The immune system (IS) maintains the integrity of the organism; recognizes harmful from harmless and protects the organism from ex- and endogenous harmful substances. It belongs together with the nervous system and the endocrine system between the regulatory systems. Basic concepts: • Immunity: protect the organism against pathogenic microorganisms and their toxins. • Auto-tolerance: recognizes its own tissue. • Immune surveillance: recognizes internal pollutants; removes old, damaged, mutated cells. • Antigens (Ag): substances that the IS recognizes and reacts to. Communication within the immune system Communication between cells of the immune system occurs through signaling molecules: • as direct interactions of molecules in membranes, • through secreted molecules, including: • cytokines - protein molecules, • arachidonic acid derivatives (eicosanoids) -prostaglandins, leukotrienes, thromboxanes, • NO, • and oth. Typical properties of the immune system Individual signals usually does not respond (is necessary the presence of costimulatory signals, otherwise usually leads to attenuation) Signal amplification (the signal is amplified over the signal path) The presence of signal transduction systems (termination of the immune response) Cell proliferation (cell number changes as needed) Diffusion arrangement (high probability of encountering a stimulus) + cell migration (which allows targeted response at the site where it is needed) Immune reactions occur mainly in mesenchymal tissues. Each reaction is associated with damage to your own structures! If there is a stimulus on the mucosa, it will usually be attenuated. If something goes into the sub-ligament, it will probably be pathogenic and the response will take place (see mucosal immune system). Immune-privileged areas are areas where some immune mechanisms are missing. Immune reactions always damage their own structures, so they are areas with low tissue regeneration capabilities (eg, CNS). • It recognizes dangerous from harmless by Pathogen-Associated Molecular Pattern (PAMP) - phylogenetically conserved molecules that are typical for pathogens (eg viral RNA, lipopolysaccharide). • It works with specific immunity (it gives information about what is dangerous). • T-lymphocytes recognize only linear peptide fragments processed and presented by antigen-presenting cell (APC), in particular dendritic cells in the presence of costimulatory signals. They help cells with nonspecific immunity in killing pathogens. • B-lymphocytes recognize native antigen and receive costimulation from T-lymphocytes. • Autoreactive lymphocytes are eliminated. • It responds only against dangerous stimuli (this gives information non-specific immunity and apparently tissue that is pathogen-damaged). • It has an immunological memory (use in active immunization). ic immunity Identification of Pathogenic Patterns Pathogens are identified based on the presence of PAMP (Pathogen-Associated Molecular Pattern) - phylogenetically highly conserved structures. Their carriers are only microorganisms and are essential for their survival. Is part of them: bacterial wall - peptidoglycan, lipoteic acid, lipopolysaccharide, bacterial DNA - many cytosine and guanine, without methylation, dsRNA - viral. • These patterns are recognized by PTH (Pathogen Pattern Receptor) = PRR (Pathogen Recognition Receptor) receptors. There are the following types: secreted - opsonins (e.g., MBL) complement activation, endocytic - on phagocytes, mediate phagocytosis (eg MMR), MSR (macrophage scavenger receptor) - cleans up bacterial residues), signaling - activate the signaling pathway leading to cytokine production (e.g., Toll-like receptor (TLR). • Identification of endogenous patterns In connection with apoptosis, APOP (Apoptotic Cell Associated Molecular Pattern) patterns, such as the phospholipids of the inner membrane of the cell membrane, are exhibited. Apoptotic Cell Receptor (ACR) receptors are recognized, producing rather anti-inflammatory cytokines. • Antigen presentation Antigen Presenting Cells (APCs) absorb antigens, process them in lysosomes and present on HLAII molecules, class. Thus treated, antigens (or antigenic epitopes) are presented along with costimulatory signals to T lymphocytes. Note: If any cell, not just antigen presenting, is infected with an intracellular parasite, the antigen is presented on HLA class I. Hours // □ays ■ 0 6 12 1 Time after infection 4 7 Component of innate immunity Paihi yi-m A» »1« pi I .nul ^nlt-tmnJuil dubiuvuc* ... "**" *™ |j" ji" / pn«cln» »nd pcptkVt ||" *. *n> • m *lľ * « •••• » »* * * • •.•„••• » * ** If ■ . 1—-—_ 2. Ami.......j)».....li , II.. I. H K ItSľfl 1. Anatomical barrier - Physical barriers - Chemical barriers 2. Cell - Phagocytic cells - Dendritic cell ■ NK cells, ILC 3. Soluble proteins - Complement - Cytokines, Chemokines - Anti-microbial substances Kuby fmmunofogy 7th edition. Innate Immunity Adaptive Immunity PRR Immature DC PRR Monocyte PAMPs, TFs Adjuvanis (FA MP- or TF-likei (LPS or derivativ«. MPL CpG-DNA, PeptFdoolycan. Lipoprotein.. Toxin, Saponin, Synthetic Compound. HSP) ■8ind to PRR ■Recruitment of APCs MJpregulation of M HC & CM ♦Secretion of cytokines chemokines. or other TFs Immature or Mature DC MHC Adjuvants ÍVehiele-liks) ■ Mincia1 Salt, Emulsion. Micfopailiclei Macioph tyč N K Effecior T cett Mature DC ♦Antigen retention ■Slower antigen release increased antigen uptake -Prolonged antigen exposure ♦MoreMHC/T interaction T Effecter f Abbreviation: »NK: Natural Killer Cell *DC: Dendritic Celll •TCR: T Ce I Rec^ptor *CM: Cortimulatery Molecule •CMR: Costimutator/ Molecule Receptor •PAMP; Pathogen Associated Molecular Pattern •PRR: Pattern Recognition Receptor »TF: Tissue Factor tHSP: Neat Shock proteins Microbe Types of Adaptive Immunity Responding Jymphocytes Effector mechanism Functions Humoral immunity Extracellular microbes B lymphocyte Secreted antibody Block infections and eliminate extracellular microbes Cell-mediated immunity Phagocytosed microbes in macrophage Helper T lymphocyte Activate macrophages to kill phagocytosed microbes Intracellular microbes (e.gri viruses) replicating within infected cell Cytolytic T Symphocyte Kill infected cells and eliminate reservoirs of infection f.ip.iijhl 'f WO! Ell*"»r Inf f.» llfhtf KJ4frl4 The main components of the immune system Immune reactions are ensured by different kinds of cells and molecules and their interactions. IS cells + connective tissue cells —► lymphatic tissue, lymphatic organs. Immune system cells Myeloid • Monocytes (macrophages), neutrophils, basophils (mast cells), eosinophils, dendritic cells -non-specific IS component; phagocytosis, cytokine producers, soluble mediators. • Dendritic cells, monocytes and macrophages = antigen presenting cells (APC); the basis of the antigen-specific part of IS. • Myocytes also include erythrocytes and thrombocytes. Lymphoid • NK cells, lymphocytes B and T. • The development of B-lymphocytes takes place in the bone marrow and is completed after encountering Ag in secondary lymphatic organs; the final stage is the antibody-producing plasma cells. • Development of T-lymphocytes occurs mainly in thymus; 2 major phenotypically different subpopulations: precursors of helper cells (on CD4 receptor surface), cytotoxic cell precursors (CD8): upon aging with Ag on the surface of suitable APCs differentiate into mature effector T lymphocytes. • The part of T and B lymphocytes, after meeting Ag, is differentiated in a memory cell responsible for immunological memory. Suppressor Helper Cytotoxic Tcells T-cetls Tcells L A r Lyrnphoblasts _I_ 1 Alternative pathway Plasma cells Clonal B-celis Death of the body's cells that ore infected with a virus or otherwise damaged i Antibodies Memory G-cells Complement cascade Classical pathway 1. Neutrophils 1. Macrophages 3. Basophils 4. Eosinophils 5. Natural killer cells l.Skin 2. Mucous membranes 3. Saliva 4. Flushing action of urine and tears 5. Stomach acid 1 I Death of dangerous organisms Stops infection before it enters the body Direct killing of bacteria Basic molecules of the immune system • TCR, BCR (antigen-specific receptors on the surface of T and B lymphocytes); • MHC I, II. (HLA molecule); • Fc receptors (bind Fc parts of immunoglobulin molecules); • adhesive and costimulatory molecules; • immunoglobulins; • cytokines; • components of the complement system. The Immune System is the Third Line of Defense Against Infection Nonspecific defense mechanisms Specific defense mechanisms (immune system) First line of defense Second line of defense Third line of defense ■Skin * Mucous membranes - Secretions of skin and mucous membranes Phagocytic white blood cells Antimicrobial proteins The inflammatory response Lymphocytes Antibodies eigaa Addrsün wealay Longman in? Barrier Defenses Barrier defenses include the skin and mucous membranes of the respiratory, urinary, and reproductive tracts Mucus traps and allows for the removal of microbes □ Many body fluids including saliva, mucus, and tears are hostile to many microbes □ The low pH of skin and the digestive system prevents growth of many bacteria Mucosal immune system The mucosal immune system, or MALT mucosa associated lymphoid tissue (in GIT called GALT (gut), BALT (bronchus)) is the lymphatic tissue in the mucosal or sub-lymphatic ligament. Peyer's plaques in the distal section of the ilea, histological specimen d-MALT - diffuse lymphatic tissue (cells are dispersed in the mucosa or submucosa) o-MALT - Organized lymphatic tissue (cells are arranged in lymphatic follicles that can be isolated (folliculi lymphatici aggregati) or associated with so-called follicular lymphatic aggregates. Over the lymphatic follicles, the intestinal wall is covered with FAE (epithelium associated with follicles), which contains a large number of M-cells (membrane cells - from the intestinal lumen endocytopes the antigens and transmit it to lymphocytes). The First Line of Defense -Skin- The dead, outer layer of skin, known as the epidermis, forms a shield against invaders and secretes chemicals that kill potential invaders You shed between 40-50 thousand skin cells every day! Immune function of GIT Large surface The significance of intact gastrointestinal mucosa □ Mucosal barrier - mucus, lysozymes, phagocytes, pH of environment, humoral factors □ The immune system of the digestive tract: □ Peyer plaques - lymphoid follicles, antibody production □ Immune cells - intraepithelial lymphocytes, the lymphocytes in the lamina propria immunoglobulin production □ Drainage system of portal blood and lymph The First Line of Defense -Saliva- What's the first thing you do when you cut your finger? Saliva contains many chemicals that break down bacteria Thousands of different types of bacteria can survive these chemicals, however 'InMi; I. Saliva components li nd functions [4). Parameter Characteristics Volume Electrolytes Secretory proteins/peptides Immunoglobulins Small organic Other components 600-1000ml/day Na+, K+r Cl-r Ca2+r Mg2+and F- Amylase, proline-rich proteins, mucins, histatin, cystatin, peroxidase, lysoiyme, lactoferrin and defenses. Secretory immunoglobulins A, immunoglobulins Q and M Glucose, amino acids, urea, uric acid, and lipid molecules Epidermal growth factor, insulin, cyclic adenosine monophosphate-binding proteins, and serum albumin Functions Coi11|XmCNf■ "■ |"i"■ ■>iij111 Miiin tiiiiiiJig mucosa integrit; Mucins, electrolytes, water { leLinsiJiL: Witter Eiull'er c;i|niut\ ;m1lI rc-mincvLilisiilitin [Sic;i rhona le. phL^ph;iLc1. c;ilcium. staierin. proline-rich niiionic pr etc in is. Iltionde Preparing food for *.v- Lillo^nii: Water, mucins Digestion Amylase, lipase. ii bo nucleuses, proteases. ^Liter, mucins Taste Witter, gustin Phcniition Wuter, mucin The First Line of Defense -Stomach Acid- Swallowed bacteria are broken down by HC1 in the stomach - The stomach must produce a coating of special mucus or this acid would eat through the stomach! Duodenum Jejunum Ileum Clostridium Lactobacillus Enterococcus Colon Bacilli 4 Streptococcaceae 10 ^Actinobacteria Actinomycinaeae Corynebacteriaceae 107 1012 fLachnospiraceae Bacteroidetes c Birth Bacteroides Bifidobacterium Streptococcus Enterobacteriacea Enterococcus Clostridium Lactobacillus Ruminococcus 1 year Death cells/gram Distal Gl tract Increasing numbers Increasing diversity Influences: Maternal colonization Diet Environmental exposures Antimicrobial therapies Numbers are maintained Composition evolves continuously Small intestine Lumen MAMPs MceJI R.OO 1 0° B cells Peyer's patch Isolated lymphoid follicle Lamina propria Goblet cells - mucins M cells - ability to take up antigen from the lumen via endocytosis, phagocytosis, or transcytosis to antigen presenting cells, such as dendritic cells, and lymphocytes Paneth cells - synthesize and secrete substantial quantities of antimicrobial peptides and proteins Lungs and immunity Table 27-1 Siüfacmnt Apoproteins Apoprotein Solubility Role 5P-A Water Innate immunity Formation of tubular myelin SP-B Lipid Speeds formation of monolayer Formation of tubular myelin SP-C Lipid Speeds formation of monolayer SP-D Water Innate immunity Metabolism of surfactant? = opsonins to coat bacteria and viruses, thereby promoting phagocytosis by macrophages resident the alveoli Innate or Genetic Immunity: Immunity an organism is born with. □ Genetically determined. □ May be due to lack of receptors or other molecules required for infection. [ Innate human immunity to canine distemper. □ Immunity of mice to poliovirus. Acquired Immunityrlmmunity that an organism develops during lifetime. □ Not genetically determined. □ May be acquired naturally or artificially. □ Development of immunity to measles in response to infection or vaccination. Innate versus acquired immunity Innate immunity neutrophils, macrophages, NK cells Toll and toll-like receptors = affinity to bacterial lipopolysaccharides, lipoproteins, peptidoglycans, DNA = molecular patterns expressed by pathogens llngelltn iriaeyfcted |pQfOSllK| diacytared lipoproteins (pom" boctefia] lymown (tungl) TlR12 " ^Jf^ A PU PTOSIS EFFECTOR MECHANISMS OF INNATE IMMUNITY ® KILLER CELLS NK cell Virus-infected cell Killing of infected cells Macrophage with phagocytosed microbes PHAGOCYTIC CELLS Kilting of phagocytosed microbes COMPLEMENT SYSTEM Effector functions Initiation of complement M!crobe activation Alternative Classical Lectin pathway pathway pathway Anlibddy Mannosci-binding lectin C3bls >mt? _. deposited ^Llcjrj on microbe I C3b: opsonization and phagocytosis Late steps Complement proteins form mem b rone attach complex Lysis of microbe Professional antigen-presenting cells Dendritic cell Macrophage Bcell viral in <$ antigen bacterium microbial toxin » i Cell type virus Vi ^ infecting the dendritic cell Location in lymph node T-ceil areas fo^^^^^^ Antigen uptake +++ Macropinocytosis and phagocytosis by tissue dendritic cells Viral infection Phagocytosis +++ Antigen-specific receptor (Ig) ++++ MHC expression Low on tissue dendritic cells High on dendritic cells in lymphoid tissues Inducible by bacteria and cytokines - to +++ Constitutive Increases on activation +++ to ++++ Co-stimulator delivery Constitutive by mature, nonphagocytk lymphoid dendritic cells ++++ Inducible - to +++ Inducible - to +++ Antigen presented Peptides Viral antigens Allergens Particulate antigens Intracellular and extracellular pathogens Soluble antigens Toxins Viruses Location Ubiquitous throughout the body Lymphoid tissue Connective tissue Body cavities Lymphoid tissue Peripheral blood Figure 8.11 The Immune System, 3ed. [© Garland Science 2009) PHAGOCYTOSÍS Macrophages and neutrophils are the primary phagocytes. (a) Some patfiogens bind directly to phagocyte receptors. Lysosome Njcieus Membrane proteins Pathogen Phagocytosis brings pathogens into immune celis. Lysosome contains enzymes and oxidants, Digested antigen- ' ^ Phagosome contains ingested pathogen. Ingested pathogen Bacteria with capsules must be coated with antibody before phagocytes can recognize and ingest, them. Membrane receptor Polysaccharide capsule Antibody molecules Antigen-presenting macrophage displays antigen fragments on surface receptors. Lysosomal enzymes digest pathogen, producing antigenic fragments. Antigen-presenting cell (ARC) Professional APCs DCs and macrophages Key features ■ Phagocytic • Express receptors for apoptotic cells, DAMPs and PAMPs • Localize to tissues • Localize to T cell zone of lymph nodes following activation (DCs) • Constitutively express high levels of MHC class II molecules and antigen processing machinery • Express co-stimulatory molecules following activation B cells Key features • Internalize antigens via BCRs • Constitutive^ express MHC class II molecules and antigen processing machinery • Express co-stimulatory molecules following activation Atypical APCs Basophils Eosinophils Key features * Inducible expression of MHC class II molecules * Antigen-presenting functions limited to specific immune environments {especially type 1 immune settings) * Lack of compelling evidence that they can activate naive CD4+ T cells in an antigen-specific manner Nature Reviews | Immunology Innate versus acquired immunity Acquired immunity □ □ Ability of lymphocytes to produce antibodies (B cells) or cell-surface receptors (T cells) = specific! Antigens (proteins, polypeptides, nucleic acids, lipids) Humoral immunity -circulating antibodies (plasma cells, activation of complement system, bacterial infection) Cellular immunity - T-lymphocytes Adaptive Immunity Humoral immunity Cell-mediated immunity CO> Col Extracellular microt»s B Lympnocyte Priagocytosed microbes in macrophage Dendritic cells display antigen fragments 1o T cells 0 Intracellular microbes within infected cell Elimination of i-i: I ■■: ■■■ 1 Activation o( macroflhaga leading to microbial killing £0 /sAxljL cytokines Lysis: infected cell^^^ \—J Humoral (antibody-mediated) immune response r B tell Plasma tells ^SecretedJ^ antibodies A. 4 # Antigen (1st exposure) I Engulfed by Antigen-presenting cell _ Cell-mediated immune response I ♦ Helper T cell Memory Helper T cells uioiy cell Key Stimulates Gives rise to Cytotoxic T cell c Antigen (2nd exposure) 1 ryi HemoiyB cells - » Cytotoxic T cells ^ Cytotoxic T cells I Reticuloendothelial system - tissue macrophage system Waste disposal Bone marrow and fetal liver ® Upiake and y degradation r of erythroid nuclei Failure: fFN-[i production and disruption of hematopoiesis Red pulp macrophages and Kupffer cells Erythrocyte clearance Failure: impaired erythrocyte clearance and iron recycling Bone Osteoclasts M-CSF HANKL Failure: osteopetrosis Bone Other development Ductal branching in mammary glands and pancreatic islets Hy pot h alam ic-pituitary * gonadal development Angiogenesis Homeostatic and inflamed tissue macrophages »• * Apoptotic ceil \t* / clearance Failure: uptake of apoptotic material by dendritic ceils in immunogenic context leading to autoimmunity Alveolar macrophages GM-CSF ^/ +—/—-Surfactant j^^^^/ clearance Failure: alveolar proteinosis Initiation and resolution of inflammation Adipose tissue Pathogen recognition: TLRs and lectins jOk (ii) Inflammatory response: # TNF, IL-6, KG, G-CSF C^^S*^I (iii) Resolution: TGF-fj, A IL-10, lipid mediators \^ J Failure: chronic inflammation, tissue damage, fibrosis White adipose tissue macrophages Lipolysis ' Mo rad re na line Eosinophil^ Insulin sensitivity Failure: insulin resistance Brown adipose tissue macrophages ? IL-4 and/or AdaPtive . \ IH 3 thermogenesis f K Noradrenaline Failure: loss of adaptive thermogenesis Macrophages {M<í>) Tissue Functions Pathology Microglia Osteoclasts Heart M4> Kupffer cells Alveolar M$ Brain Bone Brian development (12 I), immune surveillance, synaptic remodeling (122) Bone modeling and remodeling, bone resorption (124), support to hematopoiesis (125) Heart and vasculature Surveillance Liver Lung Adipose tissue-associated Adipose tissue M Bone marrow M$ Intestinal M4> Langerhans cells Marginal zone MO, red pulp M$ Inflammatory M*a Healing M*b Bone marrow Gut Skin Spleen All tissues All tissues Toxin removal, lipid metabolism, iron recycling, erythrocyte clearance, clearance of microbes, and cell debris from blood (128, 129) Surfactant clearance, surveillance for inhaled pathogens (132) Metabolism, adipogenesis, adaptive thermogenesis (134) Reservoir of monocytes, waste disposal (131) Tolerance to microbiota, defense against pathogens, intestinal homeostasis (135) Immune surveillance (137) Erythrocyte clearance, iron processing, capture of microbes from blood (139) Defense against pathogens, protection against dangerous stimuli ( ) Branched morphology, angiogenesis (142) Neurodegeneration (123) Osteoporosis, osteopetrosis, arthritis (126) Atherosclerosis (127) Fibrosis (130), impaired erythrocyte clearance (131) Alveolar proteinosis (133) Obesity, diabetes, insulin resistance, loss of adaptive thermogenesis (131) Disruption of hematopoiesis (131) Inflammatory bowel disease (136) Insufficient healing, fibrosis (138) Impaired iron recycling and erythrocyte clearance (140) Chronic inflammation, tissue damage, autoimmunity (91) Cancer, fibrosis, epithelial hyperplasia (91) 3Also known as inflammatory macrophages or Ml macrophages. bAlso known as deactivated or M2 macrophages. Types of Acquired Immunity I. Naturally Acquired Immunity: Obtained in the course of daily life. A. Naturally Acquired Active Immunity: □ Antigens or pathogens enter body naturally. □ Body generates an immune response to antigens. □ Immunity may be lifelong (chickenpox or mumps) or temporary (influenza or intestinal infections). B. Naturally Acquired Passive Immunity: □ Antibodies pass from mother to fetus via placenta or breast feeding (colostrum). □ No immune response to antigens. □ Immunity is usually short-lived (weeks to months). □ Protection until child's immune system develops. Types of Acquired Immunity (Continued) II. Artificially Acquired Immunity: Obtained by receiving a vaccine or immune serum. 1. Artificially Acquired Active Immunity: □ Antigens are introduced in vaccines (immunization). □ Body generates an immune response to antigens. □ Immunity can be lifelong (oral polio vaccine) or temporary (tetanus toxoid). 2. Artificially Acquired Passive Immunity: □ Preformed antibodies (antiserum) are introduced into body by injection. Snake antivenom injection from horses or rabbits. □ Immunity is short lived (half life three weeks). □ Host immune system does not respond to antigens. Duality of Immune System Humoral (Antibody-Mediated) Immunity □ Involves production of antibodies against foreign antigens. □ Antibodies are produced by a subset of lymphocytes called B cells. □ B cells that are stimulated will actively secrete antibodies and are called plasma cells. □ Antibodies are found in extracellular fluids (blood plasma, lymph, mucus, etc.) and the surface of B cells. □ Defense against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they enter cells. □ Also cause certain reactions against transplanted tissue. Antibodies are Proteins that Recognize Specific Antig Ant igen -binding site Antigen Epitope (antigenic determinant) {a) Antibody molecule Ö1BBB AcJcJaün Wesl-sy Longman, frK. (b) Enlarged antigen-binding cite Duality of Immune System II. Cell Mediated Immunity □ Involves specialized set of lymphocytes called T cells that recognize foreign antigens on the surface of cells, organisms, or tissues: Helper T cells Cytotoxic T cells □ T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc. □ Defense against: Bacteria and viruses that are inside host cells and are inaccessible to antibodies. Fungi, protozoa, and helminths Cancer cells Transplanted tissue The Thymus Gland The thymus gland is a two-1 obed organ located in the thorax just above the heart. The thymus gland reaches its greatest size during adolescence.Then it shrinks and is largely replaced by adipose tissue as a person ages. During development in the thymus, those cells that would be self-reactive are elim inated. Those that do not react with "self tissues multiply to form clones. Thymus Thyroid gland Trachea The thymus gland produces: • T lymphocytes • Peptides thymosin thymopoietin thymulin ® FIGURE QUESTION New T lymphocyte production in the thymus is low in aduHs, but the number of T lymphocytes in the blood does not decrease. What conciusion(s) about T lymphocytes can you draw from this information? T LYMPHOCYTES (a) T lymphocyte development During embryonic development, T lymphocytes insert their T-cell receptors into the membrane. migrates to Multipotent stem cell in bone marrow T-cell precursor (b) T lymphocyte activation When T-ceil receptors bind to antigen presented on MHC receptors, MHC-antigen complex f- kilt->■ Cytotoxic T cells Helper T cells Cell binds to T lymphocyte. ús% Signal transduction activates T lymphocyte. T-cell receptor 0 Bind to MHC antigen-presenting celts MCH receptor T lymphocyte FIGURE QUESTIONS What kind of T cell is shown if the MHC receptor is MHC-I? MHC-]]? MHC Class I target cells Cytokines that *■ activate other immune cells Most are proteins or large polysaccharides from a foreign organism. □ Microbes: Capsules, cell walls, toxins, viral capsids, flagella, etc. □ Nonmicrobes: Pollen, egg white , red blood cell surface molecules, serum proteins, and surface molecules from transplanted tissue. □ Lipids and nucleic acids are only antigenic when combined with proteins or polysaccharides. □ Molecular weight of 10,000 or higher. Hapten: Small foreign molecule that is not antigenic. Must be coupled to a carrier molecule to be antigenic. Once antibodies are formed they will recognize hapten. Antigens Epitope: Small part of an antigen that interacts with an antibody. □ Any given antigen may have several epitopes. □ Each epitope is recognized by a different antibody. C'iaga Au:=ůn Wesley L.ůngnifl/i. lne- Proteins that recognize and bind to a particular antigen with very high specificity. Made in response to exposure to the antigen. One virus or microbe may have several antigenic determinant sites, to which different antibodies may bind. □ Each antibody has at least two identical sites that bind antigen: Antigen binding sites. □ Valence of an antibody: Number of antigen binding sites. Most are bivalent. □ Belong to a group of serum proteins called immunoglobulins (IGs). Antibody Structure Monomer: A flexible Y-shaped molecule with four protein chains: □ 2 identical light chains □ 2 identical heavy chains Variable Regions: Two sections at the end of Y's arms. Contain the antigen binding sites (Fab). Identical on the same antibody, but vary from one antibody to another. □ Constant Regions: Stem of monomer and lower parts of Y arms. □ Fc region: Stem of monomer only. Important because they can bind to complement or cells. Antibody Structure {a) Antibody molecule Ö1BBB Addacm Vieetsy Longman, he. (b) Enlarged antigen-binding site ANTIBODIES (a) Antibody structure An antibody molecule is composed of two identical light chains and two identical heavy chains, linked by disulfide bonds. Antigen-binding Light chain Hinge region allows movement of the arms. Heavy chain Fab region Fc r«cji! - ''I (b) Antigen binding Antibodies have antigen-binding sites on the Fab regions. Antigen binding site Fab region region (c) Antibody functions (T) Activate B lymphocytes x Y Plasma ■ g 4 cells -{ Memory cells Secrete antibodies (2) Act as opsonins to tag antigens for phagocytosis Bacterial "oxi n? (3) Cause antigen clumping and inactivation of bacterial toxins Enhanced phagocytosis (4) Activate antibody-dependent cellular activity ' vW .— NK cell or eosinophil (J5) Activate complement Complement— (6) Trigger mast cell degranulation Antibody Immunoglobulin Classes I. IgG Structure: Monomer Percentage serum antibodies: 80% Location: Blood, lymph, intestine □ Half-life in serum: 23 days □ Complement Fixation: Yes □ Placental Transfer: Yes □ Known Functions: Enhances phagocytosis, neutralizes toxins and viruses, protects fetus and newborn. II. IgM Structure: Pentamer Percentage serum antibodies: 5-10% Location: Blood, lymph, B cell surface (monomer) □ Half-life in serum: 5 days □ Complement Fixation: Yes □ Placental Transfer: No □ Known Functions: First antibodies produced during an infection. Effective against microbes and agglutinating antigens. III. IgA Structure: Dimer Percentage serum antibodies: 10-15% Location: Secretions (tears, saliva, intestine, milk), blood and lymph. □ Half-life in serum: 6 days □ Complement Fixation: No □ Placental Transfer: No □ Known Functions: Localized protection of mucosal surfaces. Provides immunity to infant digestive tract. IV. IgD Structure: Monomer Percentage serum antibodies: 0.2% □ Location: B-cell surface, blood, and lymph □ Half-life in serum: 3 days □ Complement Fixation: No □ Placental Transfer: No □ Known Functions: In serum function is unknown. On B cell surface, initiate immune response. V.IgE Structure: Monomer Percentage serum antibodies: 0.002% □ Location: Bound to mast cells and basophils throughout body. Blood. □ Half-life in serum: 2 days □ Complement Fixation: No □ Placental Transfer: No □ Known Functions: Allergic reactions. Possibly lysis of worms. How Do B Cells Produce Antibodies? □ B cells develop from stem cells in the bone marrow of adults (liver of fetuses). □ After maturation B cells migrate to lymphoid organs (lymph node or spleen). □ Clonal Selection: When a B cell encounters an antigen it recognizes, it is stimulated and divides into many clones called plasma cells, which actively secrete antibodies. □ Each B cell produces antibodies that will recognize only one antigenic determinant. LYMPHOCYTE CLONES (a) A done is a group of lymphocytes ttiat are specific to one antigen. © FIGURE QUESTION Which clone will this antigen activate? 1 --r ^ PRIMARY IMMUNE RESPONSE (b) Exposure to an antigen triggers clonal expansion and the immune response. Upon first exposure to an antigen, naive lymphocytes reproduce, Clone 1 C!one2 _W Clone 3 (c) B lymphocytes secrete antibodies. f^L*^ ^Clonal , * ~ , expa™-,, . ■ .... Effector cells (B lymphocyte Short-lived effector cells carry out the immediate response. Plasma ceils Antibodies Clonal expansion leads to immunologic memory. SECONDARY IMMUNE RESPONSE (d) When memory cells are reexposed to the appropriate antigen, the clone expands more rapidly to create additional effector and memory cells- I PRIMARY IMMUNE RESPONSE — Antibody ^s^con centration Memory cells are long lived and continue to reproduce, First antigen exposure -Time [weeks) - ...... Plasma ceils Antibodies u Q. /^SECONDARY IMMUNE RESPONSE f--Antibody concentration Antibody production in response to the first exposure to an antigen is both slower and weaker than antibody production following subsequent exposures to the same antigen. Second antigen exposure 2 3 -Time {weeks) - Humoral Immunity Apoptosis □ Programmed cell death ("Falling away"). □ Human body makes 100 million lymphocytes every day. If an equivalent number doesn't die, will develop leukemia. □ B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to dispose of their remains. □ Many virus infected cells will undergo apoptosis, to help prevent spread of the infection. Consequences of Antigen-Antibody Binding Antigen-Antibody Complex: Formed when an antibody binds to an antigen it recognizes. Affinity: A measure of binding strength. 1. Agglutination: Antibodies cause antigens (microbes) to clump together. □ IgM (decavalent) is more effective that IgG (bivalent). □ Hemagglutination: Agglutination of red blood cells. Used to determine ABO blood types and to detect influenza and measles viruses. 2. Opsonization: Antigen (microbe) is covered with antibodies that enhances its ingestion and lysis by phagocytic cells. Consequences of Antibody Binding Enhances phagocytosis and reduces number of infectious units to be deal! with Agglutination PROTECTIVE MECHANISM OF BINDING ANTIBODIES TO ANTIGENS Activation of complement Disruption of cell by complement/ reactive protein attracts phagocytic and other defensive immune system cells Blocks adhesion of bacteria and viruses to mucosa Neutralization Antibodies attached to target cell cause destruction by non-specific immune system cells OS BENJAMIN^CUMMIMOS Humoral Immunity 3. Neutralization: IgG inactivates viruses by binding to their surface and neutralize toxins by blocking their active sites. 4. Antibody-dependent cell-mediated cytotoxicity: Used to destroy large organisms (e.g.: worms). Target organism is coated with antibodies and bombarded with chemicals from nonspecific immune cells. 5. Complement Activation: Both IgG and IgM trigger the complement system which results in cell lysis and inflammation. The multiple activities of the complement system. LYSIS OPSONIZATION Complement J9 r Target cell X ACTIVATION OF INFLAMMATORY CLEARANCE OF RESPONSE IMMUNE COMPLEXES Complement receptor complex *^*Tl Degranulation Phagocyte Complement pathways Classical pathway J Antibodies bind antigen following invasion. The complex is recognized by some complement proteins, which immediately bind and activate a cascade of events. Mannan-binding lectin pathway T Mannose (sugar residues on pathogen surfaces) binds leptin. This binding triggers the activation of serine proteases that initiate the complement cascade. Alternative pathway I Pathogen surfaces spontaneously lead to complement activation. Complement activation cascade Activation of C3 produces complement proteins with 3 major roles: f Chemotaxis and inflammation C3a, C5a I Recruit phagocytes to the site of injury/pathogen invasion. Opsonization of pathogens C3b Tag pathogens for destruction by the phagocytic cells. 1 Membrane attack complex (MAC) C5b, C6b, C7b, C8b, C9b Peptides adhere to cell surface and disrupt the phospholipid bilayer, leading to cell lysis and death. Consequences of Antibody Binding Binding of antibodies to antigens Inactivates antigens by f J Neutralization Agglutination of {blocks viral binding sites; antigen-bearing particles, coats bacteria a nd/or sue h as microbes opsonization) Virus Bacterium Vf* ^_ Bacteria Enhances I Phagocytosis T Precipitation of soluble antigens Soluble antigens J Complement fivation (activation of complement) Complement Lesion iCCCP "-££00 Foreign cell Leads to I Cell lysis öl 999 Addison Wesley Longman Inc Immunological Memory Antibody Titer: The amount of antibody in the serum. Pattern of Antibody Levels During Infection Primary Response: □ After initial exposure to antigen, no antibodies are found in serum for several days. □ A gradual increase in titer, first of IgM and then of IgG is observed. □ Most B cells become plasma cells, but some B cells become long living memory cells. Gradual decline of antibodies follows. Immunological Memory (Continued) Secondary Response: □ Subsequent exposure to the same antigen displays a faster and more intense antibody response. □ Increased antibody response is due to the existence of memory cells, which rapidly produce plasma cells upon antigen stimulation. Time (days) T Cells and Cell Mediated Immunity Antigens that stimulate this response are mainly intracellular. Requires constant presence of antigen to remain effective. Unlike humoral immunity, cell mediated immunity is not transferred to the fetus. Cytokines: Chemical messengers of immune cells. □ Over 100 have been identified. □ Stimulate and/or regulate immune responses. □ Interleukins: Communication between WBCs. □ Interferons: Protect against viral infections. Chemokines: Attract WBCs to infected areas. T Cells and Cell Mediated Immunity Cellular Components of Immunity: □ T cells are key cellular component of immunity. □ T cells have an antigen receptor that recognizes and reacts to a specific antigen (T cell receptor). □ T cell receptor only recognize antigens combined with major histocompatability (MHC) proteins on the surface of cells. [ MHC Class I: Found on all cells. □ MHC Class II: Found on phagocytes. □ Clonal selection increases number of T cells. Antigen-presenting cell (a macrophage) Class II MHC molecule Antigen fragment T-cell receptor Helper T cell (TH) T Cells and Cell Mediated Immunity Types of T cells 1. T Helper (TH) Cells: Central role in immune response. Most are CD4+ Recognize antigen on the surface of antigen presenting cells (e.g.: macrophage). Activate macrophages Induce formation of cytotoxic T cells Stimulate B cells to produce antibodies. Helper T cell Activation and Action 7. Antigen recognition MHC-II CD4+ Helper!" cell Aritigsrt 3. Interíeukin secretion Effc(tcrl*l0lol»:0 Capillary Circulating leukocytes - artracf - Immune Responses to Viruses This figure assumes prior exposure to the virus and preexisting antibodies. Preexisting antibodies MHC-I- Vlral- antigen 1 Uninfected host cell tnterferon-a activates antiviral response. Infected host cell MHC-ll Infected cell undergoes apoptosis and dies. © Macrophage ingests virus. Viral antigen MHC-ll I Macrophage presents antigen fragments. 3 G Attacked by cytotoxic T cells • © *tv ■ . ■, ' T- Perforins, granzymes < Cytokines Inflammatory response Activates helper T cell FIGURE QUESTION Identify the cell-mediated and humoral immunity steps in this map. , J~ Antibodies V* ALLERGIC RESPONSES FIRST EXPOSURE 9 Allergen Allergen ingested and processed by antigen-presenting cell. Antig en-presenting cell activates helper T cell. Helper T cell B lymphocyte Memory B and T cells retain memory of exposure to allergen. Antibodies K Vasodilation Bronchooonstrtction f Vascular permeabifrty Inflammation