РATHOLOGY РATHOLOGY OF IMMUNE OF IMMUNE REACTIVITYREACTIVITY..

АLLERGYАLLERGY

20.09.2012

By M.D., Marta R. GerasymchukBy M.D., Marta R. GerasymchukPATHOPHYSIOLOGY DEPARTMENTPATHOPHYSIOLOGY DEPARTMENT

IFNMUIFNMU

By M.D., Marta R. GerasymchukBy M.D., Marta R. GerasymchukPATHOPHYSIOLOGY DEPARTMENTPATHOPHYSIOLOGY DEPARTMENT

IFNMUIFNMU

ResistanceResistance is a state of insusceptibility of an is a state of insusceptibility of an organism to the influence of organism to the influence of pathogenicpathogenic factors. factors. There are such types of There are such types of resistanceresistance: : ► active and passive, active and passive, ► primary and secondary, primary and secondary, ► specific and unspecific. specific and unspecific. Active Active resistanceresistance is a result of the organism adaptation to is a result of the organism adaptation to

the long time pathological factor influences. the long time pathological factor influences. Passive Passive resistanceresistance is a result of anatomical and is a result of anatomical and

physiological peculiarities of each organism. physiological peculiarities of each organism. Primary (congenital) Primary (congenital) resistanceresistance is a result of the inherited is a result of the inherited

peculiarities of an organism and it manifest itself after peculiarities of an organism and it manifest itself after birth of the person. birth of the person.

Secondary (acquired) Secondary (acquired) resistanceresistance is a result of organism is a result of organism functional reactions changes, which occur during the functional reactions changes, which occur during the whole life. whole life.

Unspecific Unspecific resistanceresistance is the is the oppositionopposition to the influence of to the influence of many pathological agents. many pathological agents.

Specific Specific resistanceresistance is the is the oppositionopposition to the defined agent to the defined agent influence, for example, microorganisms; its result is influence, for example, microorganisms; its result is activation of the immune system.activation of the immune system.

ReactivityReactivity is ability of the organism is ability of the organism to alter functional activity of the to alter functional activity of the systems and organs for the systems and organs for the adaptation of organism to new adaptation of organism to new conditions of the environment for conditions of the environment for the survival. The concept the survival. The concept “reactivity“reactivity”” is connected with is connected with the  concept the  concept “resistance”“resistance”..

Types of reactivityThere are biological reactivity and individual reactivity. BiologicalBiological reactivity reactivity is a result of the morphological

and physiological peculiarities of all individuals, which are of the same biological species. For For example: some species of birds, fishes, and animal example: some species of birds, fishes, and animal change the vital activity according to the changes of change the vital activity according to the changes of the seasons.the seasons.

Individual reactivityIndividual reactivity is the reactivity of every individual. Individual reactivity is determined by age, sex, heredity, constitution, and functional conditions of organism’s regulatory systems, external environmental influences. For example: For example: some diseases arise only in infant organism some diseases arise only in infant organism (measles, roseola, small pox,(measles, roseola, small pox, rachitis rachitis, , scarlet-feverscarlet-fever) ) but not in adult’s one.but not in adult’s one.

 Individual reactivity of an organism is realized by Individual reactivity of an organism is realized by

specific and unspecific mechanisms.specific and unspecific mechanisms. • The specific mechanismsThe specific mechanisms are formed by immune system.

There are physiological specific mechanisms and pathological ones. • The specific physiological mechanisms of the individual reactivity are

the immune reactions, which form the specific resistance to some antigens (bacteries, viruses, fungus, tumours cells).

• The pathological specific mechanisms of the individual reactivity can cause development of the immunodeficiency or immunodepressive conditions of an organism or the allergic reactions and diseases.

• TheThe unspecific mechanismsunspecific mechanisms of the reactivity are physiological and pathological.

• Physiological unspecific reactivity is the vital reactions complex of the healthy organism in normal life conditions.

• Pathological unspecific reactivity is the complex of an organism’s reactions in abnormal life conditions as a result of the decrease of the adaptive potential of an organism (for example: shock, collapse, narcosis).

Mechanisms of the unspecific reactivity are realized by means of nervous system reactions (central nervous system, vegetative nervous system), endocrine system reactions; barrier systems; cell’s reactions; humoral reactions.

barrier systemsbarrier systemsThe barrier systems preserve an organism

against the pathological factors of the external environment. There are external and internal barriers.

The external barriers• The external barriers are skin, mucous

membranes, liver, spleen, lymphatic nodes and other organs, which have the cells of the system of mononuclear phagocytes.

Internal barriersInternal barriers• There are internal barriers in the organism, which are

named histohematic barriershistohematic barriers.. Wall of a capillary has the function of a barrier. The wall of a capillary lets in only the nutritious substances and does not let in the toxins, medicines.

• Examples of internal barriers:Examples of internal barriers: 1.1. hematoencephalichematoencephalic (blood-brain), 2.2. hematoophtalmichematoophtalmic (blood-eye tissue), 3.3. hematolabirintichematolabirintic (blood-lymph of a labyrinth), 4.4. hematoovarialhematoovarial (blood-ovarium tissue), 5.5. hematotesticalhematotestical (blood-testicular tissue)6.6. hematothyriodhematothyriod (blood-thyriod tissue), 7.7. placentaplacenta (mother’s blood-foetus blood). • Connective tissue, which surrounds the vessels and

penetrates into a tissue, executes the protective function too.

Components of the Adaptive Components of the Adaptive Immune SystemImmune System• antigens

• antibodies

• lymph system

• lymphocytes– B cells– T cells– NK cell (Natural

Killer)

AntigenAntigen

AntibodyAntibody

B cellB cell

T cellT cellNK cellNK cell

AllergyAllergy ((from Greek “allos” – “other”, “ergon” – from Greek “allos” – “other”, “ergon” – “action”) is the state of the increasing “action”) is the state of the increasing sensitiveness of the organism to the repeated sensitiveness of the organism to the repeated penetrating of allergen which is characterized penetrating of allergen which is characterized

by immunological mechanisms and self injury.by immunological mechanisms and self injury.

Allergy Allergy is an immune response, which is an immune response, which is followed by damage of own tissues.is followed by damage of own tissues.

Allergic diseases – is a group of diseases, in development base of which damage lies, caused by an immune reaction on

allergens. Allergic diseases are widely spread among people. It is considered that they cover about 10 % of earth population. In

different countries these sizes vacillate from 1 to 50 % and more.

General  etiology of allergic diseases The cause of allergic diseases is the allergen, the conditions of their

appearing are the specific peculiarities of the environment and state of organism reactivity.

AllergenAllergen – – is a substance that causes is a substance that causes development of an allergic reaction.development of an allergic reaction.

Allergens have all properties of antigens (macromolecularity, mainly protein nature, foreign for a particular organism). However allergic reactions can be caused by substances of 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. While entering the organism they become antigens (allergens) only after binding with tissues proteins. Here with complex antigens, which sensitize the organism are formed.

Classification of allergensClassification of allergens

I. By the structure the allergens are divided I. By the structure the allergens are divided into:into:

Complete (valuable)Complete (valuable) – at penetrating into the – at penetrating into the organism they cause the formation of antibodies or organism they cause the formation of antibodies or sensitized T- lymphocyte. After the chemical sensitized T- lymphocyte. After the chemical structure they are proteins.structure they are proteins.

Incomplete (partial)Incomplete (partial) – at penetrating into the – at penetrating into the organism they contact with the organism’s proteins organism they contact with the organism’s proteins (the conjugated connection). At the same times (the conjugated connection). At the same times complex antigens are generated which are capable complex antigens are generated which are capable to sensitize the organism i.e. to cause the formation to sensitize the organism i.e. to cause the formation of antibodies and sensitized T- lymphocyte. After of antibodies and sensitized T- lymphocyte. After the chemical structure they are haptens.the chemical structure they are haptens.

All allergens are divided into two groups – exogenous and endogenous allergens (autoallergens).

Exogenous allergens come into the organism from outside, endoallergens are formed in the organism. There are few allergens classifications. According to the origin exogenous allergens are divided into following groups:             

a)a)allergens of noninfectious origin:allergens of noninfectious origin: •epidermal, •home, •pollen, •food, •industrial and officinal;b) allergens of infectious origin:b) allergens of infectious origin:•bacterial, •fungous, •viral.Domestic allergens. Main role among them domestic dust plays,

which includes particles, bed-clothes, furniture, bacteria.

Canine and cat allergensCanine and cat allergens     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 an 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.

Pollen allergens. Allergic diseases are caused by shallow plants, pollen. It is called pollinosispollinosis. 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.

Pollen allergens

Food allergens. Many food products can be by allergens. They are usually fish, wheat, beans, tomatoes, milk, eggs. Chemical substances added to food products (dye-stuffs, antioxidants, aromatic and other substances) may also be allergens.

Food 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.

Washing means

Allergens of infectious origin.Allergens of infectious origin. Those infectious diseases, in pathogenesis of which allergy plays a leading role, were named infectiously allergic. These are all the chronic infections (tuberculosis, lepra, brucellosis, rheumatism, syphilis, 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 a possibility of sensitization on enterprises on production of stern squire, vitamins, antibiotics, enzymes arises.

Lepra

Fungi

The ways of the allergens penetrating The ways of the allergens penetrating into the organism:into the organism:

Enteral (alimentary, nutritional, nutritive Enteral (alimentary, nutritional, nutritive way).way).

Inhalation.Inhalation. Parenteral.Parenteral. Contact.Contact. Transplantation.Transplantation.

Pathogenesis of allergic reactionsR.A.CookR.A.Cook picked out allergic reactions of •immediate typeimmediate type and •allergic reactionsallergic reactions of delayed-typeof delayed-type or

hypersensitization of delayed-typehypersensitization of delayed-type.

In the base of classification the time of appearing of reaction after contact with allergen has been placed.

The reactions of immediate type developed 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.

CLASSIFICATION OF ALLERGY CLASSIFICATION OF ALLERGY BY R.A. COOKBY R.A. COOK

Immediate-type allergyImmediate-type allergy

1. Anaphylaxis 2. Serum sickness3. Atopic allergy а) pollinosis (hay fever, rhinitis, conjunctivitis)b) bronchial asthmac) Hivesd) Quinke’s edema

DelayedDelayed-type -type allergyallergy

1. Bacterial1. Bacterial 2. Contact dermat2. Contact dermatosiosiss 3. 3. AAutoallergyutoallergy 4. 4. TTransplant ransplant rejectionrejection

23

HYPERSENSITIVITY

IMMEDIATE DELAYED

TYPE I Ig E - mediated

TYPE IICytotoxic

TYPE IIIImmune Complex

TYPE IVCellular

The classification The classification by by P.Gell, R.CoombsP.Gell, R.Coombs is is

widely widely spread in the world. It is spread in the world. It is based on pathogenic principle. based on pathogenic principle.

By Rought (in 1980)By Rought (in 1980) V type - stimulating.V type - stimulating.

II – – IgE IgE, , II, IIIII, III – – IgM, G,IgM, G,

IVIV – – T-effectorsT-effectors, , VV - - IgM, GIgM, G

Lymphocytes are heterogenic according to their functions, Lymphocytes are heterogenic according to their functions, markers, receptors.markers, receptors.

The The T-lymphocytesT-lymphocytes acquire the specific antigen receptors, with the acquire the specific antigen receptors, with the help of which they identify an antigen and other markers. help of which they identify an antigen and other markers.

There are such types of There are such types of T-cellsT-cells: T-helpers, T-effectors. The last ones : T-helpers, T-effectors. The last ones form sensitized lymphocytes or killers, which participate in form sensitized lymphocytes or killers, which participate in realization of allergic reaction of delayed-type and realize cytotoxic realization of allergic reaction of delayed-type and realize cytotoxic action on cell-target. action on cell-target.

The The B-lymphocytesB-lymphocytes produce 5 produce 5 classes of immunoglobulins classes of immunoglobulins IgG, IgM, IgA, IgE, IgD.IgG, IgM, IgA, IgE, IgD.

These cells during ripening These cells during ripening acquire the receptors for acquire the receptors for antigen on their membranes. antigen on their membranes.

During binding of such During binding of such B-cellsB-cells with proper allergens and after with proper allergens and after the signal, received from the signal, received from T-T-helperhelper, they become activated, , they become activated, and proliferation and and proliferation and differentiation into antibody differentiation into antibody producing cells starts.  producing cells starts.  

Immune Response SummaryImmune Response Summary

Antigen

Macrophage

Helper T - Cell

Active Cytotoxic T-Cell Active B - Cell

Kills Infected Cells Memory T- Cell Plasma Cell Memory B-Cell

Antibodies

Deactivates Antigens

Displays copy of antigen on surface of cell

Cellular ImmunityCellular Immunity Antibody ImmunityAntibody Immunity

Cellular Immunity .vs. Antibody Immunity

• Carried out by T-Cells• Infected cells are killed by

Cytotoxic T –Cells.

• Carried out by B-cells• Antibodies are produced

and dumped into blood stream.

• Antibodies bind to antigens and deactivate them.

Cellular Immunity Antibody or Humoral Immunity

AntibodiesAntibodies• agglutination and

precipitation– enhances phagocytosis by gathering

antigens into clumps

• opsonization– coating an antigen with antibody

enhances phagocytosis

Antibodies

THE PATHOGENESIS OF THE PATHOGENESIS OF ALLERGIC REACTIONSALLERGIC REACTIONS

Stage I:Stage I: immunological.immunological.

Stage II:Stage II: pathochemical changes. pathochemical changes.

Stage III:Stage III: pathophysiological changes pathophysiological changes..

In the development In the development of allergic reaction of allergic reaction

there are three there are three stages:stages:

1. 1. Immunological stage.Immunological stage. It covers all It covers all the changes in immune system during the changes in immune system during the the penetrationpenetration of an allergen into the organism, of an allergen into the organism, formation formation

of antibodiesof antibodies or or sensitized lymphocytessensitized lymphocytes and their binding and their binding with the with the repeatedly entering allergenrepeatedly entering allergen. .

2. 2. Pathochemical stage.Pathochemical stage. Its sense is in Its sense is in formation of formation of biological active substancesbiological active substances. The stimulus to their . The stimulus to their formation is the binding of allergen to antibodies or formation is the binding of allergen to antibodies or sensitized lymphocytes at the end of immunological sensitized lymphocytes at the end of immunological stage. stage.

3. 3. Pathophysiological stage.Pathophysiological stage. It is described by pathogenic It is described by pathogenic action of formed action of formed mediatorsmediators onto cells, organs and tissues onto cells, organs and tissues of the organism with a clinical display. of the organism with a clinical display.

Sensibilization Sensibilization is the is the

immunologically mediated immunologically mediated

increasing sensitiveness of increasing sensitiveness of

the organism to the allergens.the organism to the allergens. Sensibilization Sensibilization

(sensitizing)(sensitizing) are: are: active active (independent (independent

production of immunoglobulin production of immunoglobulin

by the organism)by the organism) passivepassive (introduction of the ready antibodies from (introduction of the ready antibodies from

actively sensitized animals). The synthesis of the actively sensitized animals). The synthesis of the antibodies begins on the 3rd - 4th day after the first antibodies begins on the 3rd - 4th day after the first penetrating of the allergen and achieves the maximum in penetrating of the allergen and achieves the maximum in 2 weeks.2 weeks.

Type I hypersensitivity reaction

• IgE and IgG4 are formed as an answer to penetrating of allergen into the organism. They get fixed on the mast cells and basophiles of blood.

• These cells have on their surface  Fc-receptors for immunoglobulin.

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, trombocytes. Depending on the quantity of molecules of IgE-antibodies connected to antigen, quantity of antigen we can observe either inhibition of activity of the cell or its activation and transfer of the process to the next, pathochemical stage.

1. Initial antigen contact

Stage II Stage II (pathochemical)pathochemical)

At the repeated At the repeated

penetrating the allergen penetrating the allergen

associates with the associates with the

Fc-fragment of IgE Fc-fragment of IgE

activating of basophiles activation activating of basophiles activation

of arachidonic acid cascade is of arachidonic acid cascade is

liberation of prostaglandins and liberation of prostaglandins and

leukotrienes degranulation of leukotrienes degranulation of

mast cells (the freeing of biologically mast cells (the freeing of biologically

active substances (BAS).active substances (BAS).

• Activation of the mast and basophile cells leads to releasing of different mediators.

• 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 promotesStimulation 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 effectsStimulation of H2 causes the opposite effects. Besides this releasing of histamine from basophile leucocytes and

from the lungs is diminished through them, the function of the lymphocytes modulates, formation of migration ingibitory factor

(MIF) by T-lymphocytes gets oppressed, releasing of lysosome enzymes by neutrophile leucocytes diminishes as well. In many cases the increasing of quantity of histamine in blood is observed in the intensive stage of bronchial asthma, nettle-rash, officinal allergy.

Stage III. Stage III. Under the influence of mediators the permeability of vessels and Under the influence of mediators the permeability of vessels and

chemotaxis of neutrophiles and eosinophiles increase, which leads chemotaxis of neutrophiles and eosinophiles increase, which leads to to development of inflammatory reactiondevelopment of inflammatory reaction. .

The The increasing of permeability of vesselsincreasing of permeability of vessels promotes the exit of fluid, promotes the exit of fluid, immunoglobulins and complement into tissues. With the help of immunoglobulins and complement into tissues. With the help of mediators and also through the IgE-antibodies, the cytotoxic effect mediators and also through the IgE-antibodies, the cytotoxic effect of macrophages is activated, secretion of enzymes, prostaglandins of macrophages is activated, secretion of enzymes, prostaglandins and leukotriens, trombocyte activating factor is stimulated. and leukotriens, trombocyte activating factor is stimulated.

The released mediators cause also a damaging action onto cells The released mediators cause also a damaging action onto cells and connective tissue structures. and connective tissue structures.

BronchospasmBronchospasm develops in respiratory organs. These effects are develops in respiratory organs. These effects are clinically manifested by attacks of bronchial asthma, rhinitis, clinically manifested by attacks of bronchial asthma, rhinitis, conjunctivitis,  nettle-rash, skin itch, diarrhea. conjunctivitis,  nettle-rash, skin itch, diarrhea.

They distinguish the They distinguish the local local reactions of the reactions of the anaphylactic typeanaphylactic type. . E.g.: bronchial asthma, pollinosis (or pollen disease, grass pollen E.g.: bronchial asthma, pollinosis (or pollen disease, grass pollen allergy, hay fever), nettle-rash (or hives) allergy, hay fever), nettle-rash (or hives)

and and general general ones (anaphylactic shock). ones (anaphylactic shock).

39

► Is the Most Dangerous Form of a Type I Is the Most Dangerous Form of a Type I HypersensitivityHypersensitivity

► Allergens in the bloodstream can trigger Allergens in the bloodstream can trigger mast cell degranulation that contracts mast cell degranulation that contracts smooth musclesmooth muscle

► Small veins constrict and capillary pores Small veins constrict and capillary pores expand, forcing fluid into the tissuesexpand, forcing fluid into the tissues A drop in blood pressure, edema, and rash A drop in blood pressure, edema, and rash

occuroccur

► Contractions in the gastrointestinal tract and Contractions in the gastrointestinal tract and bronchial muscles cause cramps and bronchial muscles cause cramps and shortness of breathshortness of breath

► The lungs fill with carbon dioxideThe lungs fill with carbon dioxide This can cause death by asphyxiation in 10-15 This can cause death by asphyxiation in 10-15

minutesminutes

Anaphylactic Anaphylactic shockshock

Anaphylactic shockAnaphylactic shock develops in severe complication. develops in severe complication. Spasm of smooth muscles of internal organs with Spasm of smooth muscles of internal organs with clinical manifestation of clinical manifestation of bronchospasm bronchospasm (cough, (cough, expiratory breathlessness), expiratory breathlessness),

spasm of gastro-intestinal tract musclesspasm of gastro-intestinal tract muscles (spastic pain (spastic pain in the whole abdomen, nausea, vomiting, diarrhea), in the whole abdomen, nausea, vomiting, diarrhea),

spasm of uterus in womenspasm of uterus in women (pain below abdomen) are (pain below abdomen) are observed. observed.

Spastic phenomena are worsened by edemas of mucous Spastic phenomena are worsened by edemas of mucous covers of internal organs, during the edema of larynx covers of internal organs, during the edema of larynx the picture of asphyxia may develop. the picture of asphyxia may develop.

The The arterial pressure is sharply decreasedarterial pressure is sharply decreased, the heart , the heart insufficiency, ischemia of brain, seizes paralysis insufficiency, ischemia of brain, seizes paralysis develop, danger for the life of the patient appears.develop, danger for the life of the patient appears.

Cytotoxic reaction

• Antigens:Antigens: a) components of membranes of own cells (unchanged and

changed under the action of different factors); b) antigens are fixed (adsorbed) on cellular membranes (for

example, medicinal preparations); c) noncellular components of tissues (collagen, myelin).• Antibodies:Antibodies: IgG1, IgG2, IgG3, rare Ig M and Ig A.IgG1, IgG2, IgG3, rare Ig M and Ig A.

THE PATHOGENESIS OF THE CYTOTOXIC TYPE ALLERGIC THE PATHOGENESIS OF THE CYTOTOXIC TYPE ALLERGIC REACTIONSREACTIONS

► Stage II:Stage II:

Mediators of the cytotoxic type allergic reactions:Mediators of the cytotoxic type allergic reactions:► Complement components; Lysosomal enzymes;Complement components; Lysosomal enzymes;► Oxygen’s radicals; TNF;Oxygen’s radicals; TNF;► Perforin (channelPerforin (channel--forming protein)forming protein)..

The damage of the cell with the antigen properties The damage of the cell with the antigen properties

may be caused by three reasons:may be caused by three reasons: ► the 1st variant – the 1st variant – complement-mediated cytotoxicitycomplement-mediated cytotoxicity. . ► the 2nd variant – the 2nd variant – antibody-mediated immune clearanceantibody-mediated immune clearance

(phagocytosis(phagocytosis). ). ► the 3rd variant – the 3rd variant – antibody-dependent [cell-mediated] antibody-dependent [cell-mediated]

cytotoxicitycytotoxicity

Stage III:Stage III:► Remedies [medicamentous] allergy;Remedies [medicamentous] allergy;► Hemolytic anemia (illness) of newborns;Hemolytic anemia (illness) of newborns;► Post transfusion reactions (shock) in incompatible Post transfusion reactions (shock) in incompatible

blood transfusion after the groups of АВО or Rhesus factor;blood transfusion after the groups of АВО or Rhesus factor;► Auto allergic diseases.Auto allergic diseases.

CytotoxicCytotoxic type of the allergy can be a manifestation of officinal allergy with the development of leucocytopenia, trombocytopenia, hemolytic anemia etc. This may also happen in blood transfusion and also in rhesus incompatibility of mother and fetus.

Immunological stage. Many exogenous and endogenous antigens participate in formation of immune complexes. Among them there are officinal preparations (penicillin, sulfanilamides), antitoxic vaccines, allogen gamma-globulins, food product (milk, egg white), inhalation allergen (home dust, fungi). An antigen and antibody are in the free state (not fixed on the surface of cells). Their co-operation takes place in blood and other liquids of organism. 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. Pathochemical stage. Under the influence of immune complexes the following mediators are formed: fragments C3a, C5a, C4a of the complement, lyzosomal enzymes of phagocytes, kinines, superoxyde anion-radical.

Pathogenesis of immune complex diseases

The inflammation may lead to formation of ulcers, hemorrhages, thrombosis is possible in the vessels. This type of allergic reactions is the prominent one in development of serum, some cases of officinal and food allergy, some autoallergic diseases (rheumatoid arthritis, systemic red lupus erythematosus). In case of massive activation of complement anaphylactic shock, bronchial asthma may develop.

Pathophysiological stage. Usually immune complexes are placed on vessels of cannalicular apparatus of kidneys, inflammation with alteration, exudation and proliferation (glomerulonephritisglomerulonephritis) develops, in case if the complexes are placed in the lungs alveolitis appears, in skin – dermatitis.

48

In In systemic lupus systemic lupus erythematosuserythematosus (a.k.a. SLE, (a.k.a. SLE, lupus), nuclear components lupus), nuclear components of disintegrating white blood of disintegrating white blood cells elicit IgG productioncells elicit IgG production Immune complexes aggregate Immune complexes aggregate

in the skin and organs, in the skin and organs, causing rash and lesionscausing rash and lesions

Rheumatoid arthritisRheumatoid arthritis (RA) (RA) is an inflammatory condition is an inflammatory condition resulting in accumulation of resulting in accumulation of immune complexes in jointsimmune complexes in joints

Cell-Mediated Cell-Mediated ImmunityImmunity

cytotoxic T cells recognize the non-self cell and induce apoptosis (cell self death) in the viral infected or other microbial infected cell– this process also recognizes cancer cells

and destroys them– unfortunately this process also

recognizes and destroys non-self tissue or organ transplants

1. Initial contact with antigen

Cell-mediated hypersensitivity reactionCell-mediated hypersensitivity reactionImmunological stage.Immunological stage. ☻ The foreign antigen is phagocyted by macrophagesphagocyted by macrophages and get to T-helpers. ☻ At the same time macrophages secrete  IL-1, which stimulates T-helpersstimulates T-helpers. The latest excrete the growth factor pro-T-lymphocytes – IL-2, which activates and supports proliferation of antigen stimulated T-cells. ☻ This process leads to formation of sensitized formation of sensitized lymphocyteslymphocytes. ☻ They belong to T-lymphocytes and in the cell membrane they have receptors of the antibodyreceptors of the antibody type, which are able to connect with the antigenconnect with the antigen. ☻ In case of repeated penetration of the allergen into the organism it binds binds with the sensitized with the sensitized lymphocyteslymphocytes.

Pathochemical stage. This 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 excretion of different mediators, which are called lymphokineslymphokines. With the help of lymphokines (MIF, interleukines, chemotaxic factors, factor of transfer) mobilization of different cells (macrophages, polymorph-nuclear), increasing of chemotaxic activity and placing in the site of allergen occur. • MIF MIF promotes accumulation of macrophagesaccumulation of macrophages in the site of allergic damage, increases their activity and phagocytosisincreases 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. • There are several kinds of chemotaxic factorschemotaxic factors, each of which is called chemotaxis of leukocytes – macrophages, neutrophiles, eosinophiles and basophiles. Lymphotoxins cause damage and destroying of all different target-cells. • InterferonInterferon is secreted by lymphocytes and under the influence of α-interferon and nonspecific mitogens. It acts a modulating influence on cellular and humoral  mechanisms of immune reaction. • Besides lymphokines, lizosome enzymeslizosome enzymes also provide a 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. A particular form of lymphokines (lymphotoxin, interferon) shows a cytotoxic action and decreases activity of cell. In allergic reaction of delayed type damaging action may develop in several ways:

• 1) direct cytotoxic action of sensitized T-lymphocytesdirect cytotoxic action of sensitized T-lymphocytes on target-cells, which acquired autoallergen properties;

• 2) cytotoxic activitycytotoxic activity of T-lymphocytes, mediated  by mediated  by lymphotoxinlymphotoxin;               

• 3) releasing of lysosome enzymereleasing of lysosome enzyme, which damage tissue structures during phagocytosis.

• Inflammation that is associated to immune reaction  by action of mediators is a component of allergic reaction of allergic reaction of delayed-typedelayed-type. Nevertheless inflammation is at the same time a factor of damage of function of the organs.

• Allergic reactions of delayed type make the base of development of infectious-allergic diseasesinfectious-allergic diseases (tuberculosis, lepra, brucellosis, syphilis), rejection of  transplantrejection of  transplant, and autoallergic diseasesautoallergic diseases (disturbance of nervous system, endocrine glands etc.).  

54

Contact dermatitis develops after exposure to a variety of allergens– Repeated exposures

cause drying to skin with erythema and scaling

55

• Transplantation of Tissues or Organs Is an Important Medical Therapy – An autograft is a graft taken

from one part of the body and transplanted to another part of the same body

– An isograft is a graft from one identical twin to the other twin

– Allografts are grafts between genetically different members of the same species

– Xenografts are grafts between members of different species (rarely successful)

Pseudoallergic reactions• Pseudoallergy is a pathological process, which is clinically similar

to allergy but doesn’t have an immune stagedoesn’t have an immune stage of its development. Pseudoallergy differs from a simple one by the absence of first (immuneabsence of first (immune) stage. The rest two stages – releasing of mediators (pathochemicalpathochemical) and pathophysiological (stage of clinical manifestationsstage of clinical manifestations) are the same both in pseudoallergy and a real one. To pseudoallergic reactions refer only processes in the development of which the leading role play mediators, which are formed also in pathochemical stage of true allergic reactions.  

• 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.

• Clinical picture  of pseudoallergic diseases is close to one of allergic diseases. Development of such pathological processes as increasing of permeability of vessels, edema, inflammation, spasm of smooth muscles, destroying of blood cells lay in the base of this clinical picture. These processes may be local, organic and systemic. They are presented by rhinitis, nettle-rash, Kvinke’s edema, periodical headaches, disturbance of gastro-intestinal tract, bronchial asthma, vaccine disease, anaphylactic shock  and also damaging of certain organs.

Preventing of allergy. Hyposensitization• Prophylaxis of an allergic disease depends on its character and group of the allergens. It

consists of measures of preventing of penetration of given allergen into the organism and preventing of the influence of different irritating factors on the organism. If sensitization has already occurred  and allergic diseases has already started, the following measures are appropriate.

• 1. Suppression of antibodiesSuppression of antibodies and sensitized lymphocytes productionsensitized lymphocytes production with the help of immune depressants, ionizing radiation, cytostatics, specific lymphocyte vaccines and monoclonal antibodies. 

• 2. Specific desensitization by BezredkaSpecific 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 substancesInactivation of biological active substances. For this purpose antihistamine preparations, inhibitors of proteolytic enzymes etc. are introduced.

• 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.).

60

Immunodeficiencies Can Involve Any Immunodeficiencies Can Involve Any Aspect of the Immune SystemAspect of the Immune System

Primary immunodeficiency is the result of Primary immunodeficiency is the result of a genetic abnormalitya genetic abnormality

Secondary immunodeficiency is acquired Secondary immunodeficiency is acquired later in lifelater in life

61

X-linked (Bruton) agammaglobulinemia is a congenital humoral immunodeficiency B cells fail to develop so patients lack mature

B cells, plasma cells, and antibodies It is a sex-linked trait, more common

in males than females

In DiGeorge syndrome, the thymus fails to mature in the embryo so T cells do not develop

Patients with Ataxia-Telangiectasia: have malfunctioning B and T cells are deficient in IgA and IgE Paralysis and dementia lead to death by age 30

62

► Severe combined Severe combined immunodeficiency disease immunodeficiency disease (SCID) (SCID) involved lymph nodes involved lymph nodes deficient in B and T cellsdeficient in B and T cells One form is caused by an One form is caused by an

enzyme deficiency that can be enzyme deficiency that can be corrected using gene therapycorrected using gene therapy

► In In Chédiak-Higashi Chédiak-Higashi syndromesyndrome, lysosome within , lysosome within phagocytes cannot release phagocytes cannot release their contents to kill microbestheir contents to kill microbes

► In In chronic granulomatous chronic granulomatous disease, disease, phagocytes do not phagocytes do not produce substances to kill produce substances to kill microbesmicrobes