Transcript 17. Clinical immunology

Clinical immunology
• 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.
• 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.
Classification of allergens
• Exogenous allergens
• Endogenous allergens
(autoallergens).
• Exogenous allergens penetrate 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 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.
Pollen
allergens
Domestic allergens
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Infectious allergens
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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.
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
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
Formation of hypersensitivity
Effectory mechanisms
hypersensitivity
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.
• 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.
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 Thelper, they become activated, and proliferation
and differentiation into antibody producing cells
starts.
Mechanisms of allergy
development
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.
Mechanisms of allergy
development
Immune mechanisms
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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.
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
• 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.
Cellular mechanisms of allergy
•
Degranulation of mast cell
Pathochemical stage
• Activation of the mast cells and basophile leads to releasing of
different mediators. The process of secretion of mediators need
energy, that’s 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.
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.
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.
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.
Platelet-activating factor (PAF)
1)
2)
3)
4)
PAF acts on target-cells through
corresponding receptors:
it causes the aggregation of thrombocytes
and releasing of histamine and serotonin out
of them
it helps to chemotaxis and secretion of
granular contents of eosinophiles and
neutrophiles
it causes spasm of smooth muscles
it increases permeability of vessels
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.
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
• 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 IgEantibodies, 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.
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
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.
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.
• 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.
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 gammaglobulins, 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.
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.
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.
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-Tlymphocytes – 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.
Mechanisms of delayed type
allergy
Cellular mechanisms of delayed
type allergy
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.
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.
• 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.
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.).