HYPERSENSITIVITY undesirable (damaging, discomfort producing and - - PowerPoint PPT Presentation

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

ANTIGEN

 soluble IMMUNO GLOBULINE  IgE



homocytotropic



binded with basophiles, mast cells

IMMUNE MECHANISM

• antigen reenters body
• attach to IgE on the

surface of mast or basophil cells



cross links the cell- bound IgE

 mast cell

degranulation - releases:

 Histamine,

Leukotrienes, SRS-A, ECF, and others

EFFECT



vasodilation



increased capillary permeability



smooth muscle spasm



skin- reaction- weal & flare

TYPE I HYPERSENSITIVITY

Induction and effector mechanisms

• Antigen enters body
• Antibodies produced
• Attach to surface of mast
• r basophil cells
• Mast cells become

sensitized

• Second or subsequent

contact with the allergen

• Anaphylaxis



Attaches to antibodies

• n 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 granules

• Histamine
• vasodilatation,
• bronchoconstriction,
• vascular permeability, mucus

secretion,

• Tryptase
• proteolysis
• Kininogenase
• kinins
• vasodilatation,
• vascular permeability, edema
• ECF-A(tetrapeptides)
• attract eosinophil and neutrophils

Newly formed mediators

• leukotriene B4
• basophil attractant
• leukotriene C4, D4
• same as histamine but 1000x

more potent

• prostaglandins D2
• edema
• pain
• PAF
• platelet aggregation
• heparin release
• microthrombi

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 OF ASTHMA PERSON EOSINOPHILIA BLOOD SMEAR OF HEALTHY PERSON BAL SMEAR OF HEALTHY PERSON BLOOD SMEAR OF ASTHMA PERSON

Eosinophils

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

• r 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.

RAST rating IgE level (IU/ml) comment < 0.35

ABSENT OR UNDETECTABLE ALLERGEN SPECIFIC IgE

1 0.35 – 0.69

LOW LEVEL OF ALLERGEN SPECIFIC IgE

2 0.70 – 3.49

MODERATE LEVEL OF ALLERGEN SPECIFIC IgE

3 3.50 – 17.49

HIGH LEVEL OF ALLERGEN SPECIFIC IgE

4 17.50 – 49.99

VERY HIGH LEVEL OF ALLERGEN SPECIFIC IgE

5 50.00 – 100.00

VERY HIGH LEVEL OF ALLERGEN SPECIFIC IgE

6 > 100.00

EXTREMELY HIGH LEVEL OF ALLERGEN SPECIFIC IgE

The RAST is scored on a scale from 0 to 6:

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

• f

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
• rdered 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

• f 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

ANTIGEN

 cellular

surface antigen

 cell + hapten IMMUNOGLOBULIN  IgG  IgM

IMMUNE MECHANIS M



complement activation- lysis



• psonisation -

macrophage phagocytosis



ADCC (NK cells)

• necrosis

EFFECT

 lysis  necrosis

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

Patient’s Serum Target RBCs

+ 

Step 1

+ 

Coombs Reagent (Antiglobulin) Step 2

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

• f 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

ANTIGEN

 soluble

IMMUNOGLO BULIN

 IgG  IgM

IMMUNE MECHANISM

 soluble immune

complexes

 complement activation

(classical pathway) - C3a, 4a and 5a

 inflammation

 immune cell infiltration

 neutrophils  platelets  Macrophages - in later

stages -in the healing process

EFFECT

 erythema  edema  necrosis

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

 cellular

IMMUNOGL OBULIN

 none  transferred

with T-cells IMMUNE MECHANISM

 cell mediated response:

 Th1 secrete cytokines

which activates:

 Tc - cytotoxic

damage

 monocytes and

macrophages, which cause the large of the damage  major lymphokines:

monocyte chemotactic factor, Il-2, INFÝ, TNFß,alpha, etc. EFFECT

 induration with

erythema as:

 contact allergy  tuberculin  granuloma

TYPE IV HYPERSENSITIVITY

Delayed hypersensitivity reactions

Type Reacti

• n

time Clinical appeara nce 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 induratio n lymphocytes, monocytes, macrophages intradermal (tuberculin, lepromin, etc.)

granuloma

21-28 days hardenin g macrophages, epitheloid and giant cells, fibrosis persistent antigen or foreign body presence (tuberculosis, leprosy, 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

• f 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

characteristics

type-I

(anaphylactic)

type-II (cytotoxic) type-III (immune complex) type-IV (delayed type) antibody IgE IgG, IgM IgG, IgM None antigen exogenous cell surface soluble tissues &

• rgans

response time 15-30 minutes minutes-hours 3-8 hours 48-72 hours appearance weal & flare lysis and necrosis erythema and edema, necrosis erythema and induration histology basophils and eosinophil antibody and complement complement and neutrophils monocytes and lymphocytes transferred with antibody antibody antibody T-cells examples allergic asthma, hay fever erythroblastosis fetalis, Goodpasture's nephritis SLE, farmer's lung disease tuberculin test, poison ivy, granuloma

Treatment

• Enviromantal control
• Hyposensitisation
• Administration of modified allergenes
• Administration of antihistamines
• Administration of coricosteroids
• Administration of immunosuppresants