Physiological mechanisms of regulation of the immune system

1. Physiological mechanisms of regulation of the immune system

2. Regulation by antigen • Induce immune response and extinction • Affinity maturation of B lymphocytes • Maintaining immunological memory • Antigenic competition • Threshold density of the complexes HLA II- Ag on APC

3. Regulation by antibodies • Antibodiescompetewiththe BCR for antigen (negative regulatorof B cell stimulation) • IgGimmunecomplexesbind to the BCR andFcR on B cells→blockingof B cell activation • Regulation via idiotypic network

4. Regulation by cytokines and cellular contact • InteractionAPC - T lymphocyte • InteractionTH1 – macrophages • InteractionTfh- B lymphocytes • MutualregulationofactivityTH1 versus TH2 • Developmentof leukocyte subpopulations

5. Negative regulation of effector cells • CTLA-4 - T cell inhibitory receptor, binds ligands CD80 and CD86 • Self-destruction interaction of the apoptotic receptor Fas with ligand FasL on the surface of activated T cells • nhibitory receptors of NK cells

6. Suppression mediated by T cells • Clonaleliminationoranergyof T lymphocytesaftercontactwith antigen on thesurfaceofothercellsthan APC • Regulatory T cells(Treg, Tr1, Th3 - CD 4+) help to maintain tolerance to autoantigens; produce TGF, IL-10

7. Factors influencing the outcome of the immune response Thesame antigen caninduceanactiveimmune response oranactivestateof tolerance, theresultof response depends on many factors: • Stateoftheimmunesystem • Propertiesof antigen • Doseof antigen • Routeof antigen administration

8. Cytokines (Tissue hormones)

9. Cytokines • Regulatory proteins and glycoproteins produced by leukocytes and other cells • Are known as interleukins (IL-1…IL-38)(except: TNF, lymphotoxin, TGF, interferons, CSF and growth factors) • Essential regulators of the immune system • Apply also in angiogenesis, tissue regeneration, carcinogenesis, treatment of many brain functions, embryonic development ...

10. Cytokines • Effectsofcytokines - autocrine - paracrine - endocrine • Cytokines - secreted     - membrane (CD 80, CD86, CD40L, FasL ..)

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. Clasification of cytokines by functions Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL- 12,IL- 18, TNF) Antiinflammatory cytokines(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-viral effect (IFN-, IFN-, IFN- )

13. Cytokine receptors • Consistof 2 or 3 subunits • Onesubunitbindscytokine, other are associatedwithcytoplasmicsignalingmolecules (protein kinases) • Signalingsubunitisshared by severaldifferentcytokinereceptors - called receptor family • Signalingthrough these receptorsmaylead to proliferation, differentiation, activationofeffectormechanismsorblockingthe cell cycleandinductionofapoptosis

14. Possibilities of therapeutic affecting of the immune system

15. 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

16. Immunomodulation = medicalprocedure to adjustthedisruptedimmunefunction Non-specificimmunosuppression • nonspecific = affects not onlyautoreactiveandaloreactivelymphocytes, butalsoothercomponentsofimmunity (risk ofreductionantiinfectiousandantitumorimmunity) • usedfortreatmentofautoimmunediseases, for organ transplantationand severe allergicconditions

17. Non-specific immunosuppression 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

18. Non-specific immunosuppression Immunosuppressantsaffectingthemetabolismof DNA (cytostatics) • cyclophosphamide (alkylating agent) • methotrexate (antimetabolite) • azathioprine (purine analogue)

19. Non-specific immunosuppression Immunosuppressantselectivelyinhibiting T cells • immunosuppressive ATB: cyclosporine A, tacrolimus, rapamycin(suppresstheexpressionof IL-2 and IL-2R in activated T cells) • anti-CD3 monoclonalantibody(imunosuppressionaftertransplantation, treatmentofrejectioncrises)

20. 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- monoclonal antibodies against TNF                           - thalidomide (TNF inhibitor) • Anti IgE antibodies (omalizumab)- severe allergic astma

21. 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

22. Antigen-specific immunomodulation • specific immunomodulation = induce of an immune response or tolerance to a specific antigen • active immunization • passive immunization • specific immunosuppression

23. Antigen-specific immunomodulation Activeimmunization (vaccination)= the induction of immunity after exposure toan antigen • activatesspecificcellularandhumoralimmunity • createslong-term immunity (memorycells) • protectagainst a pathogenbearingthis antigen orsimilar antigen (prophylaxis)

24. Antigen-specific immunomodulation activeimmunization (vaccination) • vaccines are madefrominactivatedorattenuatedmicroorganismsortheirantigens(polysaccharidecapsule, toxins) • attenuated vaccines cannot be used in immunocompromisedindividuals • risk ofinfectionoranaphylacticreactions

25. Antigen-specific immunomodulation Passiveimmunization • natural- transfer ofmaternalantibodies in fetalblood • therapeutic- the use ofanimalantibodiesagainstvarioustoxins(snaketoxins, tetanus toxin, botulinum toxin) • prophylaxis - thehumanimmunoglobulinfromimmunizedindividuals (hepatitis A, rabies, tetanus)                     - Anti-RhDantibodies – preventimmunizationofmotherwithRhD+ fetus erythrocytes • provides a temporary (3 weeks) specifichumoralimmunity • the risk anaphylacticreactions

26. Antigen-specific immunomodulation Specificimmunosuppression= inductionof tolerance to a specific antigen • inductionof tolerance by oral administrationof antigen (treatmentofcertainautoimmunediseases) • allergenimmunotherapy (pollen, insectpoisons) Vaccinationagainstcancer • immunizationwithdendriticcells

27. Antiinfection immunity

28. Defence against extracellular pathogens • Bacteria, unicellularparasites • Neutrophilgranulocytes • Opsonization(C3b, IgGandIgAantibodies, lectins, CRP...)

29. Defence against extracellular pathogens • Pathogeninduceinflammation • Neutrophils: phagocytosis, degranulation, NETs • Ingestedbacteria are destroyed by themicrobicidalsystems(productsof NADP-H oxidase, hydrolyticenzymesandbactericidalsubstances in lysosomes) • Activatedphagocytesproduceproinflammatorycytokines(IL-1, IL-6, TNF)

30. Defence against extracellular pathogens • Pathogensactivate complement • IgM - complement activation • IgG - complement activation, opsonization • IgA - opsonizationsIgA prevents against infection by intestinal and respiratory bacteria • Neutralizing antibodies apply in the defense against bacterial toxins (Clostridium tetani and botulinum …)

31. Defence against extracellular pathogens • „Indirect toxins“ - bacterial Lipopolysaccharide (LPS) stimulates big number of monocytes to release TNF, which can cause septic shock • Individuals with immunodeficiency of phagocytes, complement and antibodies production are especially at risk of infections with extracellular bacterial

32. Defense against intracellular pathogens

33. Defense against intracellular pathogens • Bacteria, fungiandunicellularparasites • Intracellularparasites are resistant to themicrobicidalmechanismsofphagocytes • Macrophagewhichengulfpathogenproduce IL-12 → TH1differentiation, productionofIFNandmembrane TNF → activationofmacrophageand NOproduction • NO killsintracellularpathogens

34. Defense against intracellular pathogens • TClymphocytesapply in the defense againstintracelularparasites, whichescapefromphagolysosomes • Individualswithcertaindisordersofphagocytesanddefectsof T lymphocytes are at risk ofinfectionswithintracellularmicroorganisms

35. Defense against intracellular pathogens

36. Anti-viral defense

37. Anti-viral defence • interferons - productionof IFNand IFNisinducedin infectedcells; IFNactivatesmacrophages (iNOS) • IFNandIFN-preventsviralreplication - induceproliferationofNK cells - increase the expression of HLA-I(AgpresentationforTc)

38. Anti-viral defence

39. ADCC Anti-viral defence • NK cells ADCC (Antibody-dependent cell-mediated cytotoxicity); NK cell bind with CD16 (Fcreceptor) to IgGwhich has bound to the surface of infected cell and then NK cell release perforins and granzymes

40. Anti-viral defence • Effector TC lymphocytes destroy infected cells in direct contact (granzym/perforin; FasL) and by produced cytokines (lymfotoxin)

41. Anti-viral defence • sIgA inhibit mucosal adhesion of viruses (defense against respiratory viruses and enteroviruses) • Neutralizing IgG and IgM antibodies activate the classical pathway of complement, that is able to lyse certain viruses • IgG and IgA opsonize viral particles • IgA and IgG have preventive effect in secondary viral infection

42. Anti-viral defence • Somevirusesafterinfectionintegrateintothe host genome, wherepersistforyears (varicellazoster, EBV, papillomavirus) • Individualswith T lymphocyteimmunodeficiencyandwithcombinedimmunedisorders are at risk by viralinfections • Increasedsusceptibility to herpes infections in individualswithdysfunctionof NK cells

43. Defense against multicellular parasites

44. 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 with IL-4 production stimulate isotype switching to IgE • IgE bind to FcRI on mast cells and basophils

45. Mast cell activation by cross-linking of IgE Fc receptors • BindingofIgE to highaffinnityFc receptor forIgE (FcRI) • Bindingof multivalent antigen (multicellular parasite) to IgE • AggregationofseveralmoleculesofFcRI

46. Mast cell activation • Cytoplasmic granules: hydrolytic enzymes, histamine, serotonin, heparin • Activation of arachidonic acid metabolism (leukotriene C4, prostaglandin D2) • Start of cytokines production (TNF, TGF, IL-4, 5,6 ...)

47. Defense against multicellular parasites Histamine • Vasodilatation, increasevascular permeability (erythema, edema, itching) • Bronchoconstriction(cough) • Increasesintestinalperistalsis (diarrhea) • IncreasedmucussecretionThishelpseliminatethe parasite.

48. Defense against multicellular parasites • Eosinophils release from granules (eosinophilic katoin protein, proteases ...) • Eosinophils phagocyte complexes of parasitic particles with IgE via its IgE receptors • IL-5 activation of eosinophils

49. Defense against multicellular parasites • eosinophils fagocyte complexesofparasiticparticleswithIgE via theirreceptorsforIgE • eosinophils use againstparasitesextracellularbactericidalsubstancesreleasedfromgranules(ECP- eosinophilcationic protein, MBP-major basic protein…) Thank you for your attention