgE antibodies to suspected or known allergens. If the serum contains antibodies to the allergen, those antibodies will bind to the allergen. Radiolabeled anti-human IgE antibody is added where it binds to those IgE antibodies already bound to the insoluble material. The unbound anti-human IgE antibodies are washed away. The amount of radioactivity is proportional to the serum IgE for the allergen. The RAST is scored on a scale from 0 to 6:
RAST rating IgE level (IU/ml) comment
ABSENT OR UNDETECTABLE 0 < 0.35 ALLERGEN SPECIFIC IgE
LOW LEVEL OF ALLERGEN 1 0.35 – 0.69 SPECIFIC IgE
MODERATE LEVEL OF ALLERGEN 2 0.70 – 3.49 SPECIFIC IgE
HIGH LEVEL OF ALLERGEN 3 3.50 – 17.49 SPECIFIC IgE
VERY HIGH LEVEL OF ALLERGEN 4 17.50 – 49.99 SPECIFIC IgE
VERY HIGH LEVEL OF ALLERGEN 5 50.00 – 100.00 SPECIFIC IgE
EXTREMELY HIGH LEVEL OF 6 > 100.00 ALLERGEN SPECIFIC IgE RIST - Radioimmunosorbent Test a radioimmunoassay technique for measuring total level of IgE immunoglobulins in serum, using radiolabeled IgE and anti-IgE bound to an insoluble matrix. Provocation tests:
Nasal provocation test Bronchial provocation test Oral provocation test
Bronchial provocation test used to detect asymptomatic allergic asthma. Testing involves exposing the patient to an allergen e.g., histamine by inhalation and then using a spirometer to measure corresponding lung function changes. Nasal provocation test Nasal provocation test is a diagnostic method involving the application of the alergen solution on the nasal cavity mucose to observe the changes in upper respiratory track. A positive nasal reaction is defined as the appearance of clinical symptoms such as rhinorrhoea, sneezing and nasal congestion combined with significant decreases in some parameters of rhinomanometry, acoustic rhinometry and/or peak inspiratory flows. Oral provocation test for oral food or drug allergy test, you ingest a food or drug in a capsule or in its natural form, and a physician observes you for the development of typical allergic symptoms. Food allergies can usually be detected using various dietary methods, in which the suspected food is excluded from the diet for a certain period of time and then reintroduced to see if symptoms appear. Food or drug allergy test is typically ordered only if the results from such dietary techniques, as well as from blood and skin allergy tests, are inconclusive or negative, but an allergy or intolerance is still suspected. TYPE I HYPERSENSITIVITY
TREATMENT: Symptomatic treatment
anti-inflammatory and immunosuppressive agents - steroids
Hyposensitization
TYPE I HYPERSENSITIVITY
Symptomatic treatment
antihistamines - block histamine receptors chromolyn sodium - inhibits mast cell degranulation, leukotriene receptor blockers inhibitors of the cyclooxygenase pathway bronchodilators (inhalants) -relief from bronchoconstriction Thophylline -elevates cAMP, is also used to relieve bronchopulmonary symptoms TYPE I HYPERSENSITIVITY
Hyposensitization =immunotherapy or desensitization allergy shots 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 IgG binds the alergen and prevent binding to IgE suppressor T cells that specifically inhibit IgE antibodies may play a role.
TYPE II HYPERSENSITIVITY TYPE II HYPERSENSITIVITY
also known as cytotoxic hypersensitivity may affect a variety of tissues – depends on type of affected cells the reaction time is minutes to hours appearance - lysis and necrosis histology - antibody and complement
TYPE II HYPERSENSITIVITY
ANTIGEN: normally : cellular -on the surface of cells f.e.: - erytrocytes, granulocytes, thrombocytes endogenous
also: exogenous (as haptens) which can attach to cell membranes: drugs chemicals
TYPE II HYPERSENSITIVITY
IMMUNE MECHANIS ANTIGEN M complement cellular activation- lysis surface opsonisation - EFFECT macrophage antigen phagocytosis lysis cell + hapten ADCC (NK necrosis cells) IMMUNOGLOBULIN - necrosis IgG IgM TYPE II HYPERSENSITIVITY cytotoxicity mechanism
TYPE II HYPERSENSITIVITY
CLINICAL MANIFESTATIONS: depends on cell types hemolytic anaemia posttransfusion reactions newborn hemolytic anaemia=erythroblastosis fetalis • affects a second baby autohemolytic anaemia: immune granulocytopenia -immunodeficiense immune thrombocytopenia -purpura tissues (organ speciffic autoimmune diseases) Goodpasture's nephritis -Ig to lung and kidney basement membrane myastenia gravis - Ig to acetylocholine receptors TYPE II HYPERSENSITIVITY
CLINICAL MANIFESTATIONS: Hemolytic anaemia
ABO incompatibility posttransfusion reactions preformed isoaglutinins of IgM type cause immediate intravascular hemolysis symptoms: fever, hypotensia, renal insufficiency Rh incompatibility IgG - incomplete cause opsonisation and phagocytosis/ADCC in liver and spleen symptoms: jaundice, anaemia
Hemolytic disease of newborn (HDN) The clinical symptons of HDN apperences within 24 hours after birth. - yellowish skin and yellow discoloration of the whites of the eyes - high-output heart failure with pallor - enlarged liver and/or spleen - generalized swelling and respiratory distress.
The diagnostic parameters: - peripheral blood morphology shows increased reticulocytes (anemia) - total bilirubin, alkaline phosphatase levels, alanine transferase – increase - direct Coombs test - positive
Coombs (Antiglobulin)Tests • Incomplete Ab • Direct Coombs Test - Detects antibodies on erythrocytes • Applications: •Hemolytic disease of newborn •Autoimmune hemolytic anemia
+
Patient’s RBCs Coombs Reagent (Antiglobulin) Coombs (Antiglobulin)Tests Indirect Coombs Test Detects anti-erythrocyte antibodies in serum
Step 1 + Patient’s Target Serum RBCs
Step 2
+
Coombs Reagent (Antiglobulin) Goodpasteur Syndrome
Immunofluorescent stain of immunoglobulin G (IgG) showing linear pattern in kidney tissue in Goodpasture's syndrome TYPE II HYPERSENSITIVITY
TREATMENT: anti-inflammatory and immunosuppressive agents
PROPHYLAXIS: antyglobulin serum – anti - Rh antibody in 72 h after childbirth eliminates the Rh+ eythrocytes and prevent the sensitization
TYPE III HYPERSENSITIVITY TYPE III HYPERSENSITIVITY
also known as immune complex hypersensitivity take 3 - 10 hours after exposure to the antigen the symptoms depens on place where complexes are deposed appearance - erythema and edema, necrosis histology - complement and neutrophils This reaction may be the pathogenic mechanism of diseases caused by many microorganisms TYPE III HYPERSENSITIVITY
ANTIGEN: is soluble not attached to the organ involved may be: exogenous -chronic bacterial, viral, infections endogenous = autontigen - e.g cytoplasmatic, nulear antigens • non-organ specific autoimmunity:e.g. SLE excess soluble antigen binds Ig and gets trapped in capilares TYPE III HYPERSENSITIVITY
IMMUNE MECHANISM ANTIGEN soluble immune soluble complexes complement activation (classical pathway) - C3a, EFFECT 4a and 5a erythema IMMUNOGLO inflammation edema BULIN immune cell infiltration necrosis IgG neutrophils platelets IgM Macrophages - in later stages -in the healing process
TYPE III HYPERSENSITIVITY Mechanism of damage in immune complex TYPE III HYPERSENSITIVITY
CLINICAL MANIFESTATIONS: depends on on place where complexes are deposed: local: skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis, glomerulonepritis), lungs (e.g., farmer's lung, aspergillosis), joints (e.g., rheumatoid arthritis) small blood vessels (e.g., polyarteritis), general: serum sickness
TYPE III HYPERSENSITIVITY
DIAGNOSTIC: detection of circulating immune complexes Polyethylene glycol-mediated turbidity (nephelometry), binding of C1q Raji cell test depletion in the level of complement ELISA, radial immunodiffusion the presence of immune complexes and complement deposites in the tissue (biopsy): indirect immunofluorescence – staining in type III hypersensitivity is granular TYPE III HYPERSENSITIVITY
TREATMENT: anti-inflammatory and immunosuppressive agents
TYPE IV HYPERSENSITIVITY TYPE IV HYPERSENSITIVITY
also known as: cell mediated -it is cellular response delayed type hypersensitivity -after 24-72h can be classified depending on the time of onset and clinical and histological presentation appearance - induration and erythema histology - monocytes and lymphocytes the classical example is tuberculin (Montoux) reaction
TYPE IV HYPERSENSITIVITY
ANTIGEN IMMUNE MECHANISM cellular cell mediated response: Th1 secrete cytokines which activates: Tc - cytotoxic EFFECT damage monocytes and induration with IMMUNOGL macrophages, which erythema as: cause the large of the OBULIN contact allergy damage none tuberculin major lymphokines: transferred monocyte chemotactic granuloma with T-cells factor, Il-2, INFÝ, TNFß,alpha, etc. TYPE IV HYPERSENSITIVITY Delayed hypersensitivity reactions
Type Reacti Clinical Histology Antigen and site on appeara time nce lymphocytes, followed epidermal ( organic 48-72 contact eczema by macrophages; chemicals, poison ivy, hr edema of epidermis heavy metals, etc.)
local lymphocytes, 48-72 intradermal (tuberculin, tuberculin induratio monocytes, hr lepromin, etc.) n macrophages
persistent antigen or macrophages, 21-28 hardenin foreign body presence granuloma epitheloid and giant days g (tuberculosis, leprosy, cells, fibrosis etc.)
Contact allergy – epidermal eczema in the place of the contact with hapten: nickel, drugs, latex…..
The hapten forms with protein a hapten-carrier complex in the epidermis. Langerhans cells recognizion the antigen and migrate via lymphatics to the regional lymph node where they present antigen to CD4+
The sensitization phase – 10- 14 days After the second contact hapten-carrier complex acitivated the memory Th CD4, which produced proinflamatory cytokines such as Il-1,Il-6 and also INFy. These cytokines activated keratinocytes and macrophages. Those cells cause the erythema and induration after 48 hours. Contact allergy The eczematous area at the stomach is due to sensitivity to nikiel in the belt buckle.
TYPE IV HYPERSENSITIVITY Mantoux intradermal tuberculin skin test for tuberculosis peaks 48 hours after the injection of antigen the lesion is characterized by: induration erythema diameter of infiltration TYPE IV HYPERSENSITIVITY
CLINICAL MANIFESTATIONS: depends on cell types: intracellular bacteria infection: tubeculosis, leprosy brucellosis, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis sarcoidosis contact dermatitis (haptens: poison ivy, chemicals, heavy metals) chronic organ rejection
TYPE IV HYPERSENSITIVITY
DIAGNOSTIC
The tests for delayed hypersensitivity include: in vivo test: include delayed cutaneous reaction (e.g. Montoux test ) patch test (for contact dermatitis). in vitro test: mitogenic response, lympho-cytotoxicity IL-2 production
Patch test The patch test simply uses a large patch which has different allergens on it. The patch is applied onto the skin, usually on the back. The allergens on the patch include latex, medications, preservatives, hair dyes, fragrances, resins and various metals. When a patch is applied the subject should avoid bathing or exercise for at least 48 hours.
Interpretation of the results
• Negative (-) • Borderline reaction (+/-) • Weak positive (+) • Strong positive (++) • Extreme reaction (+++)
Patch test TYPE IV HYPERSENSITIVITY TREATMENT: anti-inflammatory and immunosuppressive agents antibiotics
type-II type-III type-IV characteristics type-I (anaphylactic) (cytotoxic) (immune (delayed type)
complex) antibody IgE IgG, IgM IgG, IgM None
tissues & antigen exogenous cell surface soluble organs
response time 15-30 minutes minutes-hours 3-8 hours 48-72 hours
erythema and erythema and appearance weal & flare lysis and necrosis edema, induration necrosis
complement basophils and antibody and monocytes and histology and eosinophil complement lymphocytes neutrophils
transferred antibody antibody antibody T-cells with
erythroblastosis allergic SLE, farmer's tuberculin test, fetalis, examples asthma, hay lung disease poison ivy, Goodpasture's fever granuloma nephritis
Treatment
Enviromantal control Hyposensitisation Administration of modified allergenes Administration of antihistamines Administration of coricosteroids Administration of immunosuppresants