РATHOLOGYOF IMMUNEREACTIVITY. АLLERGY By M.D., Marta R. GerasymchukPATHOPHYSIOLOGY DEPARTMENT IFNMU 20.09.2012
Resistance is a state of insusceptibility of anorganism to the influence of pathogenic factors.There are such types of resistance:► active and passive,► primary and secondary,► specific and unspecific.Active resistance is a result of the organism adaptation to the long time pathological factor influences.Passive resistance is a result of anatomical and physiological peculiarities of each organism.Primary (congenital) resistance is a result of the inherited peculiarities of an organism and it manifest itself after birth of the person.Secondary (acquired) resistance is a result of organism functional reactions changes, which occur during the whole life.Unspecific resistance is the opposition to the influence of many pathological agents.Specific resistance is the opposition to the defined agent influence, for example, microorganisms; its result is activation of the immune system.
Reactivity is ability of the organism to alter functional activity of the systems and organs for the adaptation of organism to new conditions of the environment for the survival. The concept “reactivity” is connected with the concept “resistance”.
Types of reactivityThere are biological reactivity and individual reactivity.Biological reactivity is a result of the morphological and physiological peculiarities of all individuals, which are of the same biological species. For example: some species of birds, fishes, and animal change the vital activity according to the changes of the seasons.Individual 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: some diseases arise only in infant organism (measles, roseola, small pox, rachitis, scarlet- fever) but not in adult’s one.
Individual reactivity of an organism is realized by specific and unspecific mechanisms.• The 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.• The unspecific 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 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 barriers• There are internal barriers in the organism, which are named histohematic 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:1. hematoencephalic (blood-brain),2. hematoophtalmic (blood-eye tissue),3. hematolabirintic (blood-lymph of a labyrinth),4. hematoovarial (blood-ovarium tissue),5. hematotestical (blood-testicular tissue)6. hematothyriod (blood-thyriod tissue),7. placenta (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• antigens Immune System• antibodies• lymph system• lymphocytes Antigen – B cells – T cells Antibody – NK cell (Natural Killer) B cell T cell NK cell
Allergy (from Greek “allos” – “other”, “ergon” –“action”) is the state of the increasingsensitiveness of the organism to the repeatedpenetrating of allergen which is characterizedby immunological mechanisms and self injury. Allergy is an immune response, which 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 theirappearing are the specific peculiarities of the environment and state of organismreactivity. Allergen – is a substance that causes development of an allergic reaction. Allergens have all properties of antigens (macromolecularity, mainly proteinnature, foreign for a particular organism). However allergic reactions can becaused by substances of not only antigen nature, but also substances, notpossessing 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 allergensI. By the structure the allergens are dividedinto:Complete (valuable) – at penetrating into theorganism they cause the formation of antibodiesor sensitized T- lymphocyte. After the chemicalstructure they are proteins.Incomplete (partial) – at penetrating into theorganism they contact with the organism’sproteins (the conjugated connection). At the sametimes complex antigens are generated which arecapable to sensitize the organism i.e. to cause theformation of antibodies and sensitized T-lymphocyte. After the chemical structure they arehaptens.
All allergens are divided into two groups – exogenous andendogenous allergens (autoallergens). Exogenous allergens come into the organism from outside,endoallergens are formed in the organism. There are few allergensclassifications. According to the origin exogenous allergens are dividedinto following groups: a)allergens of noninfectious origin: •epidermal, •home, •pollen, •food, •industrial and officinal; 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 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 preparationwith a little exception causes the development ofan officinal allergy. Medicines or theirmetabolites are, as usual, haptens. In case ofsensitization of the organism to one preparation,allergic reactions to other medicines, havingalike chemical structure can arise. Pollen allergensPollen allergens. Allergic diseases are caused by shallow plants, pollen. It is calledpollinosis. The diverse types of pollen can have the general allergens, therefore inpollinosispeople, sensitive to one type of pollen, a reaction on its other kinds is possible.
Food allergens. Many food products canbe by allergens. They are usually fish,wheat, beans, tomatoes, milk, eggs.Chemical substances added to food products(dye-stuffs, antioxidants, aromatic and othersubstances) may also be allergens. Food allergens
Industrial allergens. The industrialallergens for the most are haptens. In eachindustrial production a particular admission ofchemical 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. Thoseinfectious diseases, in pathogenesis ofwhich allergy plays a leading role, werenamed infectiously allergic. These are allthe chronic infections (tuberculosis,lepra, brucellosis, rheumatism,syphilis, chronic candidosis etc.). Thewidespread allergens are the fungi. Lepra Many nonpathogenic fungi while entering the organism cause sensitization and development ofdiverse allergic diseases (bronchialasthma). Such fungi are contained inatmospheric air, dwellings, domestic dust,food products. With biotechnologicaldevelopment a possibility of sensitizationon enterprises on production of sternsquire, vitamins, antibiotics, enzymesarises. Fungi
The ways of the allergens penetrating into the organism: Enteral (alimentary, nutritional, nutritive way). Inhalation. Parenteral. Contact. Transplantation.
Pathogenesis of allergic reactions R.A.Cook picked out allergic reactions of •immediate type and •allergic reactions of delayed-type orhypersensitization of delayed-type. delayed-type In the base of classification the time of appearing ofreaction after contact with allergen has been placed. The reactions of immediate type developed during15-20 minutes, delayed-type – after 1-2 days. However it does not envelop all the variety ofallergy displays. For example, some reactionsdevelop over 4-6 or 12-18 hours.
I – IgE, II, III – IgM, G, IV – T-effectors, The classification by V - IgM, G P.Gell, R.Coombs is HYPERSENSITIVITY widely spread in the world. It is based on pathogenic principle. IMMEDIATE DELAYEDBy Rought (in 1980)V type - stimulating. TYPE I TYPE II TYPE III TYPE IV Ig E - mediated Cytotoxic Immune Complex Cellular 23
Lymphocytes are heterogenic according to their functions, markers, receptors. The T-lymphocytes acquire the specific antigen receptors, with the help of which they identify an antigen and other markers. There are such types of T-cells: T-helpers, 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. The 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.
Immune Response Summary Displays copy of antigen on surface of cell Antigen Macrophage Cellular Immunity Helper T - Cell Antibody Immunity Active Cytotoxic T-Cell Active B - CellKills Infected Cells Memory T- Cell Plasma Cell Memory B-Cell Antibodies Deactivates Antigens
Cellular Immunity .vs. Antibody Immunity Cellular Immunity Antibody or Humoral Immunity• Carried out by T-Cells • Carried out by B-cells• Infected cells are killed by • Antibodies are produced Cytotoxic T –Cells. and dumped into blood stream. • Antibodies bind to antigens and deactivate them.
Antibodies• agglutination and precipitation – enhances phagocytosis by gathering antigens into clumps• opsonization – coating an antigen with antibody enhances phagocytosis
THE PATHOGENESIS OF ALLERGIC REACTIONSStage I: immunological.Stage II: pathochemical changes.Stage III: pathophysiological changes.
In the development of allergic reaction there are three stages: 1. Immunological stage. It covers allthe changes in immune system duringthe 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 a clinical display.
Sensibilization is theimmunologically mediatedincreasing sensitiveness ofthe organism to the allergens. Sensibilization(sensitizing) are: active (independent production of immunoglobulin by the organism) passive (introduction of the ready antibodies from actively sensitized animals). The synthesis of the antibodies begins on the 3rd - 4th day after the first penetrating of the allergen and achieves the maximum in 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 1. Initial antigen contact 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.
Stage II (pathochemical) At the repeatedpenetrating the allergenassociates with theFc-fragment of IgEactivating of basophiles activationof arachidonic acid cascade isliberation of prostaglandins andleukotrienes degranulation ofmast cells (the freeing of biologicallyactive 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 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. 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. Under the influence of mediators the permeability of vessels and chemotaxis of neutrophiles and eosinophiles increase, which leads to development of inflammatory reaction. The increasing of permeability of vessels promotes the exit of fluid, immunoglobulins and complement into tissues. With the help of mediators and also through the IgE-antibodies, the cytotoxic effect of macrophages is activated, secretion of enzymes, prostaglandins and leukotriens, trombocyte activating factor is stimulated. The released mediators cause also a damaging action onto cells and connective tissue structures. Bronchospasm develops in respiratory organs. These effects are clinically manifested by attacks of bronchial asthma, rhinitis, conjunctivitis, nettle-rash, skin itch, diarrhea. They distinguish the local reactions of the anaphylactic type. E.g.: bronchial asthma, pollinosis (or pollen disease, grass pollen allergy, hay fever), nettle-rash (or hives) and general ones (anaphylactic shock).
► Is the Most Dangerous Form of a Type I Hypersensitivity► Allergens in the bloodstream can trigger mast cell degranulation that contracts smooth muscle► Small veins constrict and capillary pores expand, forcing fluid into the tissues A drop in blood pressure, edema, and rash occur► Contractions in the gastrointestinal tract and bronchial muscles cause cramps and shortness of breath► The lungs fill with carbon dioxide This can cause death by asphyxiation in 10-15 39 minutes
Anaphylactic shockAnaphylactic shock develops in severe complication. ♦Spasm of smooth muscles of internal organs with clinical manifestation of bronchospasm (cough, expiratory breathlessness),♦ 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 is sharply decreased, the heart insufficiency, ischemia of brain, seizes paralysis develop, danger for the life of the patient appears.
Cytotoxic reaction• 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: IgG1, IgG2, IgG3, rare Ig M and Ig A.
THE PATHOGENESIS OF THE CYTOTOXIC TYPE ALLERGIC REACTIONS► Stage II:Mediators of the cytotoxic type allergic reactions:► Complement components; Lysosomal enzymes;► Oxygen’s radicals; TNF;► Perforin (channel - forming protein) .The damage of the cell with the antigen propertiesmay be caused by three reasons:► the 1st variant – complement-mediated cytotoxicity . Cytotoxic type of the► the 2nd variant – antibody-mediated immune clearance allergy can be a (phagocytosis ). manifestation of► the 3rd variant – antibody-dependent [cell-mediated] officinal allergy withcytotoxicity the development of leucocytopenia,Stage III: trombocytopenia,► Remedies [medicamentous] allergy; hemolytic anemia etc.► Hemolytic anemia (illness) of newborns; This may also happen► Post transfusion reactions (shock) in incompatible in blood transfusion and also in rhesusblood transfusion after the groups of АВО or Rhesus factor;► Auto allergic diseases. incompatibility of mother and fetus.
Pathogenesis of immune complex diseasesImmunological stage. Many exogenous and endogenous antigens participate information of immune complexes. Among them there are officinal preparations (penicillin,sulfanilamides), antitoxic vaccines, allogen gamma-globulins, food product (milk, eggwhite), 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 ofsoluble antigen into the organism IgG and IgM antibodies are formed. These antibodiescan 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 followingmediators are formed: fragments C3a, C5a, C4a of the complement, lyzosomal enzymesof phagocytes, kinines, superoxyde anion-radical.
Pathophysiologicalstage. Usually immunecomplexes are placed onvessels of cannalicularapparatus of kidneys,inflammation with alteration,exudation and proliferation(glomerulonephritis) glomerulonephritisdevelops, in case if thecomplexes are placed in thelungs alveolitis appears, inskin – dermatitis.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.
In systemic lupus erythematosus (a.k.a. SLE, lupus), nuclear components of disintegrating white blood cells elicit IgG production Immune complexes aggregate in the skin and organs, causing rash and lesions Rheumatoid arthritis (RA) is an inflammatory condition resulting in accumulation of immune complexes in joints 48
Cell-Mediated Immunity cytotoxic T cells recognizethe non-self cell and induce apoptosis(cell self death) in the viral infected orother 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
Immunological stage. Cell-mediated hypersensitivity reaction☻ The foreign antigen is 1. Initial contact with antigenphagocyted by macrophagesand get to T-helpers.☻ At the same timemacrophages secrete IL-1,which stimulates T-helpers. T-helpersThe latest excrete the growthfactor pro-T-lymphocytes –IL-2, which activates andsupports proliferation ofantigen stimulated T-cells.☻ This process leads toformation of sensitizedlymphocytes.lymphocytes☻ They belong to T-lymphocytes and in the cellmembrane they havereceptors of the antibodytype, which are able toconnect with the antigen. antigen☻ In case of repeatedpenetration of the allergeninto the organism it bindswith the sensitizedlymphocytes.lymphocytes
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 andexcretion of different mediators, which are calledlymphokines. With the help of lymphokines (MIF,lymphokinesinterleukines, chemotaxic factors, factor of transfer)mobilization of different cells (macrophages, polymorph-nuclear), increasing of chemotaxic activity and placing inthe site of allergen occur.• MIF promotes accumulation of macrophages in the siteof allergic damage, increases their activity and phagocytosis. phagocytosisIt takes part in formation of granulems during infectious-allergic diseases, increase the ability of macrophagesto destroy certain kinds of bacteria.• There are several kinds of chemotaxic factors, each factorsof which is called chemotaxis of leukocytes –macrophages, neutrophiles, eosinophiles and basophiles.Lymphotoxins cause damage and destroying of alldifferent target-cells.• Interferon is secreted by lymphocytes and under theinfluence of α-interferon and nonspecific mitogens. Itacts a modulating influence on cellular andhumoral mechanisms of immune reaction.• Besides lymphokines, lizosome enzymes also providea damaging activity. They are released duringphagocytosis and destroying of cells. Kallikreine-kininesystem is also activated. Histamine doesn’t play a big rolein 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-lymphocytes on target-cells, which acquired autoallergen properties;• 2) cytotoxic activity of T-lymphocytes, mediated by lymphotoxin; lymphotoxin• 3) releasing of lysosome enzyme, which damage tissue enzyme structures during phagocytosis.• Inflammation that is associated to immune reaction by action of mediators is a component of allergic reaction of delayed-type. Nevertheless inflammation is at the same delayed-type time a factor of damage of function of the organs.• Allergic reactions of delayed type make the base of development of infectious-allergic diseases (tuberculosis, lepra, brucellosis, syphilis), rejection of transplant, and transplant autoallergic diseases (disturbance of nervous system, endocrine glands etc.).
Contact dermatitis develops after exposure to a variety of allergens – Repeated exposures cause drying to skin with erythema and scaling 54
• 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) 55
Pseudoallergic reactions• Pseudoallergy is a pathological process, which is clinically similar to allergy but doesn’t have an immune stage of its development. Pseudoallergy differs from a simple one by the absence of first (immune) (immune stage. The rest two stages – releasing of mediators (pathochemical) and pathochemical pathophysiological (stage of clinical manifestations) are the same both in manifestations 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 antibodies and sensitized lymphocytes production with the help 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 Bezredka 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 substances 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.).
Immunodeficiencies Can Involve Any Aspect of the Immune System Primary immunodeficiency is the result of a genetic abnormality Secondary immunodeficiency is acquired later in life 60
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 61
► Severe combined immunodeficiency disease (SCID) involved lymph nodes deficient in B and T cells One form is caused by an enzyme deficiency that can be corrected using gene therapy► In Chédiak-Higashi syndrome , lysosome within phagocytes cannot release their contents to kill microbes► In chronic granulomatous disease, phagocytes do not produce substances to kill microbes 62