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Antiinfection immunity J. Ochotná
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Defence against extracellular pathogens
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NeutrophilsNeutrophils Opsonins (C3b, IgG, lectins, CRP, SAP…)Opsonins (C3b, IgG, lectins, CRP, SAP…) Antibodies (IgM, IgG, IgA)Antibodies (IgM, IgG, IgA) Defence against extracellular pathogens
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bacteria (gram-negative, gram-positive cocci, bacilli), unicellular parasites neutrophilic granulocytes are attracted to the site of the infection by chemokines (C5a, C3a and chemotactic products of bacteria) phagocytes recognized pathogens via PRR and receptor for opsonins
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Opsonization
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absorbed bacteria are destroyed by the microbicidal systems (products of NADP-H oxidase, hydrolytic enzymes and bactericidal substances in lysosomes)absorbed bacteria are destroyed by the microbicidal systems (products of NADP-H oxidase, hydrolytic enzymes and bactericidal substances in lysosomes) phagocytes produce proinflammatory cytokines (IL-1, IL-6, TNF) that induce an increase in temperature, metabolic response of the organism and synthesis of acute phase proteinsphagocytes produce proinflammatory cytokines (IL-1, IL-6, TNF) that induce an increase in temperature, metabolic response of the organism and synthesis of acute phase proteins Defence against extracellular pathogens
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IgM (complement activation, neutralization) IgG (complement activation, opsonisation, neutralization) sIgA protect against intestinal and respiratory infections by bacteria after infection persist IgG, IgA (protective effect) and memory T and B lymphocytes Defence against extracellular pathogens
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bacteria with a polysaccharide capsule may cause T-independent IgM antibody production (after the establishment to the bacteria activate the classical complement path) in the defense against bacterial toxins apply neutralizing antibodies (Clostridium tetani and botulinum...) "indirect toxins - bacterial Lipopolysaccharide (LPS) stimulates big number of monocytes to release TNF, which can cause septic shock Defence against extracellular pathogens
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individuals with disorders in the function of phagocytes, complement and antibody production are especially at risk extracellular bacterial infections Defence against extracellular pathogens
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Defence against intracellular pathogens
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Macrophages activated by T H 1 cellsMacrophages activated by T H 1 cells Cytotoxic T cellsCytotoxic T cells Defense against intracellular pathogens
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certain bacteria, fungi and unicellular parasites intracellular parasites are resistant to the microbicidal mechanisms of phagocytes macrophages, which absorbed them, produce IL-12 → T H 1 differentiation, production of IFN and membrane TNF → activation of macrophages and induction of iNOS
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Defense against intracellular pathogens
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in the defense against intracelular parasites, which escape from phagolysosomes apply T C lymphocytes intracellular microorganisms infections are at risk individuals with certain disorders of phagocytes and defects of T lymphocytes Defense against intracellular pathogens
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Anti-viral defence
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Interferons (IFN , IFN )Interferons (IFN , IFN ) NK cellsNK cells Cytotoxic T cellsCytotoxic T cells Antibodies (IgM, IgG, IgA)Antibodies (IgM, IgG, IgA) Anti-viral defence
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interferons : production of IFN and IFN is induced in infected cells (prevent viral replication in uninfected cells); IFN activates macrophages (iNOS)
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Interferons: The antiviral effectThe antiviral effect NK cells stimulationNK cells stimulation Increase the expression of HLA I → enhance the presentation to cytotoxic T cellsIncrease the expression of HLA I → enhance the presentation to cytotoxic T cells Anti-viral defence
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Viral-infected cell can be recognized by NK cellViral-infected cell can be recognized by NK cell Natural killer cell activation depends on the balance of inhibitory and activating receptor stimulationNatural killer cell activation depends on the balance of inhibitory and activating receptor stimulation Anti-viral defence
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ADCC (Antibody-dependent cell-mediated cytotoxicity) Antibodies that bind to antigens can be recognised by Fc ϒ RIII (CD16) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis. ADCC (Antibody-dependent cell-mediated cytotoxicity) Antibodies that bind to antigens can be recognised by Fc ϒ RIII (CD16) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis. infected macrophages produce IL-12 (a strong activator of NK cells) Anti-viral defence
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Effector cytotoxic T cells destroy infected cells in direct contact (granzym/perforin; FasL) and by produced cytokines (lymfotoxin)Effector cytotoxic T cells destroy infected cells in direct contact (granzym/perforin; FasL) and by produced cytokines (lymfotoxin) Anti-viral defence
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in the defense against cytopathic viruses mostly applied antibodies: sIgA inhibit mucosal adhesion of viruses (defense against respiratory viruses and enteroviruses) neutralizing IgG and IgM antibodies activate the classical way of complement, which is capable of some viruses lysis IgA and IgG derived in viral infection have a preventive effect in secondary infection Anti-viral defence
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Anti-viral defence - antibodies
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some viruses after infection integrate into the host genome, where persist for years (varicella zoster, EBV, papillomavirus) by these infections are at risk individuals with T lymphocyte immunodeficiency and with combined immune disorders increased susceptibility to herpes infections in individuals with dysfunction of NK cells Anti-viral defence
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Defense against parasites
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Defense against protozoa parasites Defense against protozoa parasites Toxoplasma gondii, Leishmania, Trypanosoma defense against protozoa parasites is similar to bacteria extracellular parasites - antibodies intracellular parasites - T H 1 lymphocytes and activated macrophages
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Defense against multicellular parasites
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Mast cellsMast cells BasophilsBasophils EosinophilsEosinophils IgE antibodiesIgE antibodies Defense against multicellular parasites
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contact of mast cells, basophils and eosinophils with parasite antigens T H 2 stimulation under the influence of IL-4 (mast cells and other APC stimulated by parasite) T H 2 stimulate B cells with BCR-specific parasite antigens isotype switching under the influence of IL-4 to IgE IgE binds to Fc RI on mast cells and basophils
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establish of multivalent antigen (multicellular parasite) using the IgE to highafinity Fc receptor for IgE (Fc RI) aggregation of several molecules Fc RI initiate mast cell degranulation (cytoplasmic granules mergers with the surface membrane and release their contents) - histamine activation of arachidonic acid metabolism (leukotriene C4, prostaglandin PGD2) - amplification of inflammatory responses cytokine production by mast cell (TNF, TGF , IL-4, 5,6...) Defense against multicellular parasites
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Histamine helps eliminate the parasite, causes: vasodilation, increased vascular permeability → erythema, edema, itching increased mucus secretion in the respiratory tract and GIT contraction of bronchial smooth muscle increases intestinal peristalsis Defense against multicellular parasites
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Activation of mast cell
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eosinophils use against parasites extracellular bactericidal substances released from granules (eosinophil cationic protein, protease) eosinophils fagocyte complexes of parasitic particles with IgE via their receptors for IgE Defense against multicellular parasites
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External regulation of immune response
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Causal treatment a) Stem cell transplantation a) Stem cell transplantation for serious congenital disorders of the immune system and some lymphoproliferative and myeloproliferative disorders complications: infectious complications Graft-versus-host disease obtaining stem cells - collection from shovel hip bone - from umbilical cord blood - from peripheral blood after stimulation with GM-CSF
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b) Gene therapy with a suitable expression vector is introduced functional gene (to replace dysfunctional gen) into the lymphocytes or stem cells used as a treatment for some cases of SCID
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Substitution treatment autologous stem cell transplantation following chemotherapy and radiotherapy treatment with intravenous immunoglobulin (derived from plasma of blood donors) substitution of C1 inhibitor for hereditary angioedema substitution of erythropoietin in patients with chronic renal failure substitution of G-CSF in agranulocytosis
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Immunomodulation = medical procedure to adjust the disrupted immune function Non-specific immunosuppressive therapy Non-specific immunosuppressive therapy nonspecific = affects not only autoreactive and aloreactive lymphocytes, but also other components of immunity (risk of reduction antiinfectious and anti- tumor immunity) used for treatment of autoimmune diseases, severe allergic conditions and for organ transplantation
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Non-specific immunosuppressive therapy Corticosteroids - anti-inflammatory, immunosuppressive effects - suppress the expression of some genes (IL-2, IL-1, phospholipase A, MHC gp II, adhesion molecules) - inhibition of histamine release from basophils - higher concentrations induce apoptosis of lymfocytes - anti-inflammatory, immunosuppressive effects - suppress the expression of some genes (IL-2, IL-1, phospholipase A, MHC gp II, adhesion molecules) - inhibition of histamine release from basophils - higher concentrations induce apoptosis of lymfocytes
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immunosuppressants affecting the metabolism of DNAimmunosuppressants affecting the metabolism of DNA - cyclophosphamide (alkylating agent) - methotrexate (antimetabolite) - azathioprine (purine analogue) - cyclophosphamide (alkylating agent) - methotrexate (antimetabolite) - azathioprine (purine analogue) Non-specific immunosuppressive therapy
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immunosuppressant selectively inhibiting T lymphocytes - immunosuppressive ATB: cyclosporine A, tacrolimus, rapamycin (suppressing the expression of IL-2 and IL-2R in activated T lymphocytes) - monoclonal antibody anti-CD3 (Immunosuppression after transplantation, treatment of rejection crises) - monoclonal antibody anti-CD3 (Immunosuppression after transplantation, treatment of rejection crises) Non-specific immunosuppressive therapy
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immunoglobulins in the immunosuppressive indication - Polyspecific intravenous immunoglobulins - Inhibition of B lymphocytes, antiidiotype activity, inhibition of cytokines, neutralization of toxins, inhibition of complement activationimmunoglobulins in the immunosuppressive indication - Polyspecific intravenous immunoglobulins - Inhibition of B lymphocytes, antiidiotype activity, inhibition of cytokines, neutralization of toxins, inhibition of complement activation Non-specific immunosuppressive therapy
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Anti-inflammatory and antiallergic treatment nonsteroidal anti-inflammatory drugs antihistamines - blocking H1 receptor - reduce the expression of adhesion molecules - reduce the secretion of histamine... inhibitors of inflammatory cytokine - receptor antagonist for IL-1 - monoclonal antibodies against TNF - thalidomide (TNF inhibitor) enzyme therapy - in the enzyme mixture has a major effect trypsin and bromelain - anti-inflammatory and immunomodulatory effects
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Non-specific immunostimulant therapy synthetic immunomodulators Methisoprinol (Isoprinosine) - used in viral infections with more severe or relapsing course bacterial extracts and lysates Broncho-Vaxom - prevention of recurrent respiratory tract infections Ribomunyl products of the immune system IL-2 - renal adenocarcinoma IFN , IFN - viral hepatitis, some leukemia Erythropoietin – renal failure G-CSF, GM-CSF – neutropenia Transfer factor (blood donors leukocytes undergoing dialysis) Thymus hormones Thymus hormones
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Antigen-specific immunomodulatory therapy specific immunomodulation = induce an immune response or tolerance against a specific antigen A) active immunization B) passive immunization C) specific immunosuppression
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a)active immunization = induction of immune response after exposure to an antigen, that can later protect against a pathogen bearing this antigen (or similar antigen) immunization vaccines are made from inactivated or attenuated microorganisms or their antigens (polysaccharide capsule, toxins) creates long-term immunity activates specific cellular and humoral immunity administration of antigen injectable or oral prophylaxis risk of infection or anaphylactic reactions
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b) passive immunization natural - transfer of maternal antibodies in fetal blood natural - transfer of maternal antibodies in fetal blood therapeutically - the use of animal antibodies against various toxins (snake toxins, tetanus toxin, botulinum toxin) prophylaxis - the human immunoglobulin from immunized individuals (hepatitis A, rabies, tetanus) - Anti-RhD antibodies - preventing maternal immunization with RhD + fetus provides a temporary (3 weeks) specific humoral immunity the risk anaphylactic reactions
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c) specific immunosuppression = induction of tolerance to a specific antigen c) specific immunosuppression = induction of tolerance to a specific antigen ongoing clinical studies induction of tolerance by oral administration of antigen (treatment of certain autoimmune diseases) allergen immunotherapy (pollen, insect poisons) d) vaccination against cancer d) vaccination against cancer immunization by dendritic cells
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Thank you for your attention
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Phagocytosis http://www.youtube.com/watch?v=7VQU28itVVw http://www.youtube.com/watch?v=r4-g6tVyUAU http://www.youtube.com/watch?v=7VQU28itVVw NK cells http://www.youtube.com/watch?v=HNP1EAYLhOs Tc http://www.youtube.com/watch?v=4_e93zRSHco Mast cells and eosinophils http://www.youtube.com/watch?v=MWh-zig8liE http://www.youtube.com/watch?v=gafekFEbUg4http://www.youtube.com/watch?v=MWh-zig8liE
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