Lymphocytes & Immunity PDF

LYMPHOCYT ES & IMMUNITY Dr. Nnamdi Lymphocytes & Immunity 02/06/2025 1 OUTLINE  Learning objectives  Introduction  The Bone Marrow; the origin of blood cells: RBC, WBC, Platelet  Effector cells  Neutrophil  Eosinoph...

LYMPHOCYT ES & IMMUNITY Dr. Nnamdi Lymphocytes & Immunity 02/06/2025 1 OUTLINE  Learning objectives  Introduction  The Bone Marrow; the origin of blood cells: RBC, WBC, Platelet  Effector cells  Neutrophil  Eosinophil  Basophil  Monocyte  Lymphocytes  Immune system; Innate and Acquired(Adaptive)  Compliment system  Wound healing Lymphocytes & Immunity 02/06/2025 2  To understand the importance of immunity and how it defend the body against infectious agents and foreign bodies Know the circulating and tissues cells that contribute to immunity and inflammatory response LEARNING To be able to describe how phagocytes kill bacteria OBJECTIVES Understand the functions of Hematopoietic growth factors, Cytokines and Chemokines To understand the role and mechanism of innate, acquired, humoral and cellular immunity. To understand the basis of inflammatory response and wound healing 02/06/2025 Lymphocytes & Immunity 3  INTRODUCTION  Throughout life, the human body is constantly under invasion by invaders  The invader includes:  Infectious agents; Viruses, Bacteria, Fungi, Parasites, Prions  Foreign bodies: Any object or antigen that does not belong to an individual  The body’s own cells that have become senescent or abnormal like cancer cell  Normal host tissue may be attacked inappropriately by the immune system in autoimmune diseases  Normal host cell may be harmed during inflammatory response by the immune system Lymphocytes & Immunity 02/06/2025 4 INTRODUCTION………… THE BONE MARROW WHERE DO THE BLOOD CELLS COME FROM?  The bone marrow is the ‘factory’ where all blood cells are ‘manufactured’ in the Bone marrow human body; RBC or Erythrocytes, WBCs or Leukocytes and Platelet or The bone marrow is the soft Thrombocytes are produced in the bone marrow tissue  It is the soft sponge tissue found in the centre of most bones that occupies the cavity of long Bones and the small spaces in  There are two types of bone marrow:(1) Red bone marrow found in the pelvis, spine, spongy bone. ribs and skull. It’s responsible for producing blood cells (2)Yellow bone marrow There are two types of found in the bones of arms and legs and contain mainly fats. Bone marrow: red and yellow. Red bone marrow fills the  RBCs carry O2 & Nutrients to the tissues, WBC fight infections, Platelet help blood cavity of clot. Nearly every bone in children. Hemopoietic tissue makes  Common diseases of the bone marrow are: Leukemia, Aplastic Anaemia and blood cells. Myelodysplastic syndrome Red bone marrow is found in the  Bone marrow transplant: healthy bone marrow is harvested and transplanted to a Skull, vertebrae, ribs, sternum patient with bone marrow disorder Proximal head of the humerus and femur. Lymphocytes & Immunity 02/06/2025 5 Yellow marrow no longer produces Blood cells Lymphocytes & Immunity 02/06/2025 6 INTRODUCTION…….  The body is constantly being called upon to defend itself against these invaders which is accomplished by the immune system.  The immune system is divided into two: 1. Innate immune system 2. Adaptive(Acquired) immune system  The immune system is compost of effectors cells that senses and respond to these invaders Lymphocytes & Immunity 02/06/2025 7  EFFECTOR CELLS Many immune effector cells circulate in the blood as WBCs also called leukocytes The immune effector cells in the tissues are also from circulating WBC Effector cell in the Effector cell in the blood tissues 1) Neutrophil( 1) Tissues Macrophages(Derived bacteria) NB: granulocytes from Monocytes) or Polymorphonucle 2) Eosinophil ar Leukocytes 2) Mast cells (Derived from Basophil) (PMNs) Extravascular migration 3) Basophil of PMNs, Tissue 4) Lymphocyte Macrophages and Mast s cell, acting together provide powerful 5) Monocytes Defense against viral, bacterial, fungal & parasitic infections as well as tumors or Lymphocytes & Immunity 02/06/2025 8 cancers) All granulocytes have cytoplasmic granules that contain biologically active Agranulocytes have no Substances involved in Granules in their cytoplasm inflammatory and allergic reactions Lymphocytes & Immunity 02/06/2025 9 NEUTROPHIL  The average half life of neutrophil in circulation is 6 hrs, therefore about 100 Billion neutrophil is produced per day.  Many neutrophils enter the tissue when triggered by bacteria or inflammatory cytockines  SELECTIN, a cell adhesion molecule attract them to endothelial surfaces and they then roll along it  They then bind firmly to Neutrophil adhesion molecule of the INTEGRIN FAMILY  Subsequently, they insinuate themselves through the wall of the capillaries between the endothelial cells by a process called DIAPEDESIS  Many neutrophil that leave the circulation end up in the GIT and are eventually lost from the body. Lymphocytes & Immunity 02/06/2025 10 Neutrophil & The Inflammatory Response  The trigger for inflammatory response is the invasion of the body by bacteria, other microorganisms or foreign bodies.  The bone marrow is usually stimulated to produce and release large amount of neutrophil during bacteria invasion. {FBC-Leukocytosis and relative Neutrophilia(>75% of Total WBC)}  Bacteria products interact with plasma factors and cells to produce chemotactic agents (Which is part of a family of agents called CHEMOKINES) that attract neutrophils to the affected area(This is called CHEMOTAXIS)  The chemotactic agents include: components of the complement system (C5a); Luekotriens, and polypeptides from lymphocytes, mast cells and basophils.  Other plasma factors make the bacteria ‘TASTY’ to the phagocytes; this is called OPSONIZATION.  The principal opsonins that coat bacteria are Immunoglobulin G(IgG) and complement proteins Lymphocytes & Immunity 02/06/2025 11 Neutrophil &The Inflammatory Response  The coated bacteria bind to G-protein coupled receptor on the neutrophil cell membrane which triggers it’s increase motor activity, EXOCYTOSIS and the so called RESPIRATORY BURST.  The increased motor activity lead to prompt ingestion of the bacteria by ENDOCYTOSIS( Also called PHAGOCYTOSIS)  By EXOCYTOSIS, neutrophil granules discharge their content into the PHAGOCYTIC VACOULES containing the bacteria and also into the interstitial space( Which is called DEGRANULATION)  The granules contain various proteases and antibacterial proteins called DEFENSINS.  In addition, the cell membrane-bound enzyme; Nicotinamide Adenine Dinucleotide Phosphate(NADPH) Oxidase is activated leading to the production of toxic oxygen metabolites.  The combination of this toxic oxygen metabolites and the proteolytic enzymes from the granules, make neutrophil a very effective killing machine Lymphocytes & Immunity 02/06/2025 12 The activation of NADPH oxidase is associated with sharp ncrease in O2 up-take and metabolism in neutrophils (Respiratory burst) and the generation of O2- by the reaction The O2- is a FREE RADICAL formed by the additional of one Electron to O2 2O2- react with 2H+ to produce H2O2 and O2 in a reaction catalyzed by the cytoplasmic form of Super Oxide Dismutase (SOD-1). Both O2- and H2O2 are oxidant that are effective Bactericidal agents The H2O2 is converted to H2O and O2 by the enzyme catalase The cytoplasmic form of SOD contain both Zinc(Zn) and Copper(Cu) and are found in many parts of the body. It is defective due to genetic mutation in a familial form of Amyotrophic Lateral Sclerosis(ALS) which is a progressive, fatal disease. It may appear that oxygen free radical (O2-) accumulate in motor neurons and kill them. Antioxidants such as Vitamin C, Vitamin E, Selenium, Zn, Glutathione and Beta-carotene etc help to neutralize harmful molecules like Free Radical (O2-) to maintain health Lymphocytes & Immunity 02/06/2025 13 Neutrophil & The Inflammatory Response  MYELOPEROXIDASE another enzyme discharged by neutrophil catalyzes the conversion of Cl-, Br-, I- & Thiocyanate(SCN-) to their corresponding acid; HOCl, HOBr, HOI, HOSCN; all of which a potent oxidants. However, Cl- is the most abundant in body fluid, hence Hypochlorus acid (HOCl) account for the principal product.  A part from Myeloperoxidases and Defensins, neutrophil granules also contain ELASTASES, METALLOPROTEINASES that attack collagen and a variety of other proteases that help destroy invading organisms.  These enzymes act in co-operative fashion with O2-, H2O2 & HOCl to produce a killing zone around activated neutrophil.  This killing zone is effective in killing invading organisms, however, in certain disease conditions such as RHEUMATOID ARTHRITIS, neutrophil may also cause local destruction of host tissues. Lymphocytes & Immunity 02/06/2025 14  EOSINOPHIL  Like Neutrophils, Eosinophils have short half life in circulation, attracted to endothelial cell surfaces by selectin, bind to integrin that attach them to the vessel wall, enter the tissue via diapedesis, release proteins, cytokines and chemokines that produce inflammation capable of killing invading organisms  However, they are selective in the way they respond and the killing molecules the secret.  Their maturation and activation in tissue is usually stimulated by IL-3, IL-5 and GM- CSF.  Eosinophil are abundant in the mucosa of the GIT where the defend against parasitic infections and in the mucosa of urinary tract and respiratory tract.  Circulating eosinophil are increased in ALLERGIC diseases such as ASTHMA and in various GM-CSF-Granulocyte-Macrophage IL-Interleukin, other infections of the Colony GIT and RTI Factor, GIT-Gastro-intestinal Tract, RTI-Respiratory Tract Stimulating Infection Lymphocytes & Immunity 02/06/2025 15 BASOPHILS  Basophil also enter tissue and release protein and cytokines  They resemble, but are not identical to Mast cell  But, like Mast cells, they contain HISTAMINE  They release histamine and other inflammatory mediators when activated by the binding of specific antigen to cell-fixed IgE molecules, and participate in immediate-type hypersensitivity (ALLERGIC) reactions.  These allergic reactions ranges from mild urticaria and rhinitis to severe anaphylactic shock.  ALLERGENS are the antigens that trigger IgE formation, Basophil and Mast cell activation and they are usually innocuous to most individuals Lymphocytes & Immunity 02/06/2025 16  MAST CELL  Mast cells are heavily granulated cell of the connective tissue that are abundant in tissue that come into contact with the external environment such beneath the endothelial surfaces.  Their granules contains PROTEOGLYCANS, HISTAMINE and many other proteases.  They degranulate when allergens bind to cell-bound IgE molecules directed against them just like Basophil.  The are involved in inflammatory response initiated by IgE and IgG that combat invading parasites.  In addition to their involvement in this acquired immunity, they release TNF-α in response to bacterial product by an antibody-independent mechanism, thus participating in the non- specific INNATE IMMUNITY that combat infections prior to the development of ADAPTIVE IMMUNE response.  Marked Mast cell degranulation produces clinical manifestation of allergy up to anaphylaxis shock *TNF-Tumor Necrotic Factor Lymphocytes & Immunity 02/06/2025 17  Macrophages contacting Bacteria in preparation To engulf them MONOCYTE  Monocytes enter the blood from the bone marrow and circulate for 72 hours and then enter the tissue to become TISSUE MACROPHAGES. They persist for up to 3 months.  Some may end up as multinucleated giant cell seen in chronic inflammatory disease like Tuberculosis  Tissue macrophages include Kupffer cells of the liver, Pulmonary Alveolar macrophages of the lungs and Microglia in the brain. They are called TISSUE MACROPHAGE SYSTEM but formerly called Reticulo-endothelial system.  Macrophages are activated by cytokines released from T-lymphocytes, among others.  Activated macrophages migrate in response to chemotactic stimuli, engulf and kill bacteria by processes similar to that of neutrophil  The play key role in innate immunity  They secret up to 100 different substances including factors that affect lymphocytes and other cells, PROSTAGLADINS of the E-series and CLOT- PROMOTING factors Lymphocytes & Immunity 02/06/2025 18 LYMPHOCYTE  Lymphocytes plays key role in ACQUIRED IMMUNTY  After birth some lymphocytes are formed in the bone marrow, but most are formed in LYMPH NODE, THYMUS and SPLEEN from precursor cell that originate from the bone marrow but processed in the THYMUS (T-Lymphocytes) and BONE MARROW (B-Lymphocytes)  Lymphocytes enter the bloodstream in most part through the lymphatic channels  At any given time, only about 2% of lymphocytes are in the peripheral blood, the rest are in the LYMPHOID ORGANS(Lymph nodes, Thymus, Spleen, Bone Marrow & *MALT).  In humans, it has been estimated that about 3.5 x 1010 lymphocytes per day enter the circulation through the THORACIC DUCT alone. But, this count include lymphocytes that re-enter the lymphatics and traverse the thoracic duct more than once.  ADRENOCORTICAL HORMONE has some effects on lymphoid organs, circulating lymphocytes and granulocytes. Lymphocytes & Immunity 02/06/2025 19 *MALT-Mucosa Associated Lymphoid Tissue LYMPHOCYTES……  During fetal development, and to a lesser extent during adult life, lymphocytes precursor comes from the bone marrow.  Those that populate the THYMUS become transformed by the environment in this organ to T-LYMPHOCYTE. NKT cells which shares features of both T-lymphocytes and Natural Killer cells(NK cell), are also formed in the thymus.  The transformation to B-LYMPHOCYTES occurs in the fetal liver during development and bone marrow, after birth. NK cells also form in these sites  After residing in the Thymus, Liver and Bone Marrow, many of the T and B lymphocytes migrate to the lymph nodes.  Morphologically, T and B lymphocytes are difficult to differentiate, however, there are markers on their cell membrane that can be used to identify them. Lymphocytes & Immunity 02/06/2025 20  LYMPHOCYTES…………  B-cell differentiate into cells capable of producing Various classes of IMMUNOGLOBULINS(Ig), and then to PLASMA CELLS.  There are two major types of T-cells: 1. HELPER/EFFECTOR T-CELLS 2. CYTOTOXIC here are at least 4 T-CELLS sub-types of helper T-cells. T-helper 1 cells(TH1): which secret IL-2 and γ-Interferon oncerned mainly with the stimulation of cellular immunity. T-helper 2 cells (TH2): Secret IL-4 and IL-5 which interact With B-cells to produce HUMORAL IMMUNITY.. T-helper 17 cells (TH17): They are induced in response o bacterial infections and produce IL-6 & IL-17 and help to ecruit neutrophils. They are also implicated in the eneration of harmful inflammatory responses that occurs autoimmune diseases.. Treg cells: which produces IL-10 to dampen T cell-driven esponses. Development of the system Mediating acquired immunity OTOXIC T CELLS destroy transplanted cells and cells expressing foreign antigen such as virally infected cells. r development is aided and directed by HELPER T CELLS. Lymphocytes & Immunity 02/06/2025 21 LYMPHOCYTES……………  The markers on the surfaces of lymphocytes are assigned CD(Clusters of Differentiation) numbers based on their reaction to a panels of monoclonal antibodies.  CD8: most cytotoxic T cells display the glycoprotein CD8  CD4: Helper T-cell display the glycoprotein CD4. *CD4 count is usually measured in HIV patients to assess their immunological status.  There are 4 main types of cytotoxic T-lymphocytes in the body: αβ T cells, γδ T cells, NK cells and NKT cells. Lymphocytes & Immunity 02/06/2025 22 LYMPHOCYTES………. MEMORY B CELL & T CELLS  After exposure to a given antigen, a small number of B and T cells persist as memory B and T cells.  And they are readily converted to effector cells by a later encounter with the same antigen.  The accelerated response to a second exposure to an antigen is a key characteristic of acquired immunity  This ability persist for a long period of time and sometimes for life(e.g immunity against measles)  After activation in lymph nodes, lymphocytes disperse widely throughout the body and are usually abundant in areas where invading organisms enter the body such as the mucosa of GIT, RT  This put memoryThis cell closethetoconcept sites of reinfections explain behind vaccinationand may account for the rapidity and and immunization strength of their against Lymphocytes & Immunity response. 02/06/2025 Polio, Measles, Tetanus, Pertussis, HBV, COVID-19 23 HPV, Rota virus, HAV, Typhoid, Malaria vaccine candidates etc  Chemokines guide activated lymphocytes to these locations. IMMUNITY  There are two types of immunity; INNATE and ADAPTIVE/ACQUIRED immunity. Invertebrates have only INNATE IMMUNITY while vertebrates have both.  Adaptive immunity is a system where B and T lymphocytes are activated by specific antigens and it complements the innate immunity.  T cell bear receptors related to antibody molecules, but remain cell-bound  When this receptor encounter there cognate antigens, the T cell is stimulated to produce cytokines that orchestrate the immune response including that of B cells  Activated B-lymphocytes form clones that produce secreted antibodies which attack foreign proteins.  After the invasion is repelled, small number of lymphocytes persist as memory cells so that a second exposure to the same antigen provokes prompt and magnified immunological attack. Lymphocytes & Immunity 02/06/2025 24  IMMUNITY………..  In vertebrate, including humans, innate immunity provide the first line of defense against infections, but it also triggers the slower but more specific acquired immune response.  Furthermore, natural and acquired immune mechanisms also attack tumors and tissue transplants from other animals.  Once activated, immune cells communicate by means of cytokine and chemokines  They kill viruses, bacteria and other foreign cells by secreting other cytokines and activating the complement system. How viruses, bacteria and Lymphocytes & Immunity 02/06/2025 25 tumor triggers Innate immunity and initiate the acquired Immune INNATE IMMUNITY  The cell that mediate innate immunity include neutrophil, macrophages and NK cells  All these cells respond to molecular pattern produced by bacteria an to other substances characteristics of viruses, tumors and transplant cells.  Other cells, like the epithelium, endothelium that are not professional iimmunocytes also contribute to the innate immune response.  Activated cell produce their effect via the release of cytokines, complement and other systems Lymphocytes & Immunity 02/06/2025 26  THE COMPLEMENT SYSTEM  The cell-killing effects of innate and acquired immunity are mediated in parts by a system of more than 30 plasma proteins named the complement system because they ‘complemented’ the effects of antibodies.  Three different pathways or enzyme cascade activate the system: 1. The Classic Pathway, triggered by the immune complex 2. The Mannose-Binding Lectin Pathway, triggered when this lectin binds mannose groups in bacteria. 3. The Alternative or Properdin Pathway, triggered by contact with various viruses, bacteria, fungi and tumor cells  The proteins that are produce have three functions: I. They help kill invading organisms by opsonization, chemotaxis and lysis of the cell II. They serve as a bridge from innate to acquired immunity by activating B cells and aiding immune memory III. They help dispose of waste product after apoptosis. CELL LYSIS, one of the ways that complement system kill cells, is brought about by inserting proteins called perforins into their cell membranes, creating holes which permit the free flow of ions causing disruption of membrane polarity. Lymphocytes & Immunity 02/06/2025 27 Cascade of reactions during activation of the Classic pathway of complement  “Complement” is a collective term that describes a system of about 20 proteins, many of which are enzyme precursors.  The principal actors in this system are 11 proteins designated C1 through C9, B, and D.  All these are present normally among the plasma proteins in the blood, as well as among the proteins that leak out of the capillaries into the tissue spaces.  The enzyme precursors are normally inactive, but they can be activated by the so-called classical pathway. IMPORTANT PRODUCT OF COMPLEMENT CASCADE & EFFECTS I. C3b- is an opsonin for opsonization of bacteria II. C5b6789 is a lytic complex that lysis invading bacteria cell III. C5a is a chemotactic agent for neutrophil and macrophages IV. C3a,C4a,C5a activate basophil and mast cell to release histamine and heparin to increase local blood flow V. Agglutination; some complement product promote agglutination of invading organism VI. Neutralization of viruses; Some complement Lymphocytes & Immunity 02/06/2025 28 product can attack structures in viruses and render them non-virulent. VII. Inflammatory effect; several complement product  *HUMORAL IMMUNITY is mediated by circulating immunoglobulins(Ig) antibodies ACQUIRED IMMUNITY in the γ-globulin fraction of the plasma proteins. Ig are produced by differentiated forms of B lymphocytes known as plasma cells, and they  The key to acquired immunity is the ability of lymphocytes to produce activate the complement antibodies(B-cell) or cell surface receptors(T cell) that are specific to one system and attack and of the many millions of foreign agents(Antigens) that may invade the neutralize antigens. Humoral body. immunity is a major defense against bacterial infections  The antigen stimulating the production of T cell receptors or antibodies **Cellular immunity is are usually proteins or polypeptides. But, antibodies can also be formed mediated by T lymphocytes. against nucleic acids and lipid if they are presented as nucleoproteins or It is responsible for delayed lipoproteins. This information is vital in vaccine production. allergic reactions and rejection  of transplants of foreign tissue. Antibodies to small molecules can also be produced experimentally if the Cytotoxic T cells attack and molecules are bound to proteins. destroy cells bearing the  Acquired immunity has two component antigen that activated them. They kill by inserting perforins 1. *Humoral immunity and by initiating apoptosis. Cellular immunity 2. **Cellular immunity constitutes a major defense against infections due to viruses, fungi, and a few bacteria such as the tubercle Lymphocytes & Immunity 02/06/2025 29 bacillus. It also helps defend against tumors. LYMPHOCYTE…….. Antigen Recognition  The number of different antigen recognized by lymphocytes in the body is extremely large.  Stem cells differentiate into many million different T and B lymphocytes, each with the ability to respond to a particular antigen.  When the antigen first enters the body, it can bind directly to the appropriate receptors on B cells. However, a full antibody response requires that the B cells contact helper T cells  For T cells, the antigen is taken up by an Antigen-Presenting Cell (APC) and partially digested.  A peptide fragment of it is presented to the appropriate receptors on T cells  In either case, the cells are stimulated to divide, forming clones of cells that respond to this antigen (clonal selection) Lymphocytes & Immunity 02/06/2025 30  Lymphocytes…… Antigen Presentation  APC includes specialize cells such as the Dendritic Cells in the lymph node and spleen, the Langerhans Dendritic Cell in the Skin. Macrophages, B-cell and many other cell types can also function as APC.  In APCs, polypeptide products of antigen digestion are coupled to the HLA* protein products of the Major Histocompatibility Complex (MHC) genes and presented on the surface of the cell.  The genes of the MHC, which are located on the short arm of human chromosome 6, encode glycoproteins that are divided into two classes on the basis of structure and function.  Class I antigens are composed of a 45-kDa heavy chain associated non-covalently with β2-microglobulin encoded by a gene outside the MHC. They are found on all nucleated cells.  Class II antigens are heterodimers made up of a 29- to– 34-kDa α chain associated non-covalently Lymphocytes & Immunity with a 25- to 28-kDa β chain. They are present in31 “professional” 02/06/2025 APCs, including B cells,Histocompatibility *HLA-Human and in activatedAntigen T cells.  Lymphocytes…… Antigen Presentation ……  The class I MHC proteins (MHC-I proteins) are coupled primarily to peptide fragments generated from proteins synthesized within cells. Peptides to which the host is not tolerant (eg, those from mutant or viral proteins) are recognized by T cells. The digestion of these proteins occurs in complexes of proteolytic enzymes known as proteasomes, and the peptide fragments bind to MHC proteins in the endoplasmic reticulum.  The class II MHC proteins (MHC-II proteins) are concerned primarily with peptide products of extracellular antigens, such as bacteria, that enter the cell by endocytosis and are digested in the late endosomes.  The MHC protein–peptide complexes on the surface of the APCs bind to appropriate T cells. Therefore, receptors on the T cells must recognize a very wide variety of complexes. Lymphocytes & Immunity 02/06/2025 32 Lymphocytes……. B-cell & immunoglobulins  Activated B cells proliferate and transform into memory B cells and plasma cells.  The plasma cells secrete large quantities of antibodies into the general circulation.  The antibodies circulate in the globulin fraction of the plasma and, like antibodies elsewhere, are called immunoglobulins.  The immunoglobulins are actually the secreted form of antigen- binding receptors on the B cell membrane. Lymphocytes & Immunity 02/06/2025 33 Lymphocytes……. B-cell & immunoglobulins  Circulating antibodies protect their host by binding to and neutralizing some protein toxins, by blocking the attachment of some viruses and bacteria to cells, by opsonizing bacteria, and by activating complement.  Five general types of immunoglobulin antibodies are produced by plasma cells.  The basic component of each is a symmetric unit containing polypeptide chain  The two long chains are called heavy chains, whereas the two short chains are called light chains.  There are two types of light chains, k and λ, and nine types of heavy chains.  The chains are joined by disulfide bridges that permit mobility, Lymphocytes & Immunity 02/06/2025 and 34 there are intra-chain disulfide bridges as well. HEAVY CHAIN:  The heavy chains are flexible in a region called the hinge.  Each heavy chain has a variable (V) segment in which the amino acid sequence is highly variable, a diversity (D) segment in which the amino acid segment is also highly variable, a joining (J) segment in which the sequence is moderately variable, and a constant (C) segment in which the sequence is constant. LIGHT CHAIN:  Each light chain has a V, J, and C segment.  The V segments form part of the antigen-binding sites (Fab) portion of the molecule.  The Fc portion of the molecule is the effector portion, which mediates the reactions initiated by antibodies. Lymphocytes & Immunity 02/06/2025 35  Time course of the antibody response in the circulating blood to a primary injection of antigen and to a secondary IMMUNOGLOBULINS injection several weeks later Immunoglobulins (Ig) Structure Functions Plasma Concentration (mg/dL) IgG Monomer Complement Activation 1000 IgA Monomer, Dimer with J or Localized protection in 200 Sc Chain, Trimer with J external secretion( Tears, chain Intestinal secretion etc) IgM Pentamer with J chain Complement Activation 120 IgD Monomer Antigen recognition by B- 3 cell IgE Monomer Reagin Activity; Release 0.05 Histamine from Basophils and Mast cells. Lymphocytes & Immunity 02/06/2025 36 Regulation of the immune system emphasizing the Pivotal role of T-helper cell MHC-Major Histocompatibility Complex IgM-Immunoglobulin M IgG-Immunoglobulin G IgA-Immunoglobulin A IgE-Immunoglobulin E Lymphocytes & Immunity 02/06/2025 37 Lymphocytes & Immunity 02/06/2025 38 AUTOIMMUNITY  Autoimmune diseases are as a result of failure of processes that eliminate antibodies against self-antigens  This can be T cell- or B cell- mediated and can be organ-specific or systemic. They include: 1. Type 1 Diabetes Mellitus in which antibodies are produced against pancreatic Islet B cells 2. Myasthenia gravis in which antibodies are produced against nicotinic cholinergic receptors 3. Multiple sclerosis in which antibodies are produced against myelin basic proteins 4. Graves disease in which antibodies are produced against TSH receptor which activate them and increase thyroid activities. 5. Rheumatic fever: Sometimes, autoimmune disease occurs due to the production of antibodies against invading organisms that cross-react with normal body constituents (molecular mimicry). An example is rheumatic fever following a streptococcal infection; a portion of cardiac myosin resembles a portion of the streptococcal M protein, and antibodies induced by the latter attack the former and damage the heart. Lymphocytes & Immunity 02/06/2025 39 TSH-Thyroid Stimulating Hormone  PLATELET Lymphocytes & Immunity 02/06/2025 40  THE PLATELET  Platelets are circulating cells that are important mediators of hemostasis.  They are not immune cells, per se, but they often participate in the response to tissue injury in cooperation with inflammatory cell types.  They have a ring of microtubules around their periphery and an extensively invaginated membrane with an intricate canalicular system in contact with the extracellular fluid.  Their membranes contain receptors for collagen, ADP, vessel wall von Willebrand factor(vWF), and fibrinogen.  Their cytoplasm contains actin, myosin, glycogen, lysosomes, and two types of granules: (1) Dense granules, which contain the non-protein substances that are secreted in response to platelet activation, including serotonin, ADP, and other adenine nucleotides. (2) α-granules, which contain secreted proteins. These proteins include clotting factors and platelet-derived growth factor (PDGF). PDGF is also produced by macrophages Lymphocytes & Immunity and endothelial cells. It is a dimer made up of A and 02/06/2025 41 B subunit polypeptides. Role of Platelet in blood clotting  When a blood vessel wall is injured, platelets adhere to the exposed collagen and von Willebrand factor(vWF) in the wall via receptors on the platelet membrane.  von Willebrand factor(vWF) is a very large circulating molecule that is produced by endothelial cells.  The binding produces platelet activations, which release the contents of their granules.  The release ADP acts on the ADP receptors in the platelet membranes to produce further accumulation of more platelets (platelet aggregation). Lymphocytes & Immunity 02/06/2025 42 Role of Platelet in blood clotting…….  Humans have at least three different types of platelet ADP receptors  These are obviously attractive targets for drug development, and several new inhibitors have shown promise in the prevention of myocardial infarctions and strokes.  Aggregation is also fostered by platelet-activating factor (PAF), a cytokine secreted by neutrophils, monocytes and platelets. This compound also has inflammatory activity.  It is an ether phospholipid which is produced from membrane lipids. It acts via a G-protein–coupled receptor to increase the production of arachidonic acid derivatives, including thromboxane A2.  This compound play a role in the balance between clotting and anticlotting activity at the site of vascular injury. Lymphocytes & Immunity 02/06/2025 43  Regulation of platelet production  Platelet production is regulated by the *CSFs that control the production of the platelet precursors in the bone marrow, known as megakaryocytes. Thrombopoietin, a circulating protein factor also regulate the production of platelet.  Thrombopoietin, which facilitates megakaryocyte maturation, is produced constitutively by the liver and kidneys, and there are thrombopoietin receptors on platelets.  Consequently, when the number of platelets is low, less of thrombopoietin is bound and more is available to stimulate production of platelets.  Conversely, when the number of platelets is high, more thrombopoietin is bound and less is available, producing a form of feedback control of platelet production.  The amino terminal portion of the thrombopoietin molecule has the platelet- stimulating activity, whereas the carboxyl terminal portion contains many carbohydrate residues and is concerned with the bioavailability of the molecule. Lymphocytes & Immunity 02/06/2025 44 *CSF-Colony Stimulating Factor Thrombocytopenia & Thrombocytosis  When the platelet count is low, clot retraction is deficient and there is poor constriction of ruptured vessels.  The resulting clinical syndrome (thrombocytopenic purpura) is characterized by easy bruisability and multiple subcutaneous hemorrhages.  Purpura may also occur when the platelet count is normal, and in some of these cases, the circulating platelets are abnormal (thrombasthenic purpura).  Individuals with thrombocytosis are predisposed to thrombotic events. Lymphocytes & Immunity 02/06/2025 45  INFLAMMATION & WOUND HEALING Lymphocytes & Immunity 02/06/2025 46 LOCAL INJURY  Inflammation is a complex localized response to foreign substances such as bacteria or in some instances to internally produced substances. It can be acute or chronic  It includes a sequence of reactions initially involving cytokines, neutrophils, adhesion molecules, complement, and IgG. PAF, an agent with potent inflammatory effects, also plays a role.  Later, monocytes and lymphocytes are involved.  Arterioles in the inflamed area dilate, and capillary permeability is increased.  When the inflammation occurs in or just under the skin, it is characterized by redness, swelling, tenderness, pain and loss of function  It is a key component of asthma, ulcerative colitis, Crohn disease, rheumatoid arthritis, and many other diseases. Lymphocytes & Immunity 02/06/2025 47 SYSTEMIC RESPONSE TO INJURY  Cytokines produced in response to inflammation and other injuries, Time course of changes In as well as disseminated infection, also produce systemic some major acute phase responses. proteins  These include alterations in plasma acute phase proteins, defined as proteins whose concentration is increased or decreased by at least 25% following injury.  Many of the proteins are of hepatic origin.  The causes of the changes in concentration are incompletely understood, but it can be said that many of the changes make homeostatic sense.  For example, an increase in C-reactive protein activates monocytes and causes further production of cytokines.  Other changes that occur in response to injury include somnolence, negative nitrogen balance, and fever Lymphocytes & Immunity 02/06/2025 48  WOUND HEALING  When tissue is damaged, platelets adhere to exposed matrix via integrins that bind to collagen and laminin.  Blood coagulation produces thrombin, which promotes platelet aggregation and granule release.  The platelet granules generate an inflammatory response. White blood cells are attracted by selectins and bind to integrins on endothelial cells, leading to their extravasation through the blood vessel walls.  Cytokines released by the white blood cells and platelets up-regulate integrins on macrophages, which migrate to the area of injury, and on fibroblasts and epithelial cells, which mediate wound healing and scar formation.  Plasmin aids healing by removing excess fibrin. This aids the migration of keratinocytes into the wound to restore the epithelium under the scab. Collagen synthesis is up-regulated producing the scar.  Wounds gain 20% of their ultimate strength in 3 weeks and later gain more strength, but they never reach more than about 70% of the strength of normal skin. Lymphocytes & Immunity 02/06/2025 49 Cutaneous wound 3 days after injury, showing the multiple cytokines and growth factors affecting the repair process. FGF-fibroblast growth factor IGF- insulin-like growth factor PDGF- platelet-derived growth factor TGF- transforming growth factor VEGF-vascular endothelial growth factor Note: The epidermis growing down under the fibrin clot, restoring skin continuity. Lymphocytes & Immunity 02/06/2025 50  SUMMARY  Immune and inflammatory responses are mediated by several different cell types—granulocytes, lymphocytes, monocytes, mast cells, tissue macrophages, and antigen-presenting cells.  Granulocytes mount phagocytic responses that engulf and destroy bacteria. These are accompanied by the release of reactive oxygen species and other mediators into adjacent tissues that may cause tissue injury.  Mast cells and basophils underpin allergic reactions to substances that would be treated as innocuous by non allergic individuals.  A variety of soluble mediators orchestrate the development of immunologic effector cells and their subsequent immune and inflammatory reactions.  Innate immunity represents a primitive response to stereotypical microbial components.  Acquired immunity is slower to develop than innate immunity, but long-lasting and often more effective due to its greater specificity  Inflammatory responses occur in response to infection or injury, and serve to resolve the threat, although they may cause damage to otherwise healthy tissue. Lymphocytes & Immunity 02/06/2025 51 RECOURCES  Ganong’s review of medical physiology; section 1, Chapter 3  Guyton and hall physiology review; chapter 34 and 35  Google search Lymphocytes & Immunity 02/06/2025 52 HANK YOU FOR YOUR ATTENTION Lymphocytes & Immunity 02/06/2025 53