Medical Immunology Lecture Notes PDF

‫ﻛﻠﯿﺔ اﻟﻌﻠﻮم اﻟﻄﺒﯿﺔ اﻟﺘﻄﺒﯿﻘﯿﺔ ﺑﯿﻨﺒﻊ‬ College of Applied Medical Sciences, Yanbu Introduction to The Immune System Medical Immunology Dr. Alhanouf I. Al-Harbi...

‫ﻛﻠﯿﺔ اﻟﻌﻠﻮم اﻟﻄﺒﯿﺔ اﻟﺘﻄﺒﯿﻘﯿﺔ ﺑﯿﻨﺒﻊ‬ College of Applied Medical Sciences, Yanbu Introduction to The Immune System Medical Immunology Dr. Alhanouf I. Al-Harbi Department of Medical Laboratory Technology [email protected]  Lecture 1: Introduction to The Immune System  Learning Objectives At the end of the lecture you will be capable to: 1. Identify the cells and organs of the immune system 2. Understand the basic concepts of immunity 3. Distinguish between innate and adaptive immune responses 4. Recognize the importance of immunology studies and investigation Where does the Immune System located? The immune system is found throughout your body!  The immune system Similar to each system inside the body, the immune system comprises of cells and organs: § Such as: Ø Respiratory system ü Lung (organ) ü epithelial cells (cells) The immune system  Organs of Immune System Primary Organs: Secondary Organs Ø Thymus: Ø Adenoids Where lymphocytes mature. Ø Tonsils Ø Bone Marrow: Ø Lymph nodes Where blood cells formed Ø Spleen: Stores lymphocytes and filters blood Ø Peyer’s patches Ø Appendix  What is Immunology? Immunology is the study of how the body protects itself from pathogens, tumours and other foreign substances in its environment. Immune cells of the body have various functions ranging from defence against pathogens and tumours to tolerance towards harmless antigens. This implies that the cells need resources to aid them in these functions, and the requirements can change according to the needs of the hour. Immunometabolism is the area of immunology that is concerned with the energy requirements for functions and differentiation of immune cells.  How Immune Systems Works? The principal features of the immune system include: 1. Protection of the body with two related actions; recognition and response 2. Identifying foreign invaders from self components (self, non self-differentiation) 3. Recognition of host cells that are modified (neoplasm) 4. Turning initial recognition into a variety of effector responses (elimination, neutralization, etc.) 5. Formation of memory response distinguished by a more active and heightened response 6. Learning and orientation to disease prevention or treatment by vaccination  Antigens (Ags) § Foreign substance ---- Antigen § If able to produce immune response ------- immunogen or complete antigen § If unable to initiate immune response alone called partial antigen § All immunogens are antigenic but not all antigens are immunogenic § Immune system does not react against the whole pathogen but parts of it (Ags) and not against the whole Ag but parts of it (chemical groups) called epitopes § Each Ag has variable number of epitopes  Properties of Antigens (Ags) 1. Foreignness a) Autologous antigens : Self antigens and there will be no immune response. b) Allogenic antigens : from the same species and there may be reaction, eg. Blood transfusion, kidney transplant c) Heterologous antigens: from different species. These antigens will be rejected and there will be severe immune response  Properties of Antigens (Ags) 2. Chemical complexity Most antigens contain at least one amino acid in their structures. More amino acid more antigenicity 3. Molecular weight More than 100,000 Dalton more immunogenic  How your immune systems works? The two major arms of the immune systems: § Innate immunity § Adaptive immunity 1. Present from birth. 1. Not present at birth but acquired during life as 2. First line of defence against infection. immune system develops 3. non-specific defence. 2. 2ed line of defence against infection. 4. Rapid defence min-hours. 3. highly-specific detection of the immune 5. Symptoms such as fever and inflammation component (antigens). 4. Recognition and elimination of pathogens. 5. Late; start days after first infection. 6. Provides immunological memory  How your immune systems works? The two major arms of the immune systems: § Innate immunity § Adaptive immunity - No memory cells - Memory cells  How your immune systems works? § “Memory” in Adaptive immunity 1st infection * memory * 2nd infection Slow response Fast response Pathogen proliferates Pathogen being killed Disease No disease Symptoms No symptoms Elements of Innate and Adaptive Immune System  Innate Immune System All elements of the innate immune system that individual is born and that are present to protect individual before the onset of infection.  Innate Immune System Rapid recognition and reaction to all pathogens (non-specific). Bacteria Viruses Fungi Warms  Elements of Innate Immune System 1. Barriers. 2. Innate immune cells: such as the phagocytic cells and antimicrobial soluble molecules manufactured by the host that can identify and neutralize pathogens 3. Complement system 4. Other plasma proteins (acute phase response): ↑ Mannose Binding Lectin : participate in lectin pathway of complement ↑ C Reactive Protein: coat microbes and help in phagocytosis ü All these elements either affect pathogenic invaders directly or enhance the effectiveness of host reactions to them.  Elements of Innate Immune System Barriers: a) Physical barriers: - Protect the body from invasion of pathogens. - For example: skin and mucus membrane b) Mechanical barriers: - Effective barriers to environmental agents - For example: the longitudinal flow of air and fluid movement of mucus by cilia c) Chemical barriers (Secretions): - Create sufficient barriers against invasion by various microorganisms such as pH and secreted fatty acids. - HCL of stomach: kill ingested microbes, and Tears in eye: lysozyme kills bacteria by breaking the peptidoglycan layer of cell walls. d) Biological barriers - Commensal microbes or flora inhibit growth of pathogenic bacteria Physical and Chemical Barriers- Skin § Microorganisms normally associated with skin prevent potential pathogens from "Colonizing". § Sebaceous glands secrete fatty acids and lactic acid § which lower the skin pH (pH 4-6) § Skin integrity itself acts as barrier that prevents colonization § The skin has a low moisture content Physical and Chemical Barriers- Mucosal Membranes § Ciliated epithelial cells lining the trachea remove microbes inhaled § through the nose and mouth. § Mucus secreted by these cells prevent the microbes from associating "Too closely" with the cells § Cilia push microbes upwards until they are caught in oral secretions and expectorated or swallowed. Physical and Chemical Barriers- Normal Flora of the gastrointestinal tract Physical and Chemical Barriers- Lysozyme of The Eye and Kidney § Lysozymes constantly bath the kidney and the surface of the eye (tears). (Also in the female urogenital tract, and saliva) § Lysozyme breaks the glycosidic bonds between the NAG and NAM that make up the backbone of peptidoglycan—causing bacteria to lyse. Physical and Chemical Barriers- Extracellular Fluids § Blood plasma contains bacteriocidal substances § Blood proteins called beta-lysins bind to and disrupt the bacterial cytoplasmic membrane—leads to leakage of the cytoplasmic constituents and bacterial cell death.  Elements of Innate Immune System Phagocytic Cells § Specialized cells that have the capacity to engulf, digest and destroy pathogens. § Includes: 1. Neutrophil, 2. Macrophage/Monocytes § Phagocytosis is a type of endocytosis, when the cells extend their plasma membrane around a particulate element such as a microorganism.  Phagocytic Cells Endocytosis Phagocytosis In Main Innate Immune Cells  Elements of Innate Immune System Neutrophils § Multi-lobular nucleus (PMNL) arise from bone marrow. § Highly mobile phagocytes § Acute inflammation § Containing bacteria-killing enzymes (Lyse bacterial cell walls after phagocytosis).  Elements of Innate Immune System Monocytes/ Macrophages Ø Blood Ø Tissues Ø Smaller Ø 5-10 times larger Ø More phagocytic activity Ø Named Based on Tissue They Reside Alveolar (lungs), Kupffer (liver), Microglial (brain), Osteoclasts (bone)  Elements of Innate Immune System Natural Killer (NK) Cells (CD56+) § Large round granular lymphocytes § Always remain in the circulation § Act as immunological surveyors (cytotoxic cells) Kill virally infected cells Kill tumours § However, NK cells do not require stimulation, nor they do exhibit memory cells. NK cells respond in the absence of MHC proteins. § What does CD refer to???????  CD (Cluster of Differentiation) § CD = Cluster of differentiation § Leukocytes surface antigens that are expressed on cells of a particular lineage “differentiation” § Also called CD molecules , CD antigens , CD markers § Used to classify leukocytes into functionally distinct subpopulation, e.g Ø NK cells are CD56+ Ø T - Lymphocytes CD3+ (pan T cells marker) Ø B - Lymphocytes CD19+ Ø Monocytes / Macrophages CD14+  Soluble Molecules 1. Protein lysozyme. 2. Cytokines: A group of proteins produced by virus-infected cells, or some immune cells, that can induce generalized antiviral state such as TNF, IL-1, IL-12& IFN-γ and chemokines. For example: Binding of IFN-α and IFN-β to natural killer (NK) cells makes them very effective in killing virus-infected cells. Also, IFN-γ is involved more in adaptive immune response.  Soluble Molecules 3. Complement system: Alternative pathway when serum proteins that circulate in inactive phase but when activated exert activities  Innate system recognition of microbes § Many innate immune cells can recognize pathogens the unique component via pattern recognition. § The innate immune system is activated when cells use specialized sets of receptor (Pattern recognition receptor, PRR) to recognize various microorganisms structures called pathogen- associated molecular patterns (PAMPs).  Innate system recognition of microbes § Upon microbes recognition, the innate immune system triggers an inflammatory response that leads to adaptive immune response priming against specific pathogens. Recognition of microorganism and activation of immune response Innate and Adaptive Immunity  The Specific Immune Response § Non-specific (innate) immunity IS SOMETIMES NOT ENOUGH!!! § Another more powerful type of immunity called specific (adaptive) immunity is required —That ACQUIRED ability to recognize and destroy an individual pathogen and its product  Adaptive Immune System (Acquired) The features of adaptive immune response are as follow: 1. Specificity: recognize specific antigens. 2. Adaptiveness: is the ability to respond strongly and rapidly to previously unknown molecules. 3. Differentiation between self and nonself: it is the capacity to distinguish and respond to molecules that are foreign (nonself) and to avoid making a response to those molecules that are self. 4. Immunological Memory: recognise pathogens and give a rapid immune response on re-exposure  Adaptive Immune System (Acquired) An efficient immune response includes two types of cells: 1. Lymphocytes present in the blood and lymph: a) B lymphocytes: produce antibodies that neutralize and eliminate extracellular microorganisms and toxins (humoral immunity). b) T lymphocytes: eliminate intracellular microorganisms (cell-mediated immunity). Ø All immune cells including B and T lymphocytes are bone marrow-derived distributed through out the body Ø Stem cells are the precursors to all of these cells 2. Antigen presenting cells: a) Dendritic cells b) Macrophages c) B cells The normal functional state of adaptive immune cells  Lymphocytes: B cells and T cells § Origin : Stem cells in the bone marrow § Maturation : Ø Bone marrow (B cell maturation) Ø Thymus ( T cell maturation) § From 1ry lymphoid organs distributed through lymph and blood to 2ry lymphoid organs: Ø Lymph nodes Ø Tonsils Ø Spleen Ø Mucosal tissues in lung and gut Lymphocytes: B cells and T cells Elements of Innate and Adaptive Immune System Humoral immunity Cellular immunity  T Cell Mediated Immunity § Key players : T - lymphocytes. § Two types: 1. Cytotoxic T cells (CTL) or (CD8+) 2. T helpers ( TH) cells (CD4+) § Cytotoxic T cells directly attack and destroy antigen-bearing cells especially virally infected cells and tumours § Helper T cells act indirectly by secreting proteins called cytokines that activate other cells such as macrophages to destroy the antigen-bearing cells  Mechanism of Cytotoxicity by CTL (CD8+) § T - lymphocytes CAN NOT recognize and respond to free antigens  Mechanism of Cytotoxicity by CTL (CD8+) § 1st step : virally infected or tumour transformed cells will be engulfed by the phagocytes (macrophages) at the site of infection or transformation (internalization) § Next , internalized antigen is processed inside the macrophages where the antigen is degraded and fragment of it binds to MHC class I molecule (Major Histocompatibility Class I molecule)  Mechanism of Cytotoxicity by CTL (CD8+) § Major Histocompatibility complex proteins are found on the surface of cells § T cells cannot recognize foreign antigens unless they are associated with these MHC protein Class II MHC proteins are only Class I MHC proteins are found on the surface of found on the surface of ALL B lymphocytes, macrophages nucleated cells and other antigen presenting cells § ALL MHC proteins are imbedded in the cytoplasmic membrane of cells and project outward from the cell surface  Mechanism of Cytotoxicity by CTL (CD8+) § THEN , the processed antigens bind to Class I (Ag-MHC class I complex ) are transported to the cell surface § The phagocytes (macrophages) now move toward regional lymph nodes under the influence of certain chemical substances (chemotaxis) § In the regional lymph nodes the phagocytes present the antigen in association with MHC class I molecule to lymphocytes. § That is why phagocytes (macrophages) are called antigen presenting cells (APC)  Mechanism of Cytotoxicity by CTL (CD8+) § CTL interact SPECIFICALLY with the antigen - MHC class I complex through TCR (T Cell Receptor). § Each T cell has thousands of copies of the SAME TCR on its surface § The immune system can generate TCRs that will bind nearly every known peptide antigen § The TCR can only recognize and bind a peptide antigen if the antigen is bound first to MHC proteins Structure of the T-cell receptor (TCR) The V domains of the alpha chain and beta chain combine to form the peptide antigen-binding site. § The T cell receptor extends from the surface of a T cell § Cytoplasmic membrane of a T cell Class I MHC proteins and cytotoxic T cells (Tc) § Class I pathway is useful in destroying cells that have been infected by viruses or have been transformed by tumors 1. Protein antigens manufactured in the cell by viruses or tumors are degraded in the cytoplasm and transported to the endoplasmic reticulum 2. The processed antigens bind to Class I MHCs and are transported to the cell surface 3. Together this complex interacts with the TCR of a Tc cell, the binding of the complex with the TCR is strengthened buy a CD8 coreceptor Class I MHC proteins and cytotoxic T cells (Tc) § The cell-cell interaction between the infected cell and the Tc cell is mediated by the MHC class I - antigen complex and TCR § The Tc cell produces cytotoxic proteins perforins— produce holes or pores in the target cell and granzymes enter the virus infected cell causing apoptosis or programmed cell death § The cytotoxic proteins only affect those cells to which the Tc cell has specifically interacted  Mechanism of Cytotoxicity by CTL (CD8+) § The first contact of the CTL with the antigen is called primary immune response. This will take time to develop (usually several days) and associated with development of memory cells. § When the CTL come in contact with same antigen for second time , this is called secondary immune response. Usually faster than 1ry immune response and more stronger that leads to eradication of pathogen before symptoms appear. Different Types of Antigen Presenting Cells Antigen Presenting Cells Artificial Antigen Presenting Cells Bind to TCR § MHC I : Cytotoxic T cells (CD8). § MHC II: Helper T cells (CD4). (load by specific antigen or epitope) § Activate T cells effector function. (co-stimulatory molecules; CD80 or CD86) § Cytokines stimulation such as IL-2 to enhance T cells Stimulation. Interrelationship between innate and adaptive immunity Innate and Adaptive Immune Mechanism  Innate and Adaptive Immunity § They operate as a highly interactive and cooperative system, producing a mixed response more efficient than either branch could produce by itself. Major Properties of the Innate and Adaptive Immune System  The Key Points to.. Ø Identify the cells and organs of the immune system. Ø Recognize the central concepts of immunity. Ø Distinguish between innate and adaptive immunity. Ø Understand the importance of immunology investigations.  Lecture 2: Cells of The Immune System  Learning Objectives At the end of the lecture you will be capable to: 1. Define the structure and function of cells of the immune system. 2. Understand the link between the cells of the innate and adaptive immune system.  Cells of the Immune System § Hematopoiesis: The synthesis and growth of red and white blood cells is known as hematopoiesis. § All blood cells develop from a multipotent stem cell called hematopoietic stem cell (HSC) in the bone marrow, which can self-renew and differentiate into other cell types. self-renewing  Cells of the Immune System In the bone marrow, hematopoietic stem cells differentiates to either: a) Myeloid progenitor b) Lymphoid progenitor 1. Large cells of the bone marrow that 1. Any of the cells responsible for the serve as a precursor of mainly the self-renewing production of immunity mediated by granulocytes and erythrocytes of the cells or antibodies and including blood. lymphocytes, lymphoblasts 2. Give rise to erythrocytes, 2. Give rise to T lymphocytes, B neutrophiles, basophils, eosinophils, lymphocytes and natural killer cells. monocytes and platelets. 3. Related to the lymphatic system. 3. Related to bone marrow Myeloid and Lymphoid Progenitors  Myeloid progenitor § Produce myeloid cells commonly. § Myeloid cells consist of the following population: 1. Monocular phagocytes (Monocytes and Macrophages). 2. Granulocytes ( Neutrophils, eosinophils and basophils). 3. Mast cells. 4. Dendritic cells. 5. Erythrocytes. 6. Platelets.  Monocular phagocytes Monocytes: § They increase while circling in the blood and then relocate to tissues. § They named based on tissue in which they are located: Location Name Gut Intestinal macrophages Lung Alveolar macrophages Connective tissue Histiocytes Liver Kupffer cells Monocytes Macrophages Kidney Mesangial cells Brain Microglial cells Ø Blood Ø Tissues Bone Osteoclasts Ø 5-10 times larger Ø Smaller Ø More phagocytic activity  Monocytes Differentiation § Many changes occur during the differentiation of monocytes into macrophages: § The cell multiplies by 5 to 10 times. § The number and complexity of intracellular organelles increase. § The number and complexity of intracellular organelles increase. § Increased production of hydrolytic enzymes § Secretion of numerous soluble factors § Enhanced phagocytic capacity and antigen presentation  Phagocytosis § Cells that can detect, ingest, and destroy microbes and foreign bodies. Phagocytosis stages Macrophage engulfing  Macrophage engulfing.. Tumour cells Bacteria Macrophage Activation Plasticity  Granulocytes § Granulocytes are myeloid cells, which three cells populations: Neutrophils, eosinophils and basophils. § They found circulating through blood as well as migrating to inflammatory tissues. § All granulocytes are called polymorphonuclear leukocytes (PMN). However, this term is mainly used for Neutrophils because of their multilobed nucleolus.  Neutrophils Vs. Eosinophils Vs. Basophils. Neutrophils Eosinophils Basophils Nucleus Multi-blood nucleus Two-blood nucleus A beam-shaped nucleus Phagocytic Highly Phagocytic Phagocytic Non-phagocytic Role Antimicrobial agent Anti-parasitic agent Allergic reaction Activated 1. Engulf bacteria found in the 1. Trigger inflammatory response in 1. Promotion of allergic function extracellular matrix through allergic disorder responses and augmentation phagocytosis 2. Killing antibody-coated parasites of anti-parasitic immunity. 2. Contains heparin, which prevent quick blood clotting Abundance Account for 40-75% of white Account for 1-6% of WBC Account for 0.5-1% of WBC blood cells (WBC) Lifespan 5-90 hours 8-12 hours 60-70 hours Secretion Neutrophil extracellular traps Cytokines like TNF alpha and Leukotrienes and some (NETs) interleukins, growth factors like TGF interleukins beta  Mast Cells § Mast cells are long-lived tissue resident cells. § They have two types: connective tissue-type mast cells and mucosal Mast cells. § They can be found in connective tissue, skin and mucosal epithelial tissues. § Kay player in many inflammatory response during parasitic infection and allergic reactions. § Activated function: they produce granule containing histamine and other active substance during inflammatory and allergic reactions.  Dendritic Cells (DCs) § A special type of immune cells that boost immune responses by showing antigens on its surface to other cells of the immune system. § They occur inside tissues. § They can be found in connective tissue, skin and mucosal epithelial tissues. DCs have 4 types: 1) Plasmacytoid DCs: a key player in innate immune response against viral infection. 2) Conventional DCs: They process and present antigens to T cells by the secretion of cytokines like IL-2. 3) Migratory DCs: They found in lymphoid organs like the liver, gut, and skin. These cells are called migratory DCs as these cells transfer from tissue to lymphoid organs. 4) Monocyte-DCs: Dendritic cells derived from monocytes form a new subset of dendritic cells during inflammation. § DCs play an important role in bridging innate and adaptive immune responses. § Activate upon inflammatory signals, they express an antigen presentation-specific molecule and become antigen presenting cells. Antigen Processing and presentation § MHC molecules present peptide fragments of protein antigens to T cells Comparison of the endogenous and exogenous pathway of Ag processing Antigen Presenting Cells (APC) § APC includes: § Dendritic cells, Macrophages and B lymphocytes. § Capture and transport antigens to the peripheral lymphoid tissues § Process antigens § Present the peptides derived from these antigens to T lymphocytes § They are rich in class II MHC molecules  Strategies Of Antigen Presentation 1. MHC Class II pathway: Ø Protein antigen taken from extracellular environment. Ø Proteins are degraded by lysosomal proteases. The resulting peptides are presented to CD4+ cells with MHC class II molecules. 2. MHC Class I pathway: Ø Cytosolic proteins e.g. intracellular microbes. Ø Proteins are degraded by a structure called proteosome. The resulting peptides are presented to CD8+ cells with MHC class I molecules.  Structure of MHC molecules § Composed of 4 Ig superfamily domains § MHC class I has an a- chain with 3 domains non- covalently associated with b2- microglobulin § MHC class II have an a and a b chain § a-helices and b-pleated sheet form the sides and floor of the peptide binding groove  The endogenous and exogenous pathways of antigen presentation Endogenous Pathway Exogenous Pathway § Processes cellular proteins § Processes extracellular proteins Found in all cells (target cells). § Found in “professional antigen- § Antigenic peptides are displayed on presenting cells” MHC class I § Antigenic peptides displayed on MHC § Results in CD8 T cell activation and class II target cell killing § Results in CD4 T cell activation and cytokine release Antigen Presentation Targeting Strategies Antigen presentation and induction of immune response § Antigen is taken up by antigen-presenting cells (DCs), in the presence of immunostimulatory molecules, resulting in DC maturation. ü This maturation process involves processing of antigen to display peptide epitopes on MHC class molecules alongside co-stimulatory molecules to T cells. ü Subtypes of T cells that recognize the peptide- epitope then mediate an antigen-specific cellular or humoral immune response. DCs Antigen presentation  Lymphoid Cells § Lymphocytes circle always in the blood and lymph and are able of transferring into the tissue spaces and lymphoid organs. § They can detect antigen via their antigen-specific receptor. § They can be detected by surface proteins (CD) recognized by monoclonal antibodies (mAb). § They account for 20-40% of total WBC.  Lymphoid Cells § They includes the following populations: a) T lymphocytes (T cells): mediators of cell-mediated immunity. b) B lymphocytes (B cells): Mediators of humoral immunity. c) Natural Killer cells (NK cells): cells of innate immunity.  B Lymphocytes § B cells are important antigen-presenting cells that originate in bone marrow. § They can detect bacterial and viruses antigens. § They counted for about 20-30 % of the circulating lymphocytes. § Provide humoral immune response § B cells have a membrane-bound antibody (Ab) that acts B-lymphocyte receptors involved in pathogens uptake. B lymphocytes displayed a wide number of receptors capable to recognize and engulf pathogens; they include as an antigen receptor. intra-and extracellular innate receptors like TLRs, Dec-1, complement receptors, and the adaptive BCR receptor.  B cells activation § Plasma cells: When a naive B cell is exposed to an antigen, it differentiates into plasma cells, which are effector cells. § Memory B cells: 1. They produce antibodies that are comparable to those produced by naive B cells, but are of a different isotype. 2. They have the capability of transforming into plasma cells. 3. They have a faster and larger amplitude response to the antigen after the second encounter. 4. They outlast naive B cells in terms of lifespan.  T Lymphocytes § T cells are lymphocytes that are generated in the bone marrow. They mature in the thymus gland. § They are divided into three types: : T helper, T cytotoxic, and T regulatory. § Antigens presented by antigen-presenting cells are recognized by helper T cells, which then activate B cells to generate antigens. By causing apoptosis, cytotoxic T cells kill infected cells. § Cell-mediated immunity is a type of adaptive immunity in which antigen-specific T lymphocytes play a role.  T cell-mediated immunity § T cells have a distinct antigen-binding molecule known as the T-cell receptor (TCR). § TCR only identifies antigens that are attached to a cell- membrane protein known as the Major Histocompatibility Complex (MHC) T Cells Differentiation  T Cells Differentiation T helper cells Cytotoxic T cells T regulatory cells ü TH cells develop into effector ü Tc cells develop into effector Cytotoxic ü Treg cells are distinguished by the and memory cells. T lymphocytes (CTL) and memory cells. presence of CD4 and CD25 ü Effector TH cells allow B cells, ü Kill (KILL) cells that show antigen on molecules on their membranes. TC , macrophages, and other MHC-I molecules, such as virus- ü They suppress immunological immune cells to be activated. infected cells, tumor cells, and foreign responses, acting as negative transplant cells. immune regulators. ü Treg cell members may be progenitors of memory cells.  B lymphocyte T lymphocyte arise from Bone marrow Mature in Bone marrow Thymus Bone marrow lymphocytes Name Thymus derived lymphocytes % of total blood lymphocytes 10 – 15 % Majority Stem cell → lymphoid progenitor → immature T cell → Stem cell → lymphoid progenitor → pre B leave bone marrow to thymus gland → maturaPon & cell → immature B cell → mature/naïve B selecPon → mature/naïve T cells Steps in maturation cell → leave bone marrow to meet T helper (CD4) anPgen in the 2nd lymphoid organs T cytotoxic (CD8) → leave thymus to meet anPgen in the 2nd lymphoid organs 1. CD19&CD21 1) CD 3 phenotypic markers 2. Fc receptor 2) CD 4 or CD 8 3. class II MHC molecule 3) T cell receptor (TCR) Function Antibody production (humoral immunity) Cell mediated immunity Protein only Protein , polysaccharide, lipid, nucleic acid Antigen recognized - CD4 cell recognize → peptide + MHC II molecule and small chemicals (free & soluble) - CD8 cell recognize → peptide + MHC I molecule  B lymphocyte T lymphocyte B cell receptor (BCR): membrane Immunoglobulin (Ig M TCR: 2 types α/β TCR & γ/δ TCR Antigen recognition & Ig D) α/β TCR: common type → 2 poly peptide chain α & β receptor TCR complex: B cell proliferation → differentiation into → memory cell - Ag presented on MHC, bind with variable domain of α Stimulation by Ag & plasma cell which produce antibodies to eliminate Ag & β of TCR - CD3 & zeta protein (signal transduction) → activate T cell 2 polypeptide chains → Ig α & β transmit signal inside B TCR & CD3 & zeta protein Signalling molecules cell → B cell proliferation & differentiation into plasma cell 1) T helper (CD4) → produce cytokines which help other cells e 2) Th1 help B cell to produce antibodies naive B cell 3) Th2 help macrophage to destroy ingested microbes Types plasma cell 4) T cytotoxic (CD8) memory cell Also called cytolytic as lyse virus infected cell & kill tumour cells & graft rejection T regulatory (Treg) 1) Suppress the immune response Natural Killer Cells Cytotoxic lymphocytes composing 5% to 20% of peripheral blood mononuclear cells (PBMCs) in humans NK cells have a receptor (CD16) that binds to a specific area of the antibody molecule. Recognize changes in infected cells and tumor Antibodies can bind to this receptor and drive NK cell activity, resulting in antibody-dependent cell-mediated toxicity (ADCC) Cytotoxic mediators as granzymes and perforin Pro-inflammatory cytokines as IFN-γ Activation of other innate and adaptive immune cells Developmental pathways of various hematopoietic cells from pluripotential bone marrow stem cells.  The Key Points to.. 1. Define the structure and function of cells of the immune system. 2. Understand the link between the cells of the innate and adaptive immune system.  Lecture 3: Immune cells Development and Selection  Learning Objectives At the end of the lecture you will be capable to: 1. Define the structure and function of lymphoid organs, including primary and secondary. 2. Recognize the synergistic interaction between innate and adaptive immune cells  Lymphoid Tissues and Organ § Immune organs can be classified functionally into two main groups: 1. Primary lymphoid organs: Ø Place of maturation of lymphocytes Lymphatic system Ø Interstitial fluid is returned to circulatory 2. Secondary lymphoid organs: system by lymphatic vessels Ø Mature lymphocytes interact with Ø Antigen is carried by lymph to lymph nodes antigen  Lymphocyte Development § B cells and T cells originate in the bone marrow stage § B cells develop in the bone marrow; T cells develop in the thymus § The antigen specificity of an individual B or T cell is determined at an early stage  Lymphocytes Selection § Up to 1012 different antigen receptors are made during B and T cell development § Immature B and T cells with useless antigen receptors die § B and T cells with self-reactive antigen receptors die § Mature lymphocytes respond to foreign antigens  T Cell Antigen Receptors The T cell receptor § Found on the surface of T cells § Recognises peptide fragments of intracellular antigens complexed with MHC molecules § Consist of 2 polypeptide chains – ⍺/β or 𝛾/ẟ T Cell Development  T Cell Develop in The Thymus § They originate in the bone marrow as stem cells § They pass through the thymus as thymocytes and interact with thymic stromal cells § About 98% die, 2% go to the circulation Thymocytes surrounded by a network of thymic stromal cells  TCR Production § TCR is produced by gene rearrangement. § This is a random process that produces receptors of various specificity and reactivity § Learn that TCRs must have two properties: 1. Recognizes self MHC-I and MHC-II 2. DO NOT respond to self antigens At this point, thymocytes express both CD4 and CD8 molecules i.e. called double-positive  T Cell Maturation § Educate T cell how to differentiate between self Antigen (MHC peptide) & non self Antigen T cell selection: 1. Positive selection: § Small portion of TCR react with combination of self- antigen/MHC complexes § The thymus induces death of T cells that cannot recognize self-antigen/MHC complexes § Only T cell which can bind with MHC is allowed to grow  T Cell Maturation § Educate T cell how to differentiate between self Antigen (MHC peptide) & non self Antigen T cell selection: 2. Negative selection: § only T cell which bind efficiently with MHC (auto- reactive T cell) is eliminated by apoptosis as it is a dangerous cell § The thymus induces death of T cells that react with self- antigen/MHC complexes strongly enough to cause autoimmune disease T Cell Development  B Cell Development § The bone marrow generate and select a repertoire of B cells the will protect the body from infections and do not be harmful to body tissues B cells selection: § B cells also undergo negative and positive selection processes on the basis of their reactivity with self and foreign antigens § Bone Marrow Stromal Cells are essential for B cell maturation by: 1. Direct interacts 2. Secretion of cytokines mainly IL-7  B Cell Antigen Receptors Immunoglobulins (Antibodies) “Ig” § Glycoprotein produce by plasma cell’s in response to antigens; foreign microbial / non microbial substances § Found on the surface of B cells and as released antibody § Interacts directly with antigen § Consist of 4 polypeptide chains - 2 heavy and 2 light § 4 Isotype: IgG / IgA / IgM / IgE / IgD  Stages of B Cell Development § Developing B cells receive signals from bone marrow stromal cells § Allelic exclusion ensures that only 1 heavy and 1 light chain are made  Ig-Gene Rearrangement Pro-B Cell Pre-B cell Immature B cell § Heavy chain § Light chain rearrangement rearrangement § Committed to antigenic specificity and produces IgM (functional B cell must express both IgM AND IgD on membrane) B Cell Maturation Antigen-Independent Phase 2. Negative selection: 1. Positive selection: § Secondary lymphoid organ § Bone Marrow  B cells Development Interactions of IgM of immature B cells with self-antigens  Secondary Lymphoid Organs § Situated along the vessels of the lymphatic system § Sites where immune responses are mounted to antigens § Involves lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT) § Sites for contact between lymphocyte & Antigen to initiate immune response § Primary follicle Ø Not activated lymphoid follicle § Secondary follicle Ø Follicle that is activated by antigen Ø Ring of B cells that surround § germinal center Ø Proliferating B cells and T helper cells  Secondary Lymphoid Organs Lymph Nodes Spleen § Large encapsulate ovoid structure located high in the left § Encapsulated bean-shaped structures abdominal cavity packed with lymphocytes, macrophages, § Major role in mounting immune response to antigens in the and dendritic cells blood § Traps any particulate antigen that is brought § The spleen specializes in filtering blood and trapping blood- in with the lymph borne antigens 1. Red Pulp Ø Macrophages, RBCs, and few lymphocytes 2. White Pulp 1. Cortex Surrounds branches of splenic artery Ø B cells, macrophages, dendritic Ø Forms periarteriolar lymphoid sheath cells (PALS) Ø Primary and secobdary follicles Populated by T lymphocytes 2. Paracortex Ø Primary lymphoid follicles Ø Mostly T cells, dendritic cells Rich in B cells and contain germinal center 3. Medulla Ø Marginal zone Ø Macrophages Plasma cells Lymphocytes and macrophages  Splenic Lymphocyte Activation § Initial activation of B and T cells in PALS where DC capture antigens and present them on MHC-II to TH cells. Those TH cells then activate B cells, which move to primary follicles in the marginal zone. § Then the primary follicles develop into secondary follicles with germinal center  Secondary Lymphoid Organs Mucosa-Associated Lymphoid Tissue Peyer’s Patch § Organized areas along digestive (GALT), § Large encapsulate ovoid structure located high in the left respiratory (BALT), and urogenital tracts abdominal cavity § Major role in mounting immune response to antigens in the § Very well organized areas in intestine are blood referred to as Peyer’s patches § The spleen specializes in filtering blood and trapping blood- borne antigens § Includes tonsils and appendix  Primary vs. Secondary Lymphoid Organs Primary Lymphoid Organs Secondary Lymphoid Organs Organs of immune system where Organs of immune system which maintain lymphocytes are formed and mature mature naïve lymphocytes and initiate an adaptive immune response Allow lymphoid stem cells to proliferate, differentiate and mature allow lymphoid cells to become functional Contain either T cells or B cells Contain both T cells and B cells Have no contact with antigens Have contact with antigens Undergo atrophy with age Increase size with age Case Study?  Case Study? T Cells Negative selection  The Key Points to.. 1. Define the structure and function of lymphoid organs, including primary and secondary. 2. Recognize the synergistic interaction between innate and adaptive immune cells