MHC immuno

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    How does a T cell know that a pathogen is inside a cell?

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    Receptors and ligands

    The receptor is the T cell receptor

    The ligandis a molecular complexthat the infected cell puts on itscell surface -A complex of a MHC molecule anda peptide from the pathogen.

    Engagement of the TCR by MHCand peptide results in stimulationof the T cell, cytokine productionand stimulation of the macrophageto become more cytotoxic.

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    ( )Major Histocompatibility Complex MHCMolecules

    ( )Human MHC HLA Human Leukocyte Antigens

    Stimulation of immune system- Transplanted tissue or against host ( )GVH

    - Autoimmunity- Against pathogens

    Steer the immune system to most effective response- Humoral extracellular microorganisms- Cellular intracellular microorganisms Education of T cells in thymus

    - -Self from non self- -Elimination of self reactive T cells

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    Ig vs. TCR

    Similarities

    Constant region

    Variable region

    Part of the same multigenefamily

    Differences

    Abs can be solubleTCR Cell-associated

    Ligands recognized

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    i sc on ti nu ou s o r o nf or ma ti on al e pi to pe s

    holevirus

    inearepi topes

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    InER

    InER

    InER

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    MHC class I expression

    is induced by type Iinterferons

    Plasmodium

    MHC CLASS IITRANSACTIVATOR

    BARELYMPHOCYTESYNDROME

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    JUST REMEMBER THE NUMBER 8

    MHC I x CD8 = 8

    MHC II x CD4 = 8

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    TAP

    I

    I

    I

    I

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    MHC and Transplantation

    The immune system (T cells) responds to non-self MHC on transplanted donor cells the same way that it responds to self-MHC with foreign peptide.

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    olymorphism inMHC

    120

    250

    70

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    - MHC alleles differ from each other by 1 50 amino acids mostly in antigen binding cleft

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    Allergy/Type I

    Hypersensitivity

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    Hypersensitivity Defined by two immunologists called

    Coombs and Gell They originally classified

    hypersensitivity into Types I-IV These can occur in isolation but

    diseases may present with amixture of hypersensitivityresponses

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    Hypersensitivity

    Type I Hypersensitivity: IgE mediatedactivation of mast cells

    Type II Hypersensitivity: antibodymediated binding of cell or tissuebound antigens

    Type III Hypersensitivity: antibodymediated immune complexes

    Type IV Hypersensitivity: T cellmediated DTH

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    TYPES OF HYPERSENSITIVITYGells and Coombs classification

    Type 1 - Immediate reaction - Ig Eantibodies

    Type 2 - Cytotoxicreaction - IgG &IgM Type 3 Immune complexes IgG &

    IgM Type 4 Delayed reaction 48 hrs T-

    cell mediated

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    Type I HypersensitivityReactions

    This is the immunological processwhich brings about Anaphylaxis

    Allergies The most common disorder of

    immunity About 20% of individuals in the US

    have some type of allergy

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    Hypersensitivity

    It is the typical response that occurs in

    Hay fever (allergic rhinitis) : Edema,irritation, mucus in nasalmucosa

    Asthma: bronchial constriction ,edema,

    mucus prod. Atopic dermatitis (eczema) Hives (urticaria) is usually associated with

    Type I Hypersensitivity Can be caused by other mechanisms

    An individual who has an allergy is atopic(out of place)

    Systemic anaphylaxis: bronchialconstriction, vasodilation

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    Eczema

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    Type I HypersensitivityMechanism

    Production of IgE by B cells Under Th2 control

    IgE binds to Fc RI on mast cells andbasophils

    Re-introduced antigen binds (cross-links) to IgE

    Mast cell/basophil degranulationoccurs

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    Type I Hypersensitivity If the above reaction takes place in the

    skin the response is a wheal and flarereaction

    This is seen in urticaria (hives) The reaction is called immediate It takes about 5' to occur and

    subsides within an hour

    Sometimes there is a further late phasereaction that o ccurs about 2 hours laterand peaks at about 24 hours

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    Wheal and Flare

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    Urticaria A vascular

    reaction of theskincharacterizedby erythema(flare) and

    wheal formationdue to localizedincrease of vascular

    permeability

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    Urticaria

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    IgE Some diseases are characterized by very

    high IgE levels Atopic eczema

    Levels up to 30,000 IU In many cases it is IgE specificity which is

    important i.e., what is the allergen

    Measure by a skin prick test Measure by a RAST

    (radioallergosorbent test)

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    Skin prick test

    This involves placing a small drop of a solution of the allergen to betested onto the patients skin

    Usually the back or arms Then inserting this into the intra-

    epidermis Using a hypodermic needle

    A wheal and flare response would bea positive result

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    Skin prick test

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    Regulation of IgE Synthesis

    This is induced by cytokines actingupon B cells to induce antibodyclass switching Secondary immune response

    IL-4 and IL-13 appear to induce theproduction of IgE

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    Common Allergens

    Airborne Grass Pollen Tree Pollen

    Mold Spores Animal Dander House Dust

    Mite

    Foods Fish/shellfish Eggs

    Peanuts Milk Gluten

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    A patient is stung by a bee for the first time andpresents with a wheal and flare response. What will

    your course of action be?

    A.Give immediateepinephrine to preventanaphylactic shock

    B.Give the patient aprescription forepinephrine in casethey are stung again

    C.Give the patient a

    prescription for anti-histaminesD.Admit the patient to ER

    and monitor thepatients vital signs

    E. Prescribe a to ical

    00

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    Mast Cells and Basophils

    Mast cells are tissue bound cells thatare found throughout the body

    There are differing types of mastcells in humans They vary morphologically,

    biochemically, and in their tissue

    distribution

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    Mast Cell

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    Eosinophil

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    Eosinophils

    Regulation of eosinophils appears tobe partially controlled by IL-5

    Evidence suggests a major role foreotaxin A chemokine

    During an acute helminth infection Numbers of circulating and local

    eosinophils increase

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    Mast Cell Activation Activation of mast cells and basophils

    results in Exocytosis of granules containing pre-

    formed mediators Synthesis of new mediators Secretion of cytokines, such as:

    IL-4 IL-5 IL-13

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    Mast Cell Activation

    Preformed mediators includebiogenic amines

    Histamine

    Heparin Chemotactic factors, serotonin Tryptase and chymase

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    Histamine Binds to target cell receptors called H 1 - H 4

    and causes a number of effects such as Smooth muscle contraction resulting in, forexample

    Increased peristalsis

    - Bronchospasms Vasodilation

    Large blood vessels are constricted andsmall ones are dilated

    Can give a blushing effect Effects upon the patient include

    Vascular endothelial cell retraction, plasmaleakage, the wheal and flare response

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    Newly SynthesizedMediators

    Newly synthesised from Arachdonicacid

    PGE-2 : Increases the pain response PGD-2 : increases the smooth muscle

    contraction Leukotrienes C4, D4 , E4 : same as

    PGD2 Leukotriene B4 : chemotactic for

    neutrophils

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    Physical effects of mast-celldegranulation vary by tissue

    Airways Decreased diameter, increased mucus secretion Expulsion of airway contents (phlegm, coughing)

    Skin Edema and erythema, wheal and flare response

    GI tract Increased fluid secretion, increased peristalsis Expulsion of GI contents (diarrhea, vomiting)

    Blood vessels Systemic anaphylaxis Increased blood flow and permeability Edema, inflammation, increased lymph flow

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    Prevention of ImmediateHypersensitivity

    Treatment is by:A) blocking the events leading to the

    clinical condition Anti-histamines Corticosteroids to inhibit PG and LT

    B) by reversing the physical changes

    that occur because of the reaction E.g., with epinephrine

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    Allergen Avoidance

    One needs to identify the allergen Many are common and may be

    avoided somewhat

    House dust mite Animal dander Many are common but are not easily

    avoided

    Peanuts

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    Anaphylactic Shock

    Pathophysiologic EffectsPathophysiologic Effects Clinical AnaphylaxisClinical Anaphylaxis

    Vascular dilationVascular dilation HypotensionHypotension

    Cardiac arrhythmiaCardiac arrhythmia SyncopeSyncope

    BronchoconstrictionBronchoconstriction

    Laryngeal edemaLaryngeal edema

    Laryngeal/respiratoryLaryngeal/respiratory

    obstructionobstruction Smooth muscleSmooth musclecontractioncontraction

    Abdominal cramping,Abdominal cramping,vomiting diarrheavomiting diarrhea

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    Type II Hypersensitivity

    This is where antibody (IgG or IgM) bindsto an antigen on a cell surface

    The cell is frequently part of an organ

    The kidney and lung in Goodpasture's syndrome The thyroid gland

    Graves or Hashimoto's diseases Or just an individual cell

    Immune thrombocytopenicpurpura (ITP)

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    Type II HypersensitivityMechanisms

    Once bound, the antibodies can:1.Activate complement leading to cell

    damage Immune thrombocytopenic purpura

    (ITP) Hemolytic anemia

    2.Activate ADCC for cytotoxic cellattack

    Autoimmune thyroiditis

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    Type II HypersensitivityMechanisms

    3.Antibodies can induce phagocytosisof target cells when they act asopsonins

    Extravascular autoimmune hemolyticanemia4.Bind to hormone receptors to

    activate the function of a cell ororgan Hyperthyroidism

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    Type II Hypersensitivity

    The consequences of Type IIHypersensitivity are frequentlysevere and progressive unless

    treated In some cases removal of the

    antibody can be of value

    Plasmapheresis for Goodpasture'ssyndrome

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    Type III Hypersensitivity

    This is the classic immune complex(IC) disease situation and occurswhere:

    A large amount of both antigen andspecific antibody accumulate If either antibody or antigen is in

    great XS large IC do not occur

    As seen in serum sickness and theArthus reaction

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    Type III Hypersensitivity

    They also occur when theantibody/antigen complexes do notactivate the classical complement

    cascade Can occur during a complement

    deficiency (C1, C4, C2)

    Can result in a disease similar tolupus

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    Type III Hypersensitivity This situation can also occur when

    immune complexes evadeactivation of the classical

    Complement pathway IgA

    e.g., Henoch-Schonlein purpura

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    Henoch-Schonlein Purpura

    IgA immunecomplexes aredeposited

    Two syndromes Henoch

    purpura affects

    the skinand GItract

    Schonlein

    purpura

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    Immune Complexes

    The antibody forming IC is usuallyIgM, IgG or IgA

    The antigen can be: a drug, from apathogen, a vaccine, host tissue, orantibody as in rheumatoid factor(Rf)

    IgM antibody bound to the Fc of IgG(usually)

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    Immune Complexes

    Immune complexes will circulatethroughout the body and may bedeposited in various sites The kidney The joints The peripheral vasculature (skin)

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    Immune Complexes

    Activated C will releaseanaphylatoxins

    Phagocytes will release inflammatoryand toxic molecules that will causetissue damage and plateletrecruitment

    The results can be inflammation and,if appropriate, purpura

    S i l h

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    Systemic lupus erythematosus(SLE)

    A systemic autoimmune disorder affecting The vasculature Kidneys

    Skin Joints CNS

    Serous tissue (serositis) Heart, spleen, lungs

    S i l h

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    Systemic lupus erythematosus(SLE)

    Characterized by numerousautoantibodies Especially anti-nuclear antibodies

    (ANA) Is often described as the typical Type

    III Hypersensitivity disease

    But also has elements of Type IIHypersensitivity May have positive Coombs test

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    Lupus

    S t i l th t

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    Systemic lupus erythematosus(SLE)

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    Arthus reaction

    This is a local tissue bound Type IIIHypersensitivity reaction

    It usually occurs after repeatedintramuscular (IM) injections of antigens

    It can induce pain and even necrosis

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    Type III Hypersensitivity

    Arthus reaction Local

    immunecomplexdepositiondue to

    immunization

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    Arthus Reaction

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    Immune Complex Mediated

    Disease Serum sickness This is due to the development of

    Type III Hypersensitivity

    It is a problem when administeringequine antiserum for bacterialtoxins such as:

    Diphtheria Tetanus

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    Serum sickness After repeated administration of horse

    antiserum individuals developed Arthritis

    Myalgia Vomiting Malaise

    Rashes Fever

    Contrasts Between

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    Contrasts BetweenHypersensitivity Types II and III

    Although both can affect the

    kidneys the mechanism aredifferent For example, both immune

    complexes and anti-GBMantibodies can accumulate in thekidneys but the effects aredissimilar

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    Goodpastures Syndrome

    Rapid progressive glomerulonephritisdue to anti-glomerular basementmembrane antibody, plus

    pulmonary hemorrhage Antibody cross reacts with the GBM

    and alveolar basement membrane

    (Type II Hypersensitivity)

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    Goodpastures Syndrome

    Both lupus and Goodpastures willactivate complement by theclassical pathways (C1, C2 and C4

    levels my be lower than NR) Both diseases will cause renal

    disease

    The actual effects caused byantibodies are different

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    Goodpastures Syndrome

    Goodpastures syndrome IFmicroscopy will reveal lineardeposition of IgG along the GBM

    Lupus however shows clumps of immune complexes deposited onthe GBM that have a lumpy-

    bumpy appearance

    Type IV (Delayed Type)

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    Type IV (Delayed Type)Hypersensitivity (DTH)

    This was originally defined as A hypersensitivity reaction that took

    more than 12 hours to develop

    This is typified by the classical skinreaction which occurs in responseto

    Nickel, poison ivy, latex, for example

    Type IV (Delayed Type)

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    Type IV (Delayed Type)Hypersensitivity (DTH)

    It can also take place in internalorgans The liver, gut

    The reaction is often chronic if internal and can last for years

    It occurs in conditions where the

    antigen is unknown or disputed, forexample sarcoidosis and perhapsCrohn's disease

    Type IV (Delayed Type)

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    Type IV (Delayed Type)Hypersensitivity (DTH)

    It occurs in response to somechronic infections, particularlyintracellular ones, e.g.,Mycobacterium tuberculosis (TB)

    It can also occur during graft

    rejection against solid organtransplants Liver, kidneys, heart

    It is a major mechanism forattacking solid tumors

    Delayed Type

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    Delayed TypeHypersensitivity

    It is an immune response mediatedmostly by CD4+ T cells

    t Th1 Also CD8+ T cells can contribute

    The effector cells are largely M

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    DTH

    Many of the substances inducingcontact hypersensitivity arehaptens

    Small molecules which are notantigenic until bound to a largerprotein, e.g., nickel

    They can complex with skin

    molecules Internalized by Langerhan's cells in

    the epidermis

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    DTH

    This complex is then presented with MHCClass II To CD4+ T cells

    Release cytokines ( TNF- , IL-2,IFN- )

    Approximately 24-48 hours after exposure,M accumulate

    The M release lysozomal enzymes Redness and pustules result

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    DTH

    The M can also release TNF- Active oxygen species

    The cytokines released from the Tcells will also have severe effectsupon the skin

    TNF-

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    Chronic DTH

    The M change morphology They fuse to form giant cells

    These become focused around sites

    of stimulation To form granulomas

    The tissue at the site of chronic DTHis eventually replaced by fibroustissue Fibrosis

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    Hypersensitivity and Drugs

    Type IV responses are frequently dueto topical medications

    A suspected sensitivity can beconfirmed by applying a weaksolution to the skin in a patch test.

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    Contact Hypersensitivity