Download Pathology of immune reactivity.Allergy

PATHOLOGY OF
IMMUNE
REACTIVITY.
ALLERGY.
Professor Yu.I. Bondarenko
Immune reactivity
• Immune reactivity – is capacity of organism
to answer with high specific cellular and
humoral responses to action of antigen
1. Hyperfunction (allergy)
2. Hypofunction (immunedeficiency,
immunesupressive state)
3. Immuneproliferative diseases
• 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.
• 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 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.
Classification of allergens
• Exogenous allergens
• Endogenous allergens (autoallergens).
• Exogenous allergens penetrate to the
organism from outside
• Endoallergens are formed in the
organism
Classification of allergens
a) uninfectious
allergens:
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Home dust
Epidermal
Pollen
Food
Industrial
Officinal
b) infectious
allergens:
 Bacterial
 Fungous
 Viral
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 (dyestuffs, antioxidants, aromatic and other
substances) may also be allergens.
Industrial allergens. The industrial
allergens are haptens. In each industrial
production a particular admission of
chemical matters is used. These are: resin,
glue and covering materials, plastics, dyestuffs, metals and their salts, wood
products, latex, perfumer substances,
washing means, synthetic cloths and
others.
Pollen
allergens
Domestic allergens
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formed
Infectious allergens
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Allergens of infectious origin.
All the different agents of infectious
diseases and products of their vital activity
cause the development of allergic processes.
The 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 cause
sensitization and development of allergic
diseases (bronchial asthma).
Such fungi are contained in atmospheric air,
dwellings, domestic dust, food products,
antibiotics.
Classification of endogenous
allergens
Natural
Ecquired
(brain,eye,sexuel
1.Infectious
and thyroid glands)
a) simplex
b) complex
2.Uninfectious
Pathogenesis of allergy
reactions
Classification of allergic reactions
by R.A.Cooke
• Allergy of immediate type
• Allergy of delayed-type or
hypersensitization of delayedtype
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.
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) Quincke’s edema
Atopic Rhinites
URTICARIA, HIVES, NETTLE
RASH
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
Classification of allergy by
P.Gell, R.Coombs
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Anaphylaxic
Cytotoxic
Immune-complex
Delayed hypersensitivity
Stimulating
It is based on pathogenic principle. The
peculiarities of immune mechanisms lay
in its base.
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
Stages
in development of allergy
• 1. Immunological stage. It includes 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.
Anaphilactic allergy
Mechanisms of allergy
development
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
Immunological stage
• 1. Formation of IgE and IgG4
• in replay to penetrate allergen into the organism.
• 2. Fixation of Ig on Fc receptors of mast cells
and basophiles of blood.
The state of sensitization of the organism appears.
• 3. Binding of antigen with IgE-antibodies
if
the same allergen again gets into the organism.
• The same things is observed with IgG4. They
bind with their receptors on basophiles,
macrophages, eosinophiles, thrombocytes.
• 4. Transfer to the pathochemical stage.
Cellular mechanisms of allergy
•
Degranulation of mast cell
Pathochemical stage
• 1. Activation of the mast cells and basophile leads to
releasing of different mediators.
• 2. A certain role in this process play cAMP and cGMP.
Secretion of one of the main mediators – histamine
depends on their correlation.
• 3. Some mediators are in the cell in ready form and
easily are secreted (histamine, serotonin,
eosinophiles chemotaxic factors).
• 4. Some mediators are formed after stimulation of the
cell (leukotriens, thrombocyte activating factors).
• 5. Eosinophiles, neutrophiles release mediators also –
phospholipase D, histaminase, leukotriens and
others.
Biological active substances
(Mediators of allergy)
1. Histamin
2. Heparin
3. Serotonin
4. Chemotaxic factor of eosinophiles
5. Platelet-activating factor
6. Prostaglandins
7. Leukotriens
8. Super-oxyde anion
9. Bradykinin
10. Componentes of complement
11. Lyzosomal enzymes
12. Polypeptide P
Histamine
Stimulation of H1-receptors histamine causes:
1. Contraction of smooth muscles
2. Contraction of endothelial cells of capillares
3. Increase of vessels permeability of
microcirculation
4. Development of edema and inflammation
Stimulation of H2-histamine causes the opposite
effects.
Heparin
• Heparin is activated after releasing out
of the mast cells.
• It possesses an antithrombine and
anticomplementar activity.
PAF
Thrombocyte (platelet)activating factor
is secreted by basophiles,lymphocytes,
thrombocytes and endothelial cells.
Platelet-activating factor (PAF)
1.
2.
3.
4.
PAF acts on target-cells through
corresponding receptors:
Aggregation of thrombocytes and releasing of
histamine and serotonin out of them
Chemotaxis and secretion of granular
contents of eosinophiles and neutrophiles
Spasm of smooth muscles
Increase permeability of vessels
Metabolites of arachidone acid
• Metabolites of arachidone acid are
called eicosanoates
• Under the influence of cyclooxygenase
from arachidone acid are formed
prostaglandins, tromboxans and
prostacycline.
• Under the influence of lipooxygenase
are formed leukotriens from it.
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.
Pathophysiological stage
1. Under influence of mediators permeability of vessels and
chemotaxis of neutrophiles and eosinophiles are increased,
that leads to development of inflammatory reaction.
2.The increase of permeability of vessels promotes the exit of
fluid, immunoglobulins and complement into tissues.
3. 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.
4.The released mediators cause also damaging action onto
cells and connective tissue structures.
5. Bronchospasm develops in respiratory organs.
These effects clinically are manifested by attacks of bronchial
asthma , rhinitis, conjunctivitis, nettle-rash, skin itch, diarrhea.
Medicated allergy
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.
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).
• This process promote chemical substances,
medicines, viruses, microbes. They change
antigenic structure of cellular membranes.
• The formed autoantibodies belong to IgG and
IgM. They bind with corresponding antigens of
the cells by means Fab-fragments.
Cytotoxic type
• 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.
Immune complex type
• Immunological stage. Many exogenous and endogenous
antigens form immune complexes.
• 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.
Immune complex can be formed in tissues or in the blood.
• 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.
Immune complex type
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Pathophysiological stage.
Usually immune complexes are placed in 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.
Allergic reactions of delayed type
Immunological stage.
• The cellular mechanism of immunity take place
in case of intracellular localization of the antigen
(mycobacterium, brucella, histoplasma etc.) or
when cells are antigen.
• The cells of own tissues also may acquire the
autoallergen 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 for the
contact of skin with different medicinal, industrial
and other allergens.
Immunological mechanisms
1.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.
2. This process leads to formation of
sensitized T-lymphocytes. They have on cell
membrane receptors to antibody, which are
able to bind with the antigen. In case of
repeated penetration of the allergen into the
organism it binds with the sensitized
lymphocytes.
Mechanisms of delayed type
allergy
Cellular mechanisms of delayed
type allergy
Lymphokines
1. Group A - Lymphkines influence on macrophages
(MIF,MAF,ChF,MRF)
2. Group B - Lymphkines influence on lymphocytes
(Lawrence factor, Blasttransformating
factor,Helper’s faсtor)
3. Group C - Lymphkines influence on granucytes
(ChF,Inhibition factor)
4. Group D - Lymphkines influence on cellular culture
(Interferon, Inhibition factor)
5. Group E - Lymphkines acting in whole organism
(Lymphotoxin,IL-1,IL-2,IL-3,IL-4,IL-5,IL-6)
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.
• Interferon is secreted by lymphocytes and
under the influence of α-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 doesn’t play a big role in this type of
allergic reactions.
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.
• 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.).
Allergic inflammation
Pseudoallergic reactions
• Pseudoallergy is pathological process, which is
clinically similar to allergy but doesn’t have an
immune stage of its development. The rest two
stages – releasing of mediators (pathochemical)
and pathophysiological (stage of clinical
manifestations) take place.
• 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.
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.
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,
Quincke’s edema, periodical headaches,
disturbance of gastro-intestinal tract, bronchial
asthma, vaccine disease, anaphylactic shock
and also damage of certain organs.
Skin reaction onto allergen
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.
• 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.).
Immunedeficiency
Classification of primary munedeficiency
1.Deficit of Т-system
а) Di George’s syndrome
b) Nezelof syndrome
c) Deficit of purinenucleoside phosphorilase
2.Deficit of B-system
а) Bruton’s X-linked agammaglobulinemia
b) Selective IgA deficiency
c) Disgammaglobulinemia
Immunedeficiency
3. Severe combined immunedeficiencies
а) swiss type
б) Louis-Bare’s syndrome –
immunedeficiecy with
telangiectasia and ataxia
в) immunedeficiency with
thrombocytopenia and eczema
(Wiskott-Aldrich’s syndrome)
4. Deficit of stem bloodforming cell
Secondary immunedeficiency
(immunesupressive state)
1. Protein loss (blood loss, kidney and liver
insufficiency, burn)
2. Tumor of lymphoreticular system (Burkitt’s
lymphoma, lymphosarcoma)
3. Some treatment influencies (corticosteroids, X-ray,
cytostatics, immunodepressantes)
4. Acute and chronical infectious diseases
a.Virus (AID, measles, grip)
b.Bacterial (tuberculosis, lepra)
c.Fungous (candidosis, leishmaniasis)
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