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Physiological regulation of the immune system

Physiological regulation of the immune system. Regulation by antigen. Induce immune responses and extinction Affinity maturation of B lymphocytes Maintaining immunological memory Antigenic competition Threshold density of the complex MHC II- gp Ag on APC . Regulation by antibodies.

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Physiological regulation of the immune system

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  1. Physiologicalregulationoftheimmunesystem

  2. Regulation by antigen • Induceimmuneresponsesandextinction • Affinitymaturationof B lymphocytes • Maintainingimmunologicalmemory • Antigeniccompetition • Thresholddensityofthecomplex MHC II-gpAg on APC

  3. Regulation by antibodies • Antibodies competes with the BCR for antigen (negative regulator of B lymphocyte stimulating) • IgG immune complexes bind to the BCR and FcgR on B cells, resulting in blocking activation of B lymphocytes • It is still unclear meaning of regulation via idiotypic network

  4. Regulation by cytokines and cellular contact • Interaction APC - T lymphocyte • Interaction TH1 – macrophages • Interaction TH2 - B lymphocytes • Mutual regulation of activity TH1 versus TH2 • Development of leukocyte subpopulations Negative regulation of effector cells: • CTLA-4 - T cell inhibitory receptor, binds ligands CD80 and CD86 • Inhibitory receptors of NK cells • Self-destruction interaction of the apoptotic receptor Fas with ligand FasL on the surface of activated T lymphocytes

  5. Factors influencing the outcome of the immune response The same antigen can induce an active immune response or an active state of tolerance, the result of response depends on many factors: • State of the immune system • Properties of antigen • Dose of antigen • Route of antigen administration

  6. Cytokines (Tissue hormones)

  7. Cytokines • Regulatory proteins and glycoproteins produced by leukocytes and other cells • Essential regulators of the immune system • Apply outside the immune system (angiogenesis, tissue regeneration, carcinogenesis, treatment of many brain functions, embryonic development ...) • Cytokines - secreted      - membrane (CD 80, CD86, CD40L, FasL ..)

  8. Pleiotropic effect • Operates in a cascade • Cytokine Network • Cytokine system is redundant • Effects of cytokines - autocrine - paracrine - endocrine • Are known as interleukins (exception: TNF, lymphotoxin, TGF, interferons, CSF and growth factors)

  9. B cells communicate via cytokines with other inflammatory cells, such as T cells and macrophages

  10. Distribution of cytokines by function • Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL- 12,IL- 18, TNF) • Antiinflammatory cytokines (IL-1Ra, IL-4, IL-10, TGF) • Cytokines with the activity of hematopoietic cells growth factor (IL-2, 3, 4, 5, 6, 7, 9, 11, 14, 15, CSF, SCF, LIF, EPO) • Cytokines applying in TH2 humoral immunity (IL-4, 5, 9, 13) • Cytokines applying in the cell-mediated immunity TH1 (IL-2, 12, IFN, GM-CSF, lymphotoxin) • Cytokines with anti-virus effect (IFN-, IFN-, IFN- )

  11. Overview of the most important cytokines MF – macrophages; M – monocytes; N – neutrophils; DC – dendritic cells; NK – natural killers; L – lymphocytes; B – B cell; T – T cell

  12. Cytokine receptors • Consisting of 2 or 3 subunits • One subunit binds cytokine, other are associated with cytoplasmic signaling molecules (protein kinases) • Signaling subunit is shared by several different cytokine receptors - called receptor family • Signaling through these receptors may lead to proliferation, differentiation, activation of effector mechanisms or blocking the cell cycle and induction of apoptosis

  13. External regulation of immune response

  14. Substitution treatment • 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

  15. Immunomodulation = medical procedure to adjust the disrupted immune function 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

  16. Non-specific immunosuppressive therapy • corticosteroids - anti-inflammatory, immunosuppressiveeffects                   - blockingtheactivityoftranscriptionfactors (AP-1, NFkB)                    - suppresstheexpressionofgenes (IL-2, IL-1, phospholipase A, MHC gp II, adhesionmolecules)                   - inhibitionof histamine releasefrombasophils                   - higherconcentrationsinduceapoptosisoflymfocytes • immunosuppressantsaffectingthemetabolismof DNA - cyclophosphamide, azathioprine,methotrexate

  17. 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) • immunoglobulins in the immunosuppressive indication- Polyspecific intravenous immunoglobulins                    (Inhibition of B lymphocytes, antiidiotype activity, inhibition of cytokines, neutralization of toxins, inhibition of complement activation ...)

  18. Anti-inflammatory and antiallergic treatment • nonsteroidalanti-inflammatorydrugs • antihistamines - blocking H1 receptor                          - reducetheexpressionofadhesionmolecules                         - reducethesecretionof histamine ... • inhibitorsofinflammatorycytokine - receptor antagonistfor IL-1                          - monoclonalantibodiesagainst TNF                          - thalidomide (TNF inhibitor) • enzyme therapy - in the enzyme mixture has a major effect trypsin andbromelain                           - anti-inflammatoryandimmunomodulatoryeffects

  19. 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 • IFNa, IFNb - viral hepatitis, some leukemia • Erythropoietin – renal failure • G-CSF, GM-CSF – neutropenia • Transfer factor (blood donors leukocytes undergoing dialysis) • Thymus hormones

  20. Antigen-specific immunomodulatory therapy • specificimmunomodulation = induceanimmune response or tolerance against a specific antigen a) activeimmunization b) passiveimmunization c) specificimmunosuppression d) vaccinationagainstcancer

  21. a) activeimmunization= use of antigen to induceanimmune response thatcanlaterprotectagainst a pathogenbearingthe antigen (orsimilar antigen) • immunizationvaccines are madefrominactivatedorattenuatedmicroorganismsortheirantigens (polysaccharidecapsule, toxins) • createslong-term immunity • activatecellularandantibodyimmunity • administrationof antigen injectable, oral • prophylaxis • risk ofcausinginfectionoranaphylacticreactions

  22. b) passiveimmunization • natural- transfer ofmaternalantibodies in fetalblood • therapeutically - the use ofanimalantibodiesagainstvarioustoxins (snaketoxins, tetanus toxin, botulinum toxin) • prophylaxis - thehumanimmunoglobulinfromimmunizedindividuals (hepatitis A, rabies, tetanus)                     - Anti-RhDantibodies - preventingmaternalimmunizationwithRhD+ fetus • provides a temporary (3 weeks) specifichumoralimmunity • the risk ofinductionanaphylacticreactions

  23. c) specificimmunosuppression= inductionof tolerance against a specific antigen • ongoingclinicalstudies • inductionof tolerance by oral administrationof antigen (treatmentofcertainautoimmunediseases) • allergenimmunotherapy (pollen, insectpoisons) d) vaccinationagainstcancer • s a promisingapproachappears to immunizationdendriticcells

  24. Defense against extracellular pathogens

  25. Defence against extracellular pathogens • bacteria (gram-negative, gram-positive cocci, bacilli), unicellular parasites • complement activation stimulated by bacterial cell wall • phagocytosis by neutrophil granulocytes • opsonization (C3b, lectins, antibodies ...) enhance phagocytosis

  26. Opsonisation

  27. Phagocytes are attracted to the site of infection by chemotactic substances (C5a, C3a and chemotactic products of bacteria) • 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 proteins

  28. Phagocytosis

  29. in later stages of infection are stimulated antigen-specific mechanisms • plasma cells initially produce IgM isotype after isotype switching produce IgG1 and IgA (opsonization) • sIgA protect against intestinal and respiratory infections by bacteria • bacteria with a polysaccharide capsule may cause T-independent IgM antibody production (after the establishment to the bacteria activate the classical complement path)

  30. after infection persist IgG, IgA (protective effect) and memory T and B lymphocytes • 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 • extracellular bacterial infections are especially at risk individuals with disorders in the function of phagocytes, complement and antibody production

  31. Defense against intracellular pathogens

  32. Defense against intracellular pathogens • bacteria, fungi and unicellular parasites • intracellular parasites are resistant to the microbicidal mechanisms of phagocytes • macrophages, which absorbed them, produce IL-12 → TH1 differentiation, production of IFNg and membrane TNF → activation of macrophages and induction of iNOS

  33. Obrana proti intracelulárním patogenům

  34. in the defense against intracelular parasites, which escape from phagolysosomes apply TC lymphocytes • intracellular microorganisms infections are at risk individuals with certain disorders of phagocytes and defects of T lymphocytes

  35. Defense against intracellular pathogens

  36. Anti-viral defense

  37. Anti-viral defence • interferons - in infected cells is induced production of IFNa and IFNb (prevents viral replication and in uninfected cells cause the anti-virus status); IFNg stimulates the conversion to activated macrophages (iNOS) • IFNa and IFNb induce proliferation ofNK cells

  38. Anti-viral defence - interferons

  39. NK cells - ADCC (Antibody-dependent cell-mediated cytotoxicity) = cytotoxic reaction depends on the antibodies; the NK-lymphocyte recognizes cell opsonized with IgG by stimulation Fc receptor CD16 and then activate cytotoxic mechanisms (degranulation) • infected macrophages produce IL-12 (a strong activator of NK cells)

  40. NK cell activation

  41. 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

  42. Anti-viral defence - antibodies

  43. effector TC lymphocytes destroy infected cells in direct contact (granzym/perforin; FasL) and by produced cytokines (lymfotoxin) • 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

  44. Anti-viral defence – NK cells and Tc lymphocytes

  45. Defense against multicellular parasites

  46. Defense against multicellular parasites • IgE, mast cells, basophils and eosinophils • TH2 stimulation under the influence of IL-4 (mast cells and other APC stimulated by parasite) • TH2 stimulate B cells with BCR-specific parasite antigens • isotype switching under the influence of IL-4 to IgE • IgE bind to FceRI on mast cells and basophils („antigen-specific receptors“)

  47. Mast cell activation • 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) • activation of arachidonic acid metabolism (leukotriene C4, prostaglandin PGD2) - amplification of inflammatory responses • cytokine production by mast cell (TNF, TGF, IL-4, 5,6 ...)

  48. Activation of mast cell

  49. in later stages are activated TH1 and are produced antibodies of other classes • eosinophils fagocyte complexes of parasitic particles with IgE via their receptors for IgE • eosinophils use against parasites extracellular bactericidal substances released from granules (eosinophil cationic protein, protease)

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