Immunology Lecture One 2024 PDF

OF MEDICINE COLLEGE Immunology :Non specific and specific I.R Tissues and cells of I.R ▪ By prof Wafaa Khalil zaki. ILOS: Define immunity & its types Describe specific & non specific immune response Discuss the differences between innate and adaptive immune res...

OF MEDICINE COLLEGE Immunology :Non specific and specific I.R Tissues and cells of I.R ▪ By prof Wafaa Khalil zaki. ILOS: Define immunity & its types Describe specific & non specific immune response Discuss the differences between innate and adaptive immune responses Describe organs & cells of the immune system. Identify functions of these organs & cells.  Immunity Definition Sum of defense mechanism protecting the human body against any foreign particles  Immunity Types Non-specific (Innate-Natural) Specific (Acquired-Adaptive) Non Specific IR Physiological mechanisms No specificity 1st line of defense Specific IR Acquired Specific 2nd line of defense Components of Nonspecific IR 1- Mechanical barriers 2- Chemical barriers 3- Microbial factor 4- Cellular factors 1- Mechanical barriers: 1. Intact skin 2. Oral cavity (saliva -antibodies- enzymes-mucous) 3. Mucous: Trapping of organisms, removed by: Cilia (Respiratory Tract) Cough Sneezing (Cont) 4- Shedding of cells carrying microbes. 5- Washing effects of saliva, tears, urine,…etc. 6- Vomiting and diarrhea.  2- Chemical barrier: Acidic PH (urine, stomach, vagina): No colonization of microbes. Organic acids (e.g. in sebaceous secretions). Fatty acids: affecting cell membrane of microbes. Lysozyme: affecting cell wall of microbes. Acid in gastric juice. Interferons (IFNs). Lactoferrin and transferrin (iron-binding proteins). b- Chemical barriers: Many of the secreted body fluids contain microbicidal factors Lactic acid and fatty acids present in sweat and sebaceous secretions. Lysozymes in tears, nasal secretions and saliva. The acid in gastric juice. Defensins secreted by epithelia and some leukocytes have antimicrobial properties. The protective action of defensins includes direct toxicity to microbes and activation of cells involved in inflammatory response to microbes. (Cont) 3- Microbial factors: Commensals (normal flora) decrease microbial growth by: Interference (competition on nutrients). Production of antibiotic like substance. Production of inhibitory substances as bacteriocins.  4- Cellular factors: Phagocytic cells : Including neutrophils and monocytes, performing Phagocytosis Natural Killer cells :Naturally cytotoxic cells (lymphocytes).  Phagocytosis 1- Phagocytic cells They are either circulating in blood (neutrophils and monocytes) or residing in tissues (macrophages and dendritic cells). When microbes invade blood they encounter circulating neutrophils and monocytes If microbes invades the mechanical and chemical barriers and the effect of normal flora, they will encounter macrophages and dendritic cells in subepithelial tissue.  Phagocytic cells have pattern recognition receptors that recognize characteristic structures of microbial pathogens do not present in mammalian cells. These structures are called pathogen- associated molecular patterns (PAMPs). e.g. lipopolysaccharides and teichoic acids in bacteria Toll like receptors are an example of pattern recognition receptors  The outcomes of the phagocytic event in neutrophils and tissue phagocytes are different: oNeutrophils destroy phagocytosed particles completely, while oDendritic cells and macrophages ‘preserve’ useful information from the ingested particles and are able to present it to cells of adaptive immunity (antigen presenting cells). 2- Natural Killer cells: Naturally cytotoxic lymphocytes NK cells are granular lymphocytes that can perform extracellular killing. NK cells express two surface markers: CD 16, CD56.  Macrophages Macrophages (MQ) are released from bone marrow as immature monocytes and mature in various tissue locations where they reside for weeks or years. Macrophages functions Phagocytosing microbes. They form a link between non-specific and specific immune response. Antigen presentation to the lymphoid cells through digestion of Ag by its enzymes and releasing highly immunologic parts of antigen, thus act as a major APC.  They aid in the initiation and coordination of the immune response by producing monokines as IL-1. They act as depot for maintenance of the immune response. Macrophages are important cells in delayed hypersensitivity reactions, autoimmune diseases and tumor immunity. They have secretory function; they release the following: 1) Lysozyme 2) Hydrolytic enzymes 3) Factors that influence cell differentiation (e.g., colony- stimulating factor) 4) Arachidonic acid and metabolites (e.g., prostaglandins, leukotrienes) 5) Complement components C1 to C5, properdin, and factors B, D, I and H 6) Cytokines, e.g., TNF-alpha, IFN-alpha, interleukines e.g., IL-1, IL-6 and IL-10 , IL-8). 7) Oxygen metabolites (e.g., H2O2, superoxide anion)  Neutrophils They are phagocytic cells. They have receptors for IgG (Fc–R) and complement (C3b) After engulfing & killing of bacteria they die. Phagocytosis. Phagocytosis include the following steps: 1) Recognition 2) Chemotaxis (attraction) 3) Attachment (adherence) 4) Engulfment 5) Intracellular Killing (Digestion) Steps of Phagocytosis and killing Recognition of microbes Phagocytic cells have pattern recognition receptors present on the cell surface and in endosomal vesicles Recognize characteristic structures of microbial pathogens not present in mammalian cells. These structures are called pathogen-associated molecular patterns (PAMPs). Pathogen associated molecular patterns can’t be lost or mutated e.g lipopolysaccharides and teichoic acids in bacteria and DNA in viruses. Toll like receptors are an example of pattern recognition receptors What are opsonin's? Definition Substances that bind to the foreign particles (e.g. microbes) making them more susceptible to phagocytosis. e.g. C3b, IgG (IgG1 and IgG3), leukotrienes and fibronectin 2- Chemotaxis (Attraction): -Phagocytes must come into physical contact with its target. This is facilitated by: Receptor molecules e.g. receptors for opsonin C3b, and for Fc portion of immunoglobulin molecules. Adhesion molecules: These are glycoprotein on cell surface having the following functions: A. Playing a mechanical role in binding cell- to cell or cell to extracellular matrix. B. Also involved in signal transduction controlling cell activation and proliferation. C. These adhesion molecules include selectin, integrins and immunoglobulin super family mucin. Chemotactic factors: including bacterial factors as: lipopolysaccharide (endotoxin) & host factors as: C3 a, C 5a 3- Engulfment: by endocytosis forming a phagocytic vacuole or phagosome. This phagosome bind lysosomes (membrane- bound bags of enzymes) forming phagolysosome. 4-Intracellular destruction or digestion: The engulfed material is digested by lysosomal enzymes, toxic oxygen metabolites & nitric oxide.  Antigen presenting cells (APC) Antigen presenting cells (APC) are cells that pick up antigen and migrate to secondary lymphoid tissues and interact with T and B lymphocytes Examples of antigen-presenting cells (APCs) are macrophages, B-lymphocytes, and dendritic cells. Macrophages ingest antigen by phagocytosis, degrade it, (Ag processing), then present fragments of the antigen at their surface to T&B cells (Ag presentation). When these lymphocytes (T & B cells) encounter microbial antigens, the antigen specific lymphocytes proliferate and differentiate into effector and memory cells.  Natural Killer Cells (NK cells): Derived from bone marrow Lack most markers for T and B cells. Do not undergo thymic maturation. Express CD56, a specific NK marker Express a receptor for Fc portion of IgG, called CD16,. Cytokines, especially IL-2, promote further differentiation into lymphokine-activated killer (LAK) cells NK cells regulate the immune response through the secretion of numerous cytokines such as IFN γ, IL-2 (Cont) Effector mechanisms: Similar to CTL in killing of their targets ( release perforins and granzymes) Not MHC-restricted Kill a variety of virus-infected cells, tumor cells and graft cells. Immune surveillance. Play a role in resistance to some bacterial, fungal, and parasitic infections (intracellular pathogens). IgG-coated target cells recognized by CD16 are killed by (ADCC).  1- Natural killer cells Perform extracellular killing to get rid of large particles that cannot be phagocytosed by phagocytic cells as virus infected cells or malignant cells. NK cells are granular lymphocytes that can perform extracellular killing as part of innate immune response efficiently. NK cells express two surface markers ;CD 16, CD 56  The activation of NK cells is determined by a balance between engagement of activating and inhibitory receptors expressed on the surface of NK cells. The activating receptors recognize stress molecules which are cell surface molecules expressed on cells infected with viruses and intracellular bacteria, cells stressed by malignant transformation transformation  The inhibitory receptors recognize Self-Class I MHC molecules. They block signaling by activating receptors Therefore: Class I MHC expression protects healthy cells from destruction by NK cells Mechanism of ADCC  Eosinophils They play an important role in type I hypersensitivity reaction (in controlling anaphylaxis). They have Fc & complement receptors (C3b). They are important in resistance to parasites Mast cells Mast cells reside in tissues specially under the skin and in the mucosa of respiratory and gastrointestinal tracts. Mast cells are similar to basophils in characters Both cells initiate anaphylaxis on stimulation by antigen and IgE /or activation by C3a, C5a. Their granules contain histamine, heparin, serotonin, leukotrienes and prostaglandins. Specific immune response characteristics Specific immune response has 4 essential characteristics: 1) Provides additional protection against invading pathogen 2) Specificity 3)Distinguish self from non-self 4) Memory Acquired Immunity Naturally Acquired Passive antibodies from mother to fetus (placenta-milk) Active convalescence from infections Artificially Acquired Active vaccines Passive Immunoglobulins Mechanism of specific I.R. Humoral Cell-mediated B-Lymphocytes T-lymphocytes  Tissues & Cells of specific I.R. Central Peripheral (1ry) (2ry) Thymus, B marrow Spleen ,LN, MALT Thymus-------→ T cell B marrow-------→ B cell ) Function of Lymphoid Tissues : Primary (central) lymphoid Tissue : Thymus : site in which T cells mature into Ag – recognizing T lymphocytes. Bone marrow: Site in which B cells mature into Ag – recognizing B- lymphocytes Precursor cell of T & B lymphocyte, is the stem cell. Function of Lymphoid Tissues Secondary lymphoid Tissue (Spleen – LN – MALT). 1-Trapping and concentration of foreign particles. 2- Site of contract between Ag. and Ag – recognizing lymphocytes 3- Production of abs or sensitized T cells. Cells involved in I.R ▪ B. cell.( specific IR) ▪ T cell (specific IR) ▪ Natural-killer cell.(non specific IR) ▪ Phagocytic cells.(non specific IR) monocytes (Macrophages) & Neutrophils. ▪ Other cells : as eosinophils & Mast cells. Tissues involved in I.R B. Lymphocytes Constitute 15 – 20 % of circulating lymphocytes. Short life –span (days or weeks). Mature in bone marrow from stem cell  B – cell development Originate from stem cell in bone marrow On Stimulation of B cells in 2ry lymphoid tiss - → proliferation, differentiation → 2 cells plasma cells → secreting abs. Memory cells → rapid plasma cell proliferation on 2ry I.R. (on 2nd exposure to the same Ag). B –cell surface receptors: Antigen –receptor (Ag receptor) (immunoglobulin –monomeric IgM ) on stimulation of Ag receptor , B cell undergo proliferation. differentiation → plasma cell and memory cells B cell Stimulation T-Lymphocytes : Constitute 65 – 80% of circulating lymphocytes. Long life – span (months –years) Mature in the thymus from stem cell.  T. cell development Fetal stem cell enter the thymus – proliferate and differentiate into mature T-lymphocytes under the effect of Thymic hormones. Acquire CD2, CD4, CD8, in cortex. Acquire CD3 in medulla. Then loose CD4 or CD8 - → two populations are produced: CD2, CD3, CD4 (helper or delayed sensitivity T- lymphocyte (CD4) CD2, CD3, CD8 (cytotoxic T-lymphocyte (CD8) T lymphocyte subpopulations CD2, CD3, CD4 Helper CD2, CD3, CD8 + Cytotoxic CD2, CD3, CD4 ,CD 25 Regulatory T Cell Subpopulations T. Cell surface markers; (1) Ag- receptor (T cell receptor TCR ) It consists of 2 non- identical polypeptide chains linked by disulfide bonds. (heterodimers) Called alpha & beta chains T. Cell receptor  (2) Other markers Receptors of FC portion of Ig. CD antigens ( Cluster of differentiation ) CD2: SRBC – R Sheep Red blood cell receptor Being responsible for rosette technique used for T cell enumeration CD3 : associated with T. Cell receptor , cell to cell adhesion , for signal Transduction during Ag presentation CD4 ,CD8 : these receptors bind MHC molecules during Ag presentation to T. Cell.. Complement receptor. Class I MHC molecules.  (1) CD4 T lymphocytes (65 % of T lymphocytes). T helper (Th cell) They help B cells and macrophages in induction of humoral immune response Help Tc cells.  Includes two types Th1 & Th2. Th1 : They secrete many cytokines including IL-2, IFN γ, & TNF β. IL-2 promotes the proliferation of T cells & activation of B cells and NK cells. IFN γ (type II, immune interferon): It has many functions; 1.Promotes the development of Tc cells. 2.Induction of Class I & class II MHC molecules on APCs. 3.Antiviral effect (inhibition of viral replication). 4.Direct activation effect on macrophage, NK cells, & T cells. 5.Increase expression of Fc receptor on different types of cells as macrophage. 6.Regulation of cell mediated immunity (down regulation of Th2 cell function). Th2 Directs immune response toward production of IgE. It secretes many cytokines including: IL4, IL5 & IL10. IL4 enhances class switching to IgE IL10 down regulates Th1 function IL5 mediates proliferation of eosinophils & mast cell. The Th subsets down-regulate one another: Th1 inhibits Th2 by IFN-gamma Th2 inhibits Th1 by IL10 Treg>>>>>>> ❑Natural >>tolerance to self antigen ❑Induced >>down-regulation of I.R T-regs.(CD4,CD25.T cells) Inhibit T cells proliferation and cytokine production. Was originally called suppressor T cells. Secretes immunosuppressive cytokines, transforming growth factor-β (TGFβ) and IL-10. Suppress Ig production by B cells. Prevent the occurrence of atopy by suppressing IgE secretion. Prevention of autoimmunity (inhibit self-reacting clones of lymphocytes). CD8+ T cells CD8+ cytotoxic T cells CD8+T cells constitute 35 % of peripheral T lymphocytes. Tc cells are induced by, and are active against, tumors, viruses, and allogenic graft. They cause lysis of antigen-bearing target cells. Mechanisms of killing by CD8+ CTLs: Degranulation which involves the release of "granzymes" and perforins. Fas ligand-Fas pathway. Antigen recognition stimulates CTLs to express a membrane protein called Fas ligand The interaction of Fas ligand with Fas receptor (TNF-R) on the target cell induces apoptosis.  Assay Q what are Gamma –delta T cell ??? Definition, technique and uses of Monoclonal antibodies  Rap up and summery Immune system is the sum. Of defence mechanisms protecting our body against invading pathogens and any foreign agent. It has innate and acquired immune mechanisms that are interactive , and can lead to stimulation of many cells and release of different mediators that acts as defensive mechanism against foreign invading particle