Materials can be downloaded from :

1. Materialscan be downloadedfrom: www.immunology.unideb.hu Login: student Password: download Self controls:weeks 11th and 14th Esther Bokhobza estherbokhobza@gmail.com

2. Why Immunology for Pharmacists?? Agents acting on the Immune system: Non-steroidal anti-inflammatory drugs (NSAIDs) Antihistamines Salicylates Immunomodulation; drugs that activate or suppress the immune system

3. Keep in mind..1. Many anti-inflammatory drugs are available over the counterso there is a potential for abuse and overdosing. 2.Patients on anti-inflammatory drugs block the signs and symptoms of a condition, sometimes, make it hard to correctly diagnose.3. Patients might combine these drugs and unknowingly induce toxicity.

4. NSAIDs Flurbiprofen Ibuprofen Naproxen Diclofenac

5. Salicylates Mesalazine / Mesalamine ASA

6. Immunosuppressant drugsT cell inhibitors and anti-proliferative drugs Tacrolimus Cyclosporin Mycophenolatemofetil Sirolimus/Rapamycin Methotrexate Azathioprine Cyclophosphamide

7. Immunosuppressant drugsGlucocorticoids Prednisolone Methylprednisolone Triamcinolone Budesonide Betamethasone

8. Immunosuppressant drugsantihistamins Dimetindene Loratadin Desloratadine

9. Immunosuppressant drugsLeukotriene antagonists Montelukast Zafirlukast Zileuton

10. MonoclonalAntibodies Efalizumab Rho (D) immunoglobin IL-2R antagonists Daclizumab Basiliximab

11. Immunostimulant drugs IL-2 Imiquimod Peginterferon alpha 2a Peginterferon alpha 2b

12. We live in a potentially hostile world filled with infectious agents of diverse shape, size and composition which would very happily use us as rich sanctuaries…

13. …had we not developed a series of defense mechanisms. These defense mechanisms establish a state of IMMUNITY and are the basis for our delightful subject of ‘IMMUNOLOGY’ Immunitas = freedom from (Latin) What is the function of the immune system? What about its specificity? Harmful/ Harmless The detection of stress and danger signals  Innate arm of the immune system Self / Non-self The differentiation between self and non-self  Adaptive arm of the immune system What about flexibility? (Influenza ex.) Speed? Is there room for failure? (Immunodeficiency) Keep in mind: Harmful self, like tumors! Harmless non-self, like normal flora!

14. nonspecific • immediate reaction • does not improve • no memory • highly specific • developes in several days • improves after exposure • has memory

15. Pathogens win the battle in the absence of either the innate or the adaptive arm of immunity

16. Innate immunity is often successful in eliminating pathogens. • However, it is not sufficient for survival • SCID (severe combined immunodeficiency) • “The bubble boy disease” • Facing life-threatening infections

17. Hematopoesis

18. IMMUNE CELLS Production site Fetal life: yolk sac, liver, spleen After birth:epiphysis, flat bones, red bone marrow (sternum, ribs, vertebras, skull, pelvis and femurs) Blood cells are short-lived and have to be continuously renewed, hematopoiesis is active throughout life.

19. Leukocytes derive from a common progenitor- the pluripotenthematopoietic stem cell (HSC)

20. …giving rise to the erythroid, myeloid and lymphoid progenitors

21. Polymorphonuclear leukocytes (PMNs) / The granulocytes

22. NEUTROPHIL GRANULOCYTES • Main participants in inflammatory processesagainst • extracellularinvaders • 68% of circulating leukocytes,99% of circulating granulocytes • Phagocytic cells • - Able to migrate and eliminate pathogens in infected tissues • (chemotaxis). Non-dividing, short-lived cells. • - Predominant cells in pus 12-15 μm 2-5 lobes Unstained granules BASOPHIL GRANULOCYTES • 1% of circulating leukocytes • Large granules in the cytoplasm • nucleus with 2 lobes • Like mast cells, secrete histamine and proteolytic enzymes • High affinity IgE receptors • Involved in parasite defence and allergic reactions 2 lobes Dark blue granules EOSINOPHIL GRANULOCYTES • Involved in parasite defence and allergic reactions • 2-3% of leukocytes Usually 2 lobes Bright red granules

23. Monocytes, Macrophages and Dendritic cells

24. MONOCYTES • Circulating cells of the myeloid lineage • Give rise to macrophages (Mφ) and dendritic cells (DCs) • Phagocytic cells • Together with macrophages, form the so called • ‘mononuclear phagocyte system’. 10-15 μm Bean-shaped nucleus MACROPHAGES • Phagocytic and antigen presenting cells • Part of the innate immunity but also initiates • theactivation of adaptive immuneresponse • main types (based on tissue localization): • microglia - brain • Kupffercells -liver • histiocytes-connective tissue • osteoclasts -bone • alveolar macrophages -lung • In GreekMakros=large phagein=eat  “big eaters” 21 μm

25. DENDRITIC CELLS • - Antigen presenting and phagocytic cells • - Part of the innate immunity and also act as cellular messengers initiating an adaptive defence. • - Resting dendritic cells circulate or reside in tissues, sense the environment, are able to differentiate into mature dendritic cells and migrate further to lymphoid organs to prime T cells. • In Greek Dendros= tree ! Do not mistaken them with dendrites (neuron projections).. • Types : • a) myeloid DCs: - Langerhans cells (mucosa, skin) • - interstitial DCs (liver, spleen, etc.) • b) lymphoid DCs:- thymic DCs • - PlasmacytoidDCs (pDC): Type I interferon producing cells. • Follicular DCs: Stromal cells of the lymph nodes, foundinprimary and secondaryfollicles. • similar in appearance but are not of hematopoietic origin.

27. MAST CELLS • Tissue resident cells, absent from the circulation • Cytoplasmicgranulescontainingvasoactiveaminse.g. heparin • Found around small vessels, regulating thevascularpermeability • High affinity cell surface FcεRI receptors, surface covered by IgE • - Defence and healing functions acting both in innate and adaptive immunity • - main types: a) mucosal • b) connective tissue • - Plays a role in thepatho-physiology of immunityagainsthelminths and allergic reactions

29. B LYMPHOCYTES • - Mature in bursa equivalenttissues* • (embrionic liver, later bone marrow) • 5-10% of the circulating lymphocytes. • Migrate from the bone marrow to the secondary lymphaticorgans • Express antigen-specific receptor ontheirsurface (BCR) • Professional antigenpresenting cells (APC) • Activated with antigens, interactingwith T lymphocytes,lymphokines and cytokines • Upon activation they differentiate to plasma cellsand memoryB cells • *‘B’= Bursa-derived cell, first described in the hematopoietic organ calledBursa de • Fabricius in birds PLASMA CELLS - Antibody production - Humoral immuneresponse

30. T LYMPHOCYTES • Mature in the thymuswheretheybecomematurenaive T cells and theymigratetoperipheral (secondary) lymphoidorgans • Express antigen-specific receptor ontheirsurface (TCR) • types: • - CD4+ T helper (Th1 & Th2) • - CD8+T cytotoxic (Tc) • - Regulatory T cells(Treg)

31. NK CELLS (natural killer cells) • origin: lymphoid progenitors, however, is a participant of theinnateimmunity. • They play a roleagainst intracellular infectionsbykilling infected cells. • - Granules in their cytoplasm contain perforin and granzymes. • Has no antigen-specificreceptors(„null cells”) • Recognizeabnormalcells (altered proteins and the absence of MHC class I). • Functionallysimilartocytotoxic T cells

32. The localization of blood cells NK cells

33. Relative abundance of leukocytes in peripheral blood

34. nonspecific • immediate reaction • does not improve • no memory • highly specific • developes in several days • improves after exposure • has memory

35. Professional phagocyticcells • Dendritic cells • Macrophages • Neutrophil granulocytes • Professional antigen presenting cells (APCs) • Dendriticcells • Macrophages • B lymphocytes • Pathogens are processed by APCs, theirdegradation products • (peptides) arepresented to T lymphocytes onMHC molecules

36. Coordinated and regulated actions of both arms of the immune system • ADAPTIVE IMMUNITY • developes in several days • highly specific • Improves after exposure • has memory • INNATE IMMUNITY • immediate reaction • nonspecific • Does not improve after exposure • no memory Indirectcommunicationviacytokines Directcommunicationviaadhesionmolecules communication OR

37. MOLECULES OF THE IMMUNE SYSTEM • Cell surface molecules: • Receptors (e.g. PRRs, BCR, TCR,cytokinereceptors,etc.) • MHC molecules (MHC I, MHC II) • - Co-stimulatory molecules (B7, CD40) • - Adhesion molecules (integrins, selectins,addressins, etc.) • Soluble molecules: • - Cytokines (interferons, interleukines, chemokines) • - Antibodies • Complementcomponents • Acutephaseproteins

38. The main types of cell surface molecules participating in antigen recognition and the interaction between dendritic cells and T cells

39. THE MOST IMPORTANT FEATURES OF CYTOKINES • The most important mediators of indirect cell communication in the immune system („hormones” of the immune system). • Act in low concentrations. • The responsiveness of the given cell is based on the expression of cytokine-specific receptors. hormones cytokines interleukines chemokines monokines lymphokines interferons

40. THE EFFECTS OF CYTOKINES macrophage PRR ligand T cell helpsactivation helpsactivation paracrine autocrine endocrine fever

41. CYTOKINES INTERLEUKINES (IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, TNFα) controlfunctions of leukocytes communicationbetweenleukocytes CHEMOKINES (IL-8, CCL21) inducingchemotaxis increasingadhesion activatingleukocytes TYPE I INTERFERONS (IFNα, IFNβ) parts of innateimmunity importantroleagainstviralinfections producers: infectedcells, plasmacitoidDCs TYPE II INTERFERON (IFNγ) main activators of macrophagesproducers: Th1, CD8+, NK cells

42. BIOACTIVE MOLECULESINFLUENCE THE ACTIVITY AND FUNCTION OF THE IMMUNE SYSTEM Plasma factor can affect different parts of the immune system and vise versa Carbohydrates(glucose) Lipids(cholesterol, triglycerid, phospholipid, lecitin, fat) Proteins(globulin, albumin, fibrinogen) Glycoprotein Hormones(gonadotropin, erytropoetin, thrombopoietin) Amino acids Vitamins (over and malnutrition)

44. Professionalphagocyticcells • Neutrophil granulocytes • (No presentation of Ag on MHC II) • Professional • antigen presenting cells • B lymphocytes • (no killing action, only Ag presentation) Macrophages Dendriticcells