PATHOLOGY OF

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PATHOLOGY OF IMMUNE
REACTIVITY. ALLERGY. Professor Yu.I.
Bondarenko
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• Allergy is an immune response, that 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.

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• 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.

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Classification of allergens

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

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Classification of allergens

• a) uninfectious allergens
• Home dust
• Epidermal
• Pollen
• Food
• Industrial
• Officinal

• b) infectious allergens
• Bacterial
• Fungous
• Viral

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Food allergens

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• 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.

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• 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.

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Pollen allergens
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Domestic allergens

• 
  

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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.

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Classification of endogenous allergens

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

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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

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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.

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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

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Atopic Rhinites
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URTICARIA, HIVES, NETTLE RASH
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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

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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.

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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

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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.

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• 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.

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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.

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Anaphilactic allergy
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Mechanisms of allergy development
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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.

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Mechanisms of allergy development
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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.

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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

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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, binding 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.

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Cellular mechanisms of allergy

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Degranulation of mast cell
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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.

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??diators of allergy
1. Histamin 2. Heparin 3. Serotonin
4. Eosinophiles chemotaxis factor 5.
Platelet-activating factor 6. Prostaglandins
(tromboxan, prostacyclin) 7. Leukotriens
8. Superoxyde anion-radical 9. Bradykinin
10. Components of complement (?3?, ?5?) 11.
Lyzosomal enzymes 12. Polypeptide ?
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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.

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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.

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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.

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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

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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.

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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.

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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.

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Medicated allergy
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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 membranes 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.

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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.

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Cytotoxic type
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• Pathochemical stage. The main mediator of
  cytotoxicity is the activated enzymes of
  complement. Phagocytes release some lyzosomal
  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.

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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.

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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.

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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.

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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.

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Mechanisms of delayed type allergy
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Cellular mechanisms of delayed type allergy
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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.

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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.

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• 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.

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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.

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• 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.).

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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.

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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.

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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.

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Skin reaction onto allergen

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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.

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• 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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Immunedeficiency

• Classification of primary munedeficiency
• 1. Deficit of ?-system
  
• ?) Di Georges syndrome
• b) Nezelof syndrome
• c) Deficit of purinenucleoside phosphorilase
• 2. Deficit of B-system
• ?) Brutons X-linked agammaglobulinemia
• b) Selective IgA deficiency
• c) Disgammaglobulinemia

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Immunedeficiency

• 3. Severe combined immunedeficiencies
• ?) swiss type
• ?) Louis-Bares syndrome
  immunedeficiecy with
  telangiectasia, ataxia
• ?) immunedeficiency with
  thrombocytopenia and eczema
  (Wiskott-Aldrichs syndrome)
• 4. Deficit of stem bloodforming cell

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