Clinical Immunity

Clinical Immunity Lecture Dr Monem Alshok Dec 2011
Immunologic Mechanisms of Tissue Damage( Hypersensitivity reaction ): Immunopathology:Exaggerated immune response may lead to different forms of tissue damage
1) An overactive immune response: produce more damage than it prevents e.g. hypersensitivity reactions and graft rejection
2) Failure of appropriate recognition: as in autoimmune diseases
Hypersensitivity Reaction: Hypersensitivity or allergy
* An immune response results in exaggerated reactions harmful to the host
* There are four types of hypersensitivity reactions:
Type I, Type II, Type III, Type IV
* Types I, II and III are antibody mediated
* Type IV is cell mediated
Type I: Immediate hypersensitivity:
* An antigen reacts with cell fixed antibody (Ig E) leading to release of soluble molecules
An antigen (allergen) soluble molecules (mediators)
* Soluble molecules cause the manifestation of disease
* Systemic life threatening; anaphylactic shock
* Local atopic allergies; bronchial asthma, hay fever and food allergies
* First exposure to allergen :Allergen stimulates formation of antibody (Ig E type) Ig E fixes, by its Fc portion to mast cells and basophiles
* Second exposure to the same allergen : It bridges between Ig E molecules fixed to mast cellsleading to activation and degranulation of mast cells and release of mediators
Pathogenic mechanisms:
* Three classes of mediators derived from mast cells:
1) Preformed mediators stored in granules (histamine)
2) Newly sensitized mediators:
leukotrienes, prostaglandins, platelets activating factor
3) Cytokines produced by activated mast cells, basophils
e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines
* These mediators cause: smooth muscle contraction, mucous secretion and bronchial spasm, vasodilatation, vascular permeability and edema
Anaphylaxis:
* Systemic form of Type I hypersensitivity
* Exposure to allergen to which a person is previously sensitized
* Allergens:Drugs: penicillin ,Serum injection : anti-diphtheritic or ant-tetanic serum ,anesthesia or insect venom
* Clinical picture:Shock due to sudden decrease of blood pressure, respiratory distress due to bronhospasm, cyanosis, edema, urticaria
* Treatment: corticosteroids injection, epinephrine, antihistamines
Atopy
*Local form of type I hypersensitivity
* Exposure to certain allergens that induce production of specific Ig E
* Allergens : Inhalants:dust mite faeces, tree or pollens, mould spor. Ingestants: milk, egg, fish, choclate . Contactants: wool, nylon, animal fur .Drugs: penicillin, salicylates, anesthesia insect venom
* There is a strong familial predisposition to atopic allergy
* The predisposition is genetically determined
Methods of diagnosis
1) History taking for determining the allergen involved
2) Skin tests: Intradermal injection of battery of different allergens . A wheal and flare (erythema) develop at the site of allergen to which the person is allergic
3) Determination of total serum Ig E level
4) Determination of specific Ig E levels to the different allergens

Management
1) Avoidance of specific allergen responsible for condition
2) Hyposensitization:Injection gradually increasing doses of extract of allergen
- production of Ig G blocking antibody which binds
allergen and prevent combination with Ig E
- It may induce T cell tolerance
3) Drug Therapy:corticosteroids injection, epinephrine, antihistamines
Type II: Cytotoxic or Cytolytic Reactions
* An antibody (Ig G or Ig M) reacts with antigen on the cell surface
* This antigen may be part of cell membrane or circulating antigen (or hapten) that attaches to cell membrane
Mechanism of Cytolysis
* Cell lysis results due to :
1) Complement fixation to antigen antibody complex on cell surface
The activated complement will lead to cell lysis
2) Phagocytosis is enhanced by the antibody (opsinin) bound to cell antigen leading to opsonization of the target cell
3) Antibody depended cellular cytotoxicity (ADCC):
- Antibody coated cells e.g. tumour cells, graft cells or infected cells can be killed by cells possess Fc receptors
- The process different from phagocytosis and
independent of complement

Clinical Conditions:
1) Transfusion reaction due to ABO incompatibility
2) Rh-incompatability (Haemolytic disease of the newborn)
3) Autoimmune diseases
The mechanism of tissue damage is cytotoxic reactions e.g. SLE, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, myasthenia gravis, nephrotoxic nephritis, Hashimoto’s thyroiditis
4) A non-cytotoxic Type II hypersensitivity is Graves’s disease It is a form of thyroditits in which antibodies are produced against TSH surface receptor This lead to mimic the effect of TSH and stimulate cells to over- produce thyroid hormones
- Cells most active in ADCC are:
NK, macrophages, neutrophils and eosinophils
5- Graft rejection cytotoxic reactions: In hyperacute rejection the recipient already has performed antibody against the graft
6- Drug reaction:Penicillin may attach as haptens to RBCs and induce antibodies which are cytotoxic for the cell-drug complex leading to haemolysis.Quinine may attach to platelets and the antibodies cause platelets destruction and thrombocytopenic purpura
Type III: Immune Complex Mediated Reaction:
*When antibodies (Ig G or Ig M) and antigen coexist immune complexes are formed
*Immune complexes are removed by reticuloendoth. syst.
*Some immune complexes escape phagocytosis
*Immune complexes deposited in tissues on the basement membrane of blood vessels and cause tissue injury
Mechanism Of Tissue Injury:
Immune complexes trigger inflammatory processes: 1) Immune complexes activate ------------- the C C complement, --------------- anaphylatoxins C3a, C5a ---degranulation of basophiles and mast cells-- stimulate histamine release Histamine------- vascular permeability and help deposition of immune complexes
2) Neutrophils are attracted to the site by immune complexes and release lysosomal enzymes which damage tissues and intensify the inflammat. Pro.
3) Platelets are aggregated with two consequences
a- release of histamine
b- form of microthrombi which lead to ischemia
Diseases produced by immune complexes are those in which antigens persists without being eliminated as:
a- Repeated exposure to extrinsic antigen
b- injection of large amounts of antigens
c- Persistent infections
d- Autoimmunity to self components
Two Examples :
1 . Arthus Reaction
* This is a local immune complex deposition phenomenon e.g. diabetic patients receiving insulin subcutaneously * Local reactions in the form of edema& erythema& necrosis * Immune complexes-- Deposited in small blood vessels--- leading to------------- microthrombi formation , vasculitis vascular occlusion and necrosis
2 . Serum Sickness
* A systemic immune complex phenomenon
* Injection of large doses of foreign serum
* Antigen is slowly cleared from circulation
* Immune complexes are deposited in various sites
* 10 days after injection Fever, urticaria arthralgia,lymphadenopathy,splenomegaly , glomerulonephritis e.g. treatment with antidiphtheritic serum, penicillin, sulphonamides
3- Post-streptococcal glomerulonephritis glomerulitis associated with infective endocarditis
4- Hypersensitive pneumonitis (farmer lung)
immune complexes depositition in lung after repeated inhalation of dust , mould spores
5- Endogenous antigen antibody complexes involved in autoimmune diseasese.g. e.g. SLE, rheumatoid arthritis
Type IV Cell Mediated Delayed Type Hypersensitivity triggering DTH reactions by TH1
* T-cells cause tissue injury by or directly killing target cells by CD8
* TH1 and CD8 T cells secrete cytokines (IFN-? and TNF) attract lymphocytes
* Cytokines activate macrophages induce inflammation
* Tissue damage results from products of activated macrophages
1)Tuberculin –Type Hypersensitivity
* When PPD is injected intradermally in sensitized person
* Local indurated area appears injection site (48-72 hs)
* Indurations due to accumulation macrophages and lymphocytes
* Similar reactions observed in diseases
e.g. brucellosis, lepromin test in leprosy, Frei’s test in lymphogranuloma venereum
* In chronic diseases : T.B., Leprosy, schistosomiases
* Intracellular organisms resist destruction by macrophag.
* Persistent antigen in tissues stimulate local DTH reaction
* Continuous release of cytokines leads to accumulation of macrophages which give rise to epitheloidal and giant cell granuloma
2) Contact Dermatitis
* Contact of skin with chemical substances or drugs e.g. poison, hair dyes, cosmetics, soaps, neomycin
* These substances enter skin in small molecules
* They are haptens that attached to body proteins, form immunogenic substances
* DTH reaction to these immunogenic subst. lead to Eczyma ,inflammtory reaction of skin& vesicular eruption
Type IV Hypersensitivity Other Clinical Conditions:
3 )Auto immune diseases and graft rejection are due to in part to delayed hypersensitivity reactions
4 ) Insulin dependant diabetes mellitus :
T-cells invade the pancreatic islets and specifically destroy insulin secreting beta cells