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Clinical immunology

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Title: Clinical immunology


1
Clinical immunology
2
  • Allergy is an immune response, which is
    accompanied damage of own tissues.
  • Allergic diseases are widely spread among people.
    It is considered that they occupy about 10 of
    earth population. In different countries these
    figures change from 1 to 50 and more.

3
  • The cause of allergic disease is an
    allergen.
  • Allergen is the substance that causes
    development of an allergic response.
  • Allergens have all properties of antigen
    (macromolecularity, mainly protein nature,
    foreign for particular organism).
  • However allergic reactions can be caused by
    substances not only antigen nature, but also
    substances, not possessing these properties. To
    this group belong many officinal preparations,
    bacterial products, polysaccharides, simple
    chemical substances (bromine, iodine, chrome,
    nickel). These substances are called haptens.
    They become antigens (allergens) only after
    binding with tissues proteins.

4
Classification of allergens
  • Exogenous allergens
  • Endogenous allergens (autoallergens).
  • Exogenous allergens penetrate the organism from
    outside
  • Endoallergens are formed in the organism

5
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6
Classification of allergens
  • a) uninfectious allergens
  • Home dust
  • Epidermal
  • Pollen
  • Food
  • Industrial
  • Officinal
  • b) infectious allergens
  • Bacterial
  • Fungous
  • Viral

7
Food allergens

8
  • Domestic allergens. Main role among them domestic
    dust plays, which includes particles,
    bed-clothes, furniture, bacteria.
  • Epidermal allergens. To this group refer scurf,
    wool, birds, fur, fish, scales. Professional
    sensitization by epidermal allergen is observed
    in sheepmen, horsemen, poultry farms workers,
    hairdressers.
  • Officinal allergens. Any officinal preparation
    with a little exception causes the development of
    officinal allergy. Medicines or their
    metabolites are, as usual, haptens. In case of
    sensitization of the organism to one preparation,
    allergic reactions to other medicines, having
    alike chemical structure can arise.

9
  • Pollen allergens. Allergic diseases are caused by
    shallow plants, pollen. It is called pollinosis.
    The diverse types of pollen can have the general
    allergens, therefore in people, sensitive to one
    type of pollen, a reaction on its other kinds is
    possible.
  • Food allergens. Many food products can be by
    allergens. It is usually fish, wheat, beans,
    tomatoes, milk, eggs. Chemical substances added
    to food products (dye-stuffs, antioxidants,
    aromatic and other substances) may also be
    allergens.
  • Industrial allergens. The industrial allergens
    for the most are haptens. In each industrial
    production a particular admission of chemical
    matters is used. These are resin, glue and
    covering materials, plastics, dye-stuffs, metals
    and their salts, wood products, latex, perfumer
    substances, washing means, synthetic cloths and
    others.

10
Pollen allergens
11
Domestic allergens


12
Infectious allergens
  • Allergens of infectious origin.
  • All the different causative agents of infectious
    diseases and products of their life activity
    cause the development of allergic processes.
  • Those infectious diseases, in pathogenesis of
    which allergy plays leading role, were named
    infectious allergic. These are all the chronic
    infections (tuberculosis, lepra, brucellosis,
    syphilis, rheumatism, chronic candidosis etc.).
  • The widespread allergens are the fungi. Many
    nonpathogenic fungi while entering the organism
    cause sensitization and development of diverse
    allergic diseases (bronchial asthma).
  • Such fungi are contained in atmospheric air,
    dwellings, domestic dust, food products. With
    biotechnological development possibility of
    sensitization on enterprises on production of
    stern squire, vitamins, antibiotics, enzymes
    arises.

13
Classification of endogenous allergens
  • Natural Ecquired
  • (brain,eye,sexuel 1.Infectious
  • and thyroid glands) a) simplex
  • b) complex
  • 2.Uninfectious

14
Pathogenesis of allergy reactions
  • Classification of allergic reactions
  • by R.A.Cooke
  • Allergy of immediate type
  • Allergy of delayed-type or hypersensitization of
    delayed-type

15
Characteristic of allergic types
  • The time of appearing of reaction after contact
    with allergen was placed in the base of
    classification.
  • The reactions of immediate type develop during
    15-20 minutes, delayed-type after 1-2 days.
  • However it does not envelop all the variety of
    allergy displays. For example, some reactions
    develop over 4-6 or 12-18 hours.
  • Therefore the different immunological mechanisms
    of their development was put in base of the new
    classification were based on pathogenic
    principle.

16
Classification of allergy by R.A.Cooke
  • 1.Allergy of immediate type
  • 1.1. Anaphylaxis
  • 1.2. Serum disease
  • 1.3. Atopic disease
  • a) pollinosis
  • (hay fever,rhinitis,conjunctivitis)
  • b) bronchial asthma
  • c) nettle-rash (urticaria,hives)
  • d) Quinckes edema

17
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18
Atopic Rhinites
19
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20
Classification of allergy by R.A.Cooke
  • 2. Allergy reactions of delayed-type
  • 2.1. Contact dermatosis
  • 2.2. Infectious allergy
  • 2.3. Autoallergy
  • 2.4. Reaction of graft rejection

21
Classification of allergy by P.Gell, R.Coombs
  • Anaphylaxic
  • Cytotoxic
  • Immune-complex
  • Delayed hypersensitivity
  • Stimulating
  • It is based on pathogenic principle. The
    peculiarities of immune mechanisms lay in its
    base.

22
Allergy development
  • Entering into the organism antigen causes its
    sensitization
  • Sensitization is an immunological rising of
    organism sensitiveness to antigens (allergens) of
    exogenous or endogenous origin
  • According to method of receiving there are active
    and passive sensitizations
  • Active sensitization develops in artificial
    introduction or natural penetration of the
    allergen into the organism
  • Passive sensitization is reproduced in the
    experiment by introduction of blood plasma or
    lymphoid cells of an actively sensitized donor to
    an intact recipient

23
Formation of hypersensitivity
24
Effectory mechanisms hypersensitivity
25
Stages in development of allergy
  • 1. Immunological stage. It covers all the changes
    in immune system after the penetration of an
    allergen into the organism, formation of
    antibodies or sensitized lymphocytes and their
    binding with the repeatedly entering allergen.
  • 2. Pathochemical stage. Its sense is in formation
    of biological active substances. The stimulus to
    their formation is the binding of allergen to
    antibodies or sensitized lymphocytes at the end
    of immunological stage.
  • 3. Pathophysiological stage. It is described by
    pathogenic action of formed mediators onto cells,
    organs and tissues of the organism with clinical
    display.

26
  • Immunological mechanisms lie in base of allergic
    processes development.
  • Central cell of immune system is a lymphocyte.
  • Lymphocytes are heterogenic according to their
    functions, markers, receptors.
  • They develop from a stem cell. After that
  • a lymphoid stem cell is formed, from which T-
    and B-lymphocytes develop.
  • The T-lymphocytes acquire the specific antigen
    receptors, by means of which they identify an
    antigen and other markers.

27
Immune mechanisms
  • There are 3 types of T-cells
    T-helper
  • T-suppressors
  • T-effectors
  • The last ones form sensitized lymphocytes or
    killers, which participate in realization of
    allergic reaction of delayed-type and realize
    cytotoxic action on cell-target.
  • B-lymphocytes produce 5 classes of
    immunoglobulins IgG, IgM, IgA, IgE, IgD.
  • These cells during ripening acquire the
    receptors for antigen on their membranes. During
    binding of such B-cells with proper allergens and
    after the signal, received from T-helper, they
    become activated, and proliferation and
    differentiation into antibody producing cells
    starts.

28
Mechanisms of allergy development
29
Immune mechanisms
  • The correlation between two groups of
    subpopulations of T-helpers (Th-1 and Th-2) plays
    an important role in the development of immune
    reaction.
  • They are both formed of Th-0 and differ form each
    other by the set of secreted lymphokines and
    quantity of Fc-receptors for immune globulins on
    their surface.
  • On Th-2 there are many receptors for immune
    globulins A, M, E, and on Th-1 there are a few of
    them or they are absent.

30
Mechanisms of allergy development
31
Immune mechanisms
  • Activation of Th-1 increases formation of
    IL-2, it stimulates the secretion of immune
    globulins A, M and G by B-cells and switch on
    cellular mechanism of immunity.
  • Activation of Th-2 leads though IL-4 to changing
    of synthesis of IgE by B-cells to proliferation
    of fat cells and through IL-5 to increase and
    proliferation of eosinophiles.
  • There are antagonistic relationship between these
    two ways.
  • The choice of way of activation depends on
    character of allergen.
  • Besides, that the form of allergen, conditions on
    introduction into organism and its quantity play
    role.

32
Anaphylactic type of allergy
  • Anaphylactic type includes the next atopic
    diseases
  • Atopic bronchial asthma
  • Pollinosis
  • Atopic dermatitis
  • Nettle-rash (urticaria, havis)
  • Food and officinal allergy

33
Immunological stage
  • IgE and IgG4 are formed as an answer to
    penetrated allergen into the organism.
  • They get fixed on the mast cells and basophiles
    of blood. These cells have on their surface Fc
    receptors for immune globulin. The state of
    sensitization of the organism appears.
  • If the same allergen again gets into the organism
    or it still stays in the organism after the first
    penetration, connection of antigen with
    IgE-antibodies occurs.
  • The same thing is observed with IgG4. They bind
    with their receptors on basophiles, macrophages,
    eosinophiles, thrombocytes.
  • Depending on the quantity of IgE-antibodies
    connected to antigen, quantity of antigen can
    observe either inhibition of the cell activity
    or its activation and transfer to the
    pathochemical stage.

34
Cellular mechanisms of allergy

35
Degranulation of mast cell
36
Pathochemical stage
  • Activation of the mast cells and basophile leads
    to releasing of different mediators. The process
    of secretion of mediators need energy, thats why
    blocking of energy-formation blocks also
    releasing of mediators.
  • A certain role in this process play cAMP and
    cGMP. Secretion of one of the main mediators
    histamine depends on their correlation.
  • Many different mediators have been excluded from
    the mast cells and basophiles. Some mediators
    are in the cell in ready form and easily are
    secreted (histamine, serotonin, eosinophiles
    chemotaxic factors).
  • Some mediators are formed after stimulation of
    the cell (leukotriens, thrombocyte activating
    factors). This mediators act on vessels and
    target-cells, including in the development of
    allergic reaction eosinophiles, thrombocytes and
    other cells.
  • As a result eosinophiles, neutrophiles, which
    start also to release mediators phospholipase
    D, histaminase, leukotriens and others.

37
Histamine
  • Histamine is localized in ready form in granules
    of the mast cells and basophile leucocytes.
  • In the blood of healthy people histamine almost
    totally stays in basophile leucocytes.
  • Histamine acts on the tissues cells through the
    receptors of two types H1 and H2.
  • Their correlation and spreading on the cells of
    different cells is different. Stimulation of H1
    promotes to contraction of smooth muscles,
    endothelial cells and postcapillary part of
    microcirculation. This leads to increasing of
    permeability of vessels, development of edema and
    inflammation.
  • Stimulation of H2 causes the opposite effects.

38
Histamine effects
  • Releasing of histamine from basophile leucocytes
    and from the lungs is diminished through them,
    the function of the lymphocytes modulates,
    formation of migration inhibitory factor (MIF) by
    T-lymphocytes gets oppressed, releasing of
    lysosome enzymes by neutrophile leucocytes
    diminishes as well.
  • The increasing of quantity of histamine in blood
    is observed in the intensive stage of bronchial
    asthma, nettle-rash, officinal allergy.

39
Heparin
  • Heparin is activated after releasing out of the
    mast cells.
  • It possesses an antithrombine and
    anticomplementar activity.
  • Thrombocyte (platelet)activating factor (PAF) is
    secreted by basophiles, lymphocytes, thrombocytes
    and endothelial cells.

40
Platelet-activating factor (PAF)
  • PAF acts on target-cells through
    corresponding receptors
  • 1) it causes the aggregation of thrombocytes
    and releasing of histamine and serotonin out
    of them
  • 2) it helps to chemotaxis and secretion of
    granular contents of eosinophiles and
    neutrophiles
  • 3) it causes spasm of smooth muscles
  • 4) it increases permeability of vessels

41
Metabolites of arachidone acid
  • It is metabolized in two different ways
    cyclooxygenic and lipooxygenic.
  • Under the influence of cyclooxygenase
    prostaglandins, tromboxans and prostacycline are
    formed from arachidone acid.
  • Under the influence of lipooxygenase leukotriens
    are formed from it.

42
Prostaglandins and leukotriens
  • Prostaglandins of group F possess the ability to
    cause contraction of smooth muscles, including
    bronchi, and prostaglandins of group E provide
    the relaxing action.
  • Leukotriens cause the spasm of smooth muscles,
    increase secretion of mucous, decrease coronary
    blood flow and power of heart contractions,
    increase chemotaxis of polymorphic-nuclear
    leukocytes, lead to development of prolonged
    bronchial spasm.

43
Pathophysiological stage
  • Under influence of mediators permeability of
    vessels and chemotaxis of neutrophiles and
    eosinophiles are increased, that leads to
    development of inflammatory reaction.
  • The increase of permeability of vessels promotes
    the exit of fluid, immunoglobulins and complement
    into tissues.
  • By means of mediators and also through the
    IgE-antibodies, the cytotoxic effect of
    macrophages is activated, secretion of enzymes,
    prostaglandins and leukotriens, thrombocyte
    activating factor is stimulated.
  • The released mediators cause also damaging
    action onto cells and connective tissue
    structures.
  • Bronchospasm develops in respiratory organs.
  • These effects clinically are manifested by
    attacks of bronchial asthma , rhinitis,
    conjunctivitis, nettle-rash, skin itch,
    diarrhea.

44
Medicated allergy
45
Anaphylactic shock
  • Anaphylactic shock develops as severe
    complication.
  • Spasm of smooth muscles of internal organs with
    clinical manifestation of bronchospasm (cough,
    expiratory dyspnea), spasm of gastro-intestinal
    tract muscles (spastic pain in the whole abdomen,
    nausea, vomiting, diarrhea), spasm of uterus in
    women (pain below abdomen) are observed.
  • Spastic phenomena are worsened by edemas of
    mucous covers of internal organs, during the
    edema of larynx the picture of asphyxia may
    develop.
  • The arterial pressure sharply is decreased, the
    heart insufficiency, ischemia of brain, paralysis
    develop danger for the life of the patient
    appears.

46
Cytotoxic type of allergic reactions
  • Immunological stage. It is called cytotoxic
    because the antibodies that developed to antigen
    of the cell bind to cells and cause their damage
    or even lysis (cytolytic action). For swithing of
    this mechanism cells have to acquire
    autoallergen properties. Than the formation of
    autoantibodies is started. To development of this
    process further chemical substances, usually
    medicines, viruses, microbes. They may change the
    antigen structure of cellular membranes. The
    formed autoantibodies belong to IgG and IgM. They
    connect to corresponding antigens of the cells by
    means Fab-fragments.

47
  • Pathochemical stage. The main mediator of
    cytotoxicity is the activated enzymes of
    complement. Phagocytes release some lyzosome
    enzymes and generate superoxide anion-radical.
  • Pathophysiological stage. The damage of the cell
    with antigen properties may be caused by three
    factors
  • a) due to activation of complement, the
    components of which damage the cell
    membrane
  • b) due to activation of phagocytosis of the
    cells with fixed antibodies
  • c) due to activation of T-lymphocytes, natural
    killers, K-lymphocytes.

48
Immune complex type
  • Immunological stage. Many exogenous and
    endogenous antigens participate in formation of
    immune complexes. Among them officinal
    preparations (penicillin, sulfanilamides,),
    antitoxic vaccines, allogen gamma-globulins, food
    product (milk, egg, white), inhalation allergen
    (home dust, fungi). In case of penetration of
    soluble antigen into the organism IgG and IgM
    antibodies are formed. These antibodies can cause
    the formation of precipitate and connection to
    antigen. Immune complex can be formed in tissues
    or in blood flow.
  • Patochemical stage. Under the influence of immune
    complexes the next mediators are formed
    fragments C3a, C5a, C4a of the complement,
    lyzosomal enzymes of phagocytes, kinines,
    superoxyde anion-radical.

49
Immune complex type
  • Pathophysiological stage. Usually immune
    complexes are placed on vessels of cannalicular
    apparatus of kidneys, inflammation with
    alteration, exudation and proliferation
    (glomerulonephritis) develops, in case if the
    complexes are placed in the lungs alveolitis
    appears, in skin dermatitis. The inflammation
    may lead to formation of ulcers, hemorrhages,
    thrombosis is possible in the vessels. This type
    of allergic reactions is main in development of
    serum sick, some cases of officinal and food
    allergy, some autoallergic diseases (rheumatoid
    arthritis, systemic red lupus erythematosus). In
    case of activation of complement anaphylactic
    shock, bronchial asthma may develop.

50
Allergic reactions of delayed type
  • Immunological stage. The cellular mechanism of
    immunity is usually activated in case of
    intracellular localization of the antigen
    (mycobacterium, brucella, histoplasma etc.) or
    when cells are antigen themselves. It may be
    microbes, fungi and their spores, which get into
    the organism from the outside. The cells of own
    tissues also may acquire the auto allergen
    properties. This mechanism may take place as a
    response to formation of complex allergens, in
    case of including haptens into proteins, for
    example, in case of contact dermatitis, which
    appears during the contact of the skin with
    different medicinal, industrious and other
    allergens.

51
Immunological mechanisms
  • The foreign antigen is phagocyted by macrophages
    and get to T-helpers. At the same time
    macrophages secrete IL-1, which stimulates
    T-helpers. The latest excrete the growth factor
    pro-T-lymphocytes IL-2, which activates and
    supports proliferation of T-cells. This process
    leads to formation of sensitized lymphocytes.They
    belong toT-lymphocytes and in the cell membrane
    they have receptors of the antibody type, which
    are able to connect with the antigen. In case of
    repeated penetration of the allergen into the
    organism it binds with the sensitized
    lymphocytes.

52
Mechanisms of delayed type allergy
53
Cellular mechanisms of delayed type allergy
54
Pathochemical stage
  • It leads to morphological, biochemical and
    functional change in lymphocytes.
  • They are presented by blast transformation and
    proliferation, increasing of synthesis of DNA,
    RNA and proteins and secretion of different
    mediators, which are called lymphokines. By means
    of lymphokines (MIF, interleukines, chemotaxic
    factors, factor of transfer) mobilization of
    different cells (macrophages, polymorph-nuclear),
    increasing of chemotaxic activity occur.

55
Effects of lymphokines
  • MIF promotes accumulation of macrophages in the
    area of allergic damage, increases their activity
    and phagocytosis. It takes part in formation of
    granulems during infectious-allergic diseases,
    increase the ability of macrophages to destroy
    certain kinds of bacteria.
  • Chemotaxic factors, each of which is called
    chemotaxis of leukocytes macrophages,
    neutrophiles, eosinophiles and basophiles.
  • Lymphotoxins cause damage and destroy of
    different target-cells.

56
  • Interferon is secreted by lymphocytes and under
    the influence of a-interferon and unspecific
    mitogens. It acts modulating influence on
    cellular and humoral mechanisms of immune
    reaction.
  • Lymphokines, lysosomal enzymes also provide
    damaging activity. They are released during
    phagocytosis and destroying of cells.
  • Kallikreine-kinine system is also activated.
  • Histamine doesnt play a big role in this type
    of allergic reactions.

57
Pathophysiological stage
  • Lymphokines (lymphotoxin, interferon) shows
    cytotoxic action and decrease activity of cell.
  • Damaging action in allergic reaction of delayed
    type may develop in several ways
  • a) direct cytotoxic action of sensitized
    T-lymphocytes on target-cells,
    which acquired autoallergen properties
  • b) cytotoxic activity of T-lymphocytes,
    mediated by lymphotoxin
  • c) releasing of lysosome enzyme, which
    damage tissue structures during phagocytosis.

58
  • Inflammation is associated to immune reaction
    due to action of mediators is component of
    allergic reaction of delayed-type.
  • Nevertheless inflammation is factor of damage of
    organs function.
  • Allergic reactions of delayed type lie in the
    base of development of infectious-allergic
    diseases (tuberculosis, lepra, brucellosis,
    syphilis), transplant rejection and autoallergic
    diseases (disturbance of nervous system,
    endocrine glands etc.).

59
Allergic inflammation
60
Pseudoallergic reactions
  • Pseudoallergy is pathological process, which is
    clinically similar to allergy but doesnt have an
    immune stage of its development. The rest two
    stages releasing of mediators (pathochemical)
    and pathophysiological (stage of clinical
    manifestations) take place.
  • For pseudoallergic reactions are characterized
    only processes in the development of which the
    leading role play mediators, which are formed
    also in pathochemical stage of true allergic
    reactions.

61
Pseudoallergy
  • The reason of pseudoallergy is any substance that
    acts directly on effector cells (fat cells,
    basophiles etc.) or biological fluids and cause
    releasing of mediators from the cells or
    production of them in the fluids.
  • Practically most of the allergens can lead to
    development of both allergic and pseudoallergic
    reactions.
  • This depends on nature of the substance, its
    phase, frequency of introduction into the
    organism and reactivity of the organism.
  • Pseudoallergic reactions usually occur in
    officinal and food intolerance.
  • Many remedies more usually lead to development of
    pseudoallergy than true allergy.

62
Pseudoallergy
  • Clinical picture of pseudoallergic diseases is
    similar allergic diseases.
  • Development of such pathological processes as
    increase of permeability of vessels, edema,
    inflammation , spasm of smooth muscles,
    destruction of blood cells lie in the base of
    this clinical picture.
  • These processes may be local, organic and
    systemic.
  • They are presented by rhinitis, nettle-rash,
    Quinckes edema, periodical headaches,
    disturbance of gastro-intestinal tract, bronchial
    asthma, vaccine disease, anaphylactic shock and
    also damage of certain organs.

63
Skin reaction onto allergen


64
Prevention of allergy. Hyposensitization.
  • Prophylaxis of an allergic disease depends on its
    character and group of the allergens. It directs
    to preventing of penetration of given allergen
    into the organism and influence of different
    irritating factors on the one. If sensitization
    has occurred and allergic diseases has started
    the next measures are appropriated.
  • 1. Suppression of antibodies and sensitized
    lymphocytes production by means of immune
    depressants, ionizing radiation, cytostatics,
    specific lymphocyte vaccines and monoclonal
    antibodies.

65
  • 2. Specific desensitization by Bezredka.
    Desensitization is provided by little doses of
    the antigen, which do not cause severe reactions.
    The doses are introduced repeatedly after certain
    intervals of time, during which produced
    mediators get inactivated in the organism. The
    main dose of the antigen is introduced after
    antibodies binding. This method is effective in
    introduction of foreign medical vaccines.
  • 3. Inactivation of biological active substances.
    For this purpose antihistamine preparations,
    inhibitors of proteolytic enzymes etc.
  • 4. Protection of the cells from the influence of
    biological active substance and also normalizing
    of functional disorders in organs and systems
    (narcotic, spasmolytic substances, receptor
    blockers etc.).
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