1. www.immunology.unideb.hu Login: student Password: download Esther Bokhobza estherbokhobza@gmail.com Self controls: weeks 11 th and 14 th MATERIALS CAN BE DOWNLOADED FROM:

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 COUNTER SO 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. Mesalazine / Mesalamine ASA SALICYLATES

6. IMMUNOSUPPRESSANT DRUGS T CELL INHIBITORS AND ANTI-PROLIFERATIVE DRUGS Cyclosporin Tacrolimus AzathioprineCyclophosphamide Methotrexate Mycophenolate mofetil Sirolimus/Rapamycin

7. IMMUNOSUPPRESSANT DRUGS GLUCOCORTICOIDS Methylprednisolone Prednisolone Betamethasone Budesonide Triamcinolone

8. IMMUNOSUPPRESSANT DRUGS ANTIHISTAMINS LoratadinDesloratadine Dimetindene

9. IMMUNOSUPPRESSANT DRUGS LEUKOTRIENE ANTAGONISTS Montelukast ZafirlukastZileuton

10. MONOCLONAL ANTIBODIES Efalizumab Rho (D) immunoglobin BasiliximabDaclizumab IL-2R antagonists

11. IMMUNOSTIMULANT DRUGS Imiquimod IL-2 Peginterferon alpha 2bPeginterferon alpha 2a

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! 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 Immune system Innate / NaturalAcquired / Adaptive Cellular Granulocytes Monocytes/Macrophages Natural Killer cells Dendritic cells Mast cells CD4+ (helper) T cells CD8+ (cytotoxic) T cells B cells Plasmacells Humoral Complement proteins Cytokines Acute phase proteins Antimicrobial proteins Antibodies

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 pluripotent hematopoietic stem cell (HSC)

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

21. Polymorphonuclear leukocytes (PMNs) / The granulocytes

22. NEUTROPHIL GRANULOCYTES EOSINOPHIL GRANULOCYTES -Main participants in inflammatory processes against extracellular invaders - 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 - Involved in parasite defence and allergic reactions - 2-3% of leukocytes 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 12-15 μm 2-5 lobes Unstained granules 2 lobes Dark blue granules 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’. MACROPHAGES -Phagocytic and antigen presenting cells -Part of the innate immunity but also initiates the activation of adaptive immune response -main types (based on tissue localization): a)microglia - brain b)Kupffer cells -liver c)histiocytes -connective tissue d)osteoclasts -bone e)alveolar macrophages -lung In Greek Makros=large phagein=eat  “big eaters” 10-15 μm Bean-shaped nucleus 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 - Plasmacytoid DCs (pDC): Type I interferon producing cells. Follicular DCs: Stromal cells of the lymph nodes, found in primary and secondary follicles. similar in appearance but are not of hematopoietic origin.

27. MAST CELLS -Tissue resident cells, absent from the circulation -Cytoplasmic granules containing vasoactive amins e.g. heparin -Found around small vessels, regulating the vascular permeability -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 the patho-physiology of immunity against helminths and allergic reactions

29. - Mature in bursa equivalent tissues* (embrionic liver, later bone marrow) - 5-10% of the circulating lymphocytes. - Migrate from the bone marrow to the secondary lymphatic organs - Express antigen-specific receptor on their surface (BCR) - Professional antigen presenting cells (APC) - Activated with antigens, interacting with T lymphocytes, lymphokines and cytokines - Upon activation they differentiate to plasma cells and memory B cells *‘B’= Bursa-derived cell, first described in the hematopoietic organ called Bursa de Fabricius in birds B LYMPHOCYTES PLASMA CELLS - Antibody production - Humoral immune response

30. -Mature in the thymus where they become mature naive T cells and they migrate to peripheral (secondary) lymphoid organs - Express antigen-specific receptor on their surface (TCR) -types: - CD4+ T helper (Th1 & Th2) - CD8+ T cytotoxic (Tc) - Regulatory T cells (Treg) T LYMPHOCYTES

31. NK CELLS (natural killer cells) -origin: lymphoid progenitors, however, is a participant of the innate immunity. -They play a role against intracellular infections by killing infected cells. - Granules in their cytoplasm contain perforin and granzymes. - Has no antigen-specific receptors („null cells”) - Recognize abnormal cells (altered proteins and the absence of MHC class I). - Functionally similar to cytotoxic T cells

32. NK cells The localization of blood cells

33. Relative abundance of leukocytes in peripheral blood Cell typeProportion of leukocytes (%) Neutrophil Lymphocytes Eosinophil Basophil Monocyte 40-75 20-50 1-6 <1 2-10

34. - nonspecific - immediate reaction - does not improve - no memory - highly specific - developes in several days - improves after exposure - has memory Immune system Innate / NaturalAcquired / Adaptive Cellular Granulocytes Monocytes/Macrophages Natural Killer cells Dendritic cells Mast cells CD4+ (helper) T cells CD8+ (cytotoxic) T cells B cells Plasmacells Humoral Complement proteins Cytokines Acute phase proteins Antimicrobial proteins Antibodies

35. Professional phagocytic cells 1.Dendritic cells 2.Macrophages 3.Neutrophil granulocytes Professional antigen presenting cells (APCs) 1.Dendritic cells 2.Macrophages 3.B lymphocytes Pathogens are processed by APCs, their degradation products (peptides) are presented to T lymphocytes on MHC molecules

36. INNATE IMMUNITY - immediate reaction - nonspecific - Does not improve after exposure - no memory ADAPTIVE IMMUNITY - developes in several days - highly specific - Improves after exposure - has memory communication Coordinated and regulated actions of both arms of the immune system Direct communication via adhesion molecules Indirect communication via cytokines OR

37. MOLECULES OF THE IMMUNE SYSTEM Cell surface molecules: - Receptors (e.g. PRRs, BCR, TCR, cytokine receptors, 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 - Complement components - Acute phase proteins

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 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. THE MOST IMPORTANT FEATURES OF CYTOKINES hormones cytokines chemokines interleukines monokines lymphokines interferons

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

41. INTERLEUKINES (IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, TNFα) control functions of leukocytes communication between leukocytes CHEMOKINES (IL-8, CCL21) inducing chemotaxis increasing adhesion activating leukocytes TYPE I INTERFERONS (IFNα, IFNβ) parts of innate immunity important role against viral infections producers: infected cells, plasmacitoid DCs TYPE II INTERFERON (IFNγ) main activators of macrophages producers: Th1, CD8+, NK cells CYTOKINES

42. 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) BIOACTIVE MOLECULES INFLUENCE THE ACTIVITY AND FUNCTION OF THE IMMUNE SYSTEM

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