Physiology IMMUNOLOGY I. Learning Objectives Nr.18. Judit Rosta October

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1 Physiology IMMUNOLOGY I. Learning Objectives Nr.18. Judit Rosta October

2 The Immune System recognizes and helps fight off pathogens and foreign substances. ANTIGEN-ANTIBODY REACTION Stimulate an immune response Work by binding foreign substances Pathogen with several ANTIGENS

3 Learning Objectives Nr.18. Subject and Prospect 1. leukocyte count 2. lymphatic system. 3. types of white blood cells 4. phagocytosis 5. inflammatory reaction 6. monocyte/macrophage system 7. Arachidonic Acid derivates 8. complement system 9. bradykinin-kallidin system 10."surface barriers" IMMUNOLOGY I. INNATE IMMUNITY the innate immune system is constantly defending against infection

4 INNATE IMMUNITY Initial defense prevent and elimination 1. Surface Barriers 2. Immune Effector Cells: LEUKOCYTES (WBCs) (Phagocytes, Natural Killer Cells) 3. Complement system Basic Immunology: Functions and Disorders of the Immune System 5th edition, by Abul K. Abbas, Andrew H. Lichtman, and Shiv Pillai

5 2. lymphatic system parts of the lymphatic system network of tissues and organs Generation and maturation sites of immune effector cells Bone Marrow Thymus Lymph Nodes Spleen Basic and Clinical Immunology 2nd edition, by Mark Peakman and Diego Vergani Activation sites of immune effector cells Tonsils Mucosa-Associated Lymphoid Tissue (MALT,GALT)

6 parts of the BONE MARROW, as one of the largest and most active organ produces 200 billion new red blood cells every day lymphatic system hip and thigh bones production of: blood cellular elements, mast cells, dendritic cells from Stem Cells- HEMATOPOIESIS elimination of old red blood cells (together with liver and spleen) yellow marrow may revert to red marrow Red vs. Yellow Marrow (matured-fat store)

7 parts of the lymphatic system Macrophages and Dendritic Cells kill many of the pathogens that pass through Lymph Nodes, the houses of lymphocytes Eff lymhp ér billentyűk filter and monitor the lymph for foreign particles Lymphocytes formation Aff Aff lymhp lymhp vessels ér encapsulated nodular aggregates ofpearson lymphoid 2011 Education Inc tissues

8 The Houses of Lymphocytes Where most of the lymphocytes located dendritic cells pick up antigens of microbes and transport these antigens to the lymph nodes antigens of microbes entering through epithelia become concentrated in lymph nodes Morphology of a Lymph Node Basic Immunology: Functions and Disorders of the Immune System 5th edition, by Abul K. Abbas, Andrew H. Lichtman, and Shiv Pillai

9 parts of the Lymphatic Circulation, filter and monitor the lymph for foreign particles lymphatic system lymph; 3l/day collect and filter excess tissue fluid before returning it to the venous circulation NOT actively pumped by the heart maintaining the body s fluid balance start as blind-ended capillaries transporting the cells of the immune system and some fats

10 Basic Immunology: Functions and Disorders of the Immune System 5th edition, by Abul K. Abbas, Andrew H. Lichtman, and Shiv Pillai Lymphatic Circulation parts of the lymphatic system Recirculation between blood and peripheral lymphoid organs lymphocytes be activated by antigens to become effector cells and the effector lymphocytes migrate to sites of infection

11 parts of the SPLEEN filter and monitor the blood lymphatic system white pulp: constant monitoring of the blood red pulp: removal of effete and defective red and white blood cells resources: iron in haemoglobin- recycled storing blood The importance of the spleen: (not vital, but) capacity to act as a rapid response unit in generating specific antimicrobial antibodies. It is recommended that patients who have undergone splenectomy should receive prophylactic vaccinations against several organisms

12 IMMUNE CELLS Innate Immune Reactions parts of the lymphatic system Cellular components LEUKOCYTES (WHITE BLOOD CELLS) types of white blood cells hematopoiesis phagocytosis monocyte/macrophage system

13 blood cellular components QUALITATIVE BLOOD SMEAR 60-80% Hematoxylin and eosin stain demonstration of nucleus and cytoplasmic inclusions normal values of the differential white blood cell (WBC) count (%) Neutrophil 1-5% neutrophils: 60-80% lymphocytes: 20-30% monocytes: 2-6% eosinophils: 1-5% 20-30% 0-1% Basophil 2-6% Monocytes basophils: 0-1% white blood cell count: cell/μl

14 HEMATOPOIESIS in BONE MARROW -blasts: immature forms -cytes:mature forms Colony-Stimulating Factors: proliferate progenitors, activate mature cells how blood cellular components form myeloid progenitor Hematopoietic Stem Cell lymphoid progenitor Extramedullary Heamatopoiesis: liver,spleen Zebrafish erythropoiesis and the utility of fish as models of anemia. Kulkeaw K, Sugiyama D - Stem Cell Res Ther (2012) LEUKOCYTES

15 GRANULOCYTES Neutrophil with anthrax bacteria resident in the circulation and migrate into tissue 1. NEUTROPHILS: phagocytose foreign material or dead/damaged cells at sites of inflammation produce mediators of chemotaxis (citokine, chemokine) Commons.wikimedia 2. EOSINOPHILS: 3. BASOPHILS: have all the functions of a neutrophil Immediate hypersensitivity reactions (allergic diseases) wikimedia source of most HISTAMINE IgE (plasma cells)-activated histamine-release; mediate hypersensitivity reactions

16 LYMPHOCYTES MONOCYTES Antigen Recognition Tissue Macrophages only cells that produce receptors specific for diverse antigens T and B Lymphocytes B lymphocytes are the only cells that produce ANTIBODIES maturation, activation-sec.lymph.organs participate in inflammatory response reactions or die They phagocytose pathogens and cellular debris and produce various cytokines present antigen to lymphocytes alveolar macrophag(lung) Kupffer cell (liver) mast cell (skin) microglia (brain)

17 4. phagocytosis - engulf solid particles by endocytosis PHAGOCYTOSIS MACROPHAGES whose function is to ingest and destroy foreign substances Granulocytes, Monocytes, Dendritic Cells, Natural Killer Cells Patterns, Receptors, and Signals: Regulation of Phagosome Maturation Pauwels A.M Trost M.Beyaertn R. E Hoffmann, Trend Immun 2017

18 6. monocyte/macrophage system TISSUE MACROPHAGES ( reticuloendothelial system ) They phagocytose pathogens and cellular debris and produce various cytokines present antigen to lymphocytes alveolar macrophag(lung) Kupffer cell (liver) mast cell (skin) microglia (brain)

19 types of immune cells- according to function I. Specific recognition of Antigens II. Antigen-presenting Cells III. Effector Cells Initiate adaptive immune response cells resident in tissues detect the presence of microbes capture of antigens for display to lymphocytes primary function is to alert the immune system circulate in the blood, rapidly recruited to sites of infectioninflammation ingest and destroy microbes (start the process of repairing damaged tissues)

20 types of immune cells- according to function I. Specific recognition of Antigens B Lymphocytes mediators of humoral immunity T Lymphocytes mediators of cellular immunity IMMUNOLOGY II. II. Antigen-presenting Cells III. Effector Cells Dendritic Cells Macrophages, Lymphocytes Granulocytes Monocytes Natural Killer Cells

21 types of immune cells II. Antigen-presenting Cells Photomicrograph of DCs stained with May-Grunwald Giemsa- Tan et al. 97 Malaysian J Pathol 2010; 32(2) Dendritic Cells highly specialised function in the activation and priming of lymphocytes characteristic appearance of numerous cytoplasmic processes IL-12 production=> T cell stimulating factor vital role in anti-tumour responses macrophage, mast cell and dendritic cell, the three sentinal

22 1. MIGRATION INTO TISSUES 2. ANTIGEN UPTAKE Antigen processing in endosome II. Antigenpresenting Cells Peptide MHC class II 5. MATURATION, CYTOKIN SECRETION 4. ACTIVATION OF LYMPHOCYTES (IN LYMPH NODE) 3. ANTIGEN PRESENTATION ACTIVATION OF LYMPHOCYTES MHC class II MHC: (major histocompatibility complex) a set of cell surface proteins- recognize foreign molecule

23 types of immune cells Nature Reviews-Immunology Mast Cells Mast Cell help to recruit other leukocytes 1. derived from haematopoietic progenitor cell, 2. circulate in the blood in an immature form, 3. migrating to tissues (abundant beneath epithelial surface), 4. where they undergo maturation release Histamine, Heparin (mast cells and basophils share many common features) Basophils leave the bone marrow already mature

24 types of immune cells III. Effector Cells Natural Killer Cells kill cells they detect as foreign either directly or via antibodydependent cell-mediated cytotoxicity NK cell attacks a cancer cell a functional definition: cells with this activity are capable of lysing damaged, virus-infected cells and tumour cells Unlike T lymphocytes, they do not need an education in the thymus to do this, hence the term natural have a very granular cytoplasm- cytotoxic granules (PERFORIN, GRANZYME)

25 production of IFN-γ. Dynamic changes in cellular composition at the site of infection Immunity Vol 36.,Nr. 6.,June Tissue-resident mononuclear phagocytes and DCs exit the stagereplaced by recruited monocyte; - regulated by NK cells through their

26 8. complement system Soluble Components in the Immune Responses: plasma proteins Trigger The COMPLEMENT SYSTEM as 'complement' the antibacterial activity of antibodies a proteolysis based activation cascade proceeds 2. Cell lysis due to formation of a MEMBRANE ATTACK COMPLEX 1. increased local immune responses by OPSONIZATION (C3b), CHEMOTAXIS (C5a) Membrane Attack Complex of complements: forming pole on a cell membrane binds to pathogens marking them as targets for phagocytes 3. Agglutination: clustering and binding of pathogens

27 OPSONIZATION (C3b) Three ACTIVATION Pathways of the COMPLEMENT SYSTEM -at least 30 plasma proteins (C1-) -synthesised in the liver, -circulate as inactive precursors - cleaved into two fragments: C5a is the most important peptide mediator of inflammation C5b initiates assembly of a membrane attack complex Complement halts angiogenesis gone wild. Walter H. A. Kahr; illustration by A. Y. Chen. Blood : ; a larger stays on the pathogen surface (C3b, C4b, C5b) and a smaller act as a soluble mediator (C3a, C4a, C5a)

28 5. inflammatory reaction...local INFLAMMATORY RESPONSES generated following complement acitvation recruitment of circulating blood leukocytes and various plasma proteins (complement, antibodies) to sites of infection non-specific response for all classes of microbes destroy the microbes (killing zone) and repair damaged tissue include smooth muscle contraction and release of inflammatory mediators such as BRADYKININ and Histamine 1. activation of sensory nerves- pain ( dolor ) 2. increased blood flow- redness ( rubor ), heat ( calor ) 3. increased vascular permeability- local oedema At termination phagocytes leave site of inflammation via lymphatic circulation

29 5. inflammatory reaction 1. Non-specific Recognition of bacterial products by plasma factors (opsonization C3,C5) and/or immune cells (PRRs) The Inflammatory Reaction (PRR) pattern recognition receptor: expressed by host cell (e.g. Toll-like Receptors (TLR), Scavenging receptors for LPS) Molecular Pattern recognized as nonself: characteristic molecules expressed in high amounts by pathogens (bacterial cell wall component e.g.lps, Mannose) 2. Chemokins are produced, immune cells are activated, macrophages attracted to the infected area

30 5. inflammatory reaction 2. Chemokines are released: function is to attract cells from longer distances ( chemotaxis ) CYTOKINES that regulate immune responses (induces chemotaxis and phagocytosis); produced by lymphocytes, macrophages, mast cells, endothelial cells, neurons etc. INTERLEUKINS human cytokines with known amino acid sequence IL-8, Tumor Necrosis Factor α (promotion of inflammation) INTERFERONS: secreted by virus-infected cells Interferon-g- activation of macrophages (by NKs, T helper cells) The Inflammatory Reaction soluble mediators Anaphylatoxins: small complement fragments (C3a, C4a, and C5a); bind to mast cells and basophils and trigger the release of inflammatory mediators (Histamine)

31 5. inflammatory reaction 3. macrophages attracted to the infected area: CHEMOTAXIS and entry into tissue: DIAPEDEZIS The Inflammatory Reaction Capture Rolling Adhering proinflammatory stimuli activate endothelial cells Migration

32 5. inflammatory reaction 4. ingestion of the bacteria (Opsonisation) by endocytosis-phagocytosis 5. cytotoxic granules discharge their content: degranulation into interstitial space (local destruction of host tissue) The Inflammatory Reaction Cytotoxic granules: proteases e.g.antimicrobial defensins NADPH-oxidase and superoxide-dismutase (O 2- to H 2 O 2 ) myeloperoxidase (e.g.hocl)

33 7. Arachidonic Acid derivates. The Inflammatory Reaction ARACHIDONIC ACID is metabolised to produce inflammatory mediators: EICOSANOIDS soluble mediators Membrane Phospholipids Phospholypase (PLA2) Arachidonic Acid nonsteroidal anti-inflammatory drugs Lypoxygenase (LOX) Chemotaxis 5 HETE Leukotrienes airway obstruction Increased vascular permeability CYCLOOXYGENASE (COX1, COX2) Prostaglandins PGE Prostacyclin (PGI2) Thromboxanes Inflammation, pain, oedema Platelet aggregation

34 7. Arachidonic Acid derivates. The Inflammatory Reaction Anti-Inflammatory Medicines inhibit AA-pathway soluble mediators Membrane Phospholipids Arachidonic Acid Phospholypase (PLA2) CYCLOOXYGENASE (COX1, COX2) steroids (anti-inflammatory drugs) nonsteroidal anti-inflammatory drugs- COX-INHIBITORS aspirin, ibuprofen, and naproxen PGE Prostaglandins Prostacyclin (PGI2) Thromboxanes COX-1: is constituitively expressed in most cells; COX-2 is upregulated during inflammation Selective COX-2 inhibitors with a lower incidence of side-effects Inflammation, pain, oedema Platelet aggregation Aspirin is effective at reducing cardiac event Nobel Prize in Physiology or Medicine (1982)

35 9. bradykinin-kallidin system The The BRADYKININ-KALLIDIN (KININ-KALLIKREIN) System. Inflammatory Reaction soluble mediators endogenous multiprotein cascade leads to enzymatic hydrolysis of KININOGENS triggering of the intrinsic coagulation pathway, blood pressure control, pain trigger vasodilation, increased capillary permeability Inducible Constitutive BRADYKININ: an important mediator of pain and irritation in skin, vasculature and all visceral organs

36 Protection of "surface barriers" (mechanical, chemical and biological barriers: skin, saliva, tears, gastric juice with acids and proteases, natural flora...). 10. "surface barriers" Summary- Component of Innate Immunity Examples: ciliated epithelial cells (e.g. upper respiratory tract) can facilitate removal of microbes LYSOZIME in saliva: digest bacteria cell wall maturation of immune effector cells beneath epithelial layer

37 Immunology I and II Nr.18. Nr.19. Learning Objectives Basic Immunology,

38 INNATE IMMUNITY Nr.18.

39 Prospects IMMUNOLOGY Somatic mutations in cancer can be translated into peptides, termed neoantigens, which can be recognized by the immune system as foreign epitopes... Making It Personal: Neoantigen Vaccines in Metastatic Melanoma. M. D. Hellmann, A. Snyder; 2017 August