Fig µm Chapter 43 The Immune System

Fig INNATE IMMUNITY Recognition of traits shared by broad ranges of pathogens, using a small set of receptors Rapid response Recognition of traits specific to particular pathogens, using a vast array of receptors Slower response ACQUIRED IMMUNITY Pathogens (microorganisms and viruses) Barrier defenses: Skin Mucous membranes Secretions Internal defenses: Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response: Antibodies defend against infection in body fluids. Cell-mediated response: Cytotoxic lymphocytes defend against infection in body cells.

Innate Immunity of Vertebrates Fig Microbes PHAGOCYTIC CELL Vacuole Lysosome containing enzymes Activates antimicrobial peptide by infecting with bacteria

Fig RESULTS % survival Wild type Fruit fly survival after infection by N. crassa fungi Hours post-infection Fruit fly survival after infection by M. luteus bacteria Hours post-infection % survival Mutant + drosomycin Mutant + defensin Mutant Wild type Mutant + drosomycin Mutant + defensin Mutant Can a single antimicrobial peptide protect fruit flies against infection? In 2002, Bruno Lematire et al., To test the function of a single antimicrobial peptide. Drosomycin or defensin A single antimicrobial peptide in the fly’s body can provide an effective and specific immune defense against a particular pathogen.

Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They have also been reported in plantscysteinecationicproteins vertebratesinvertebrates They are active against bacteria, fungi and many enveloped and nonenveloped viruses.bacteriafungiviruses They consist of amino acids including six (in vertebrates) to 8 conserved cysteine residues.amino acidscysteine Cells of the immune system contain these peptides to assist in killing phagocytized bacteria, for example in neutrophil granulocytes and almost all epithelial cells.immune systemphagocytizedneutrophil granulocytesepithelial cells Most defensins function by binding to microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrientsmicrobialcell membraneefflux

Innate Immunity of Vertebrates The immune system of mammals is the best understood of the vertebrates Innate defenses include barrier defenses, phagocytosis, antimicrobial peptides Additional defenses are unique to vertebrates: the inflammatory response and natural killer cells

Cellular Innate Defenses White blood cells (leukocytes) engulf pathogens in the body Groups of pathogens are recognized by TLR, Toll-like receptors

Fig EXTRACELLULAR FLUID Lipopolysaccharide Flagellin TLR4 TLR5 Helper protein TLR9 TLR3 WHITE BLOOD CELL VESICLE CpG DNA ds RNA Inflammatory responses Toll-like receptor or TLR Is the sensor of ds RNA : micro-organism or viruses

Toll-like receptor From Wikipedia,  The curved leucine-rich repeat region of Toll-like receptors, represented here by TLR3leucine-rich repeat  Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single membrane-spanning non- catalytic receptors that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs which activates immune cell responses.proteinsinnate immune systemreceptorsmicrobesskinintestinal tractmucosaimmune cell  They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein- Volhard.[1] TollDrosophilaChristiane Nüsslein- Volhard[1]

Signaling pathway of Toll-like receptors. Dashed grey lines represent unknown associations

A white blood cell engulfs a microbe, then fuses with a lysosome to destroy the microbe There are different types of phagocytic cells: Neutrophils engulf and destroy microbes Macrophages are part of the lymphatic system and are found throughout the body Eosinophils discharge destructive enzymes Dendritic cells stimulate development of acquired immunity

Dendritic cells: emerging pharmacological targets of immunosuppressive drugs Nature Reviews Immunology 4, (January 2004) | doi: /nri1256

Fig Adenoid Tonsil Lymph nodes Spleen Peyer’s patches (small intestine) Appendix Lymphatic vessels Lymph node Masses of defensive cells Blood capillary Lymphatic vessel Tissue cells Interstitial fluid

Fig PathogenSplinter Macrophage Mast cell Chemical signals Capillary Phagocytic cell Red blood cells Inflammatory Responses mast cells release histamine, which promotes changes in blood vessels; this is part of the inflammatory response

Fig PathogenSplinter Macrophage Mast cell Chemical signals Capillary Phagocytic cell Red blood cells Fluid increase local blood supply allow more phagocytes and antimicrobial proteins to enter tissues

Fig PathogenSplinter Macrophage Mast cell Chemical signals Capillary Phagocytic cell Red blood cells Fluid Phagocytosis Pus, a fluid rich in white blood cells, dead microbes, and cell debris, accumulates at the site of inflammation

Specific immunity

Fig Antigen- binding site Antigen- binding site Antigen- binding site Disulfide bridge Variable regions Constant regions Transmembrane region Plasma membrane Light chain Heavy chains T cell  chain  chain Disulfide bridge Cytoplasm of T cell (b) T cell receptor Cytoplasm of B cell (a) B cell receptor B cell V V C C V V CCCC VV

Fig Antigen-binding sites Antigen- binding sites Epitopes (antigenic determinants) Antigen Antibody B Antibody C Antibody A CC C V V V V C BCR binds an intact antiagen that is free or on the surface of a pathogen TCR: only binds to antigen fragments that are displayed, or presented, on the surface of host cells. ----Major histocompatibility complex (MHC) produce a host cell protein that can present an antigen fragment to TCR.

Fig Antigen Top view: binding surface exposed to antigen receptors Plasma membrane of infected cell Antigen Class I MHC molecule

Class I MHC molecules –are found on almost all nucleated cells of the body –They display peptide antigens to cytotoxic T cells Class II MHC molecules –are located mainly on dendritic cells, macrophages, and B cells –Dendritic cells, macrophages, and B cells are antigen-presenting cells that display antigens to cytotoxic T cells and helper T cells

Fig Infected cell Antigen fragment Class I MHC molecule T cell receptor (a) Antigen associates with MHC molecule T cell recognizes combination Cytotoxic T cell(b)Helper T cell T cell receptor Class II MHC molecule Antigen fragment Antigen- presenting cell Microbe

How do we generate such remarlable diversity in antigen receptors? protein-coding genes 1 million different B cells 10 millions different T cells A variety of combinations The capacity to generate diversity is built into the structure of the Ig light-chain gene. –40V×5J×1C ＝ 200

Fig DNA of undifferentiated B cell 1 DNA of differentiated B cell pre-mRNA mRNA Light-chain polypeptide Variable region Constant region Translation B cell B cell receptor RNA processing Transcription DNA deleted between randomly selected V and J segments Functional gene V 37 V 38 V 39 V 40 J1J1 J2J2 J3J3 J4J4 C J5J5 Intron V 37 V 38 V 39 C J5J5 Intron V 39 C J5J5 Intron V 39 C J5J5 Poly-A tailCap CV V V V V C C CC Ig gene rearrangement The mechanism of Ig diversity 1. DNA recombination 2. The joining V, D, and J domains is not always precise 3. The DNA coding for hypervariable region is hypermutation C  U

Origin of Self-Tolerance Antigen receptors are generated by random rearrangement of DNA As lymphocytes mature in bone marrow or the thymus, they are tested for self-reactivity Lymphocytes with receptors specific for the body ’ s own molecules are destroyed by apoptosis, or rendered nonfunctional

B cells that differ in antigen specificity Antibody molecules Antigen receptor Antigen molecules Clone of memory cells Clone of plasma cells Amplifying Lymphocytes by Clonal Selection Memory cells Effector cells

Fig Antibodies to A Antibodies to B Secondary immune response to antigen A produces antibodies to A; primary immune response to antigen B produces antibodies to B. Primary immune response to antigen A produces antibodies to A. Antibody concentration (arbitrary units) Exposure to antigen A Exposure to antigens A and B Time (days) The specifcity of immunological memory

Fig Humoral (antibody-mediated) immune response B cell Plasma cells Cell-mediated immune response Key Stimulates Gives rise to Memory B cells Antigen (1st exposure ) Engulfed by Antigen- presenting cell Memory Helper T cells Helper T cell Cytotoxic T cell Memory Cytotoxic T cells Active Cytotoxic T cells Antigen (2nd exposure) Secreted antibodies Defend against extracellular pathogens by binding to antigens, thereby neutralizing pathogens or making them better targets for phagocytes and complement proteins. Defend against intracellular pathogens and cancer by binding to and lysing the infected cells or cancer cells. + ++

Fig a Key Stimulates Gives rise to + Memory Helper T cells Antigen- presenting cell Helper T cell Engulfed by Antigen (1st exposure) Defend against extracellular pathogens Memory B cells Antigen (2nd exposure) Plasma cells B cell Secreted antibodies Humoral (antibody-mediated) immune response

Fig b Cell-mediated immune response Defend against intracellular pathogens Active Cytotoxic T cells Memory Cytotoxic T cells Memory Helper T cells Antigen- presenting cell Antigen (2nd exposure) Helper T cell Engulfed by Antigen (1st exposure) Cytotoxic T cell Key Stimulates Gives rise to

Fig Antigen- presenting cell Peptide antigen Cell-mediated immunity (attack on infected cells) Class II MHC molecule CD4 TCR (T cell receptor) Helper T cell Humoral immunity (secretion of antibodies by plasma cells) Cytotoxic T cell Cytokines B cell Bacterium The central role of helper T cells in humoral and cell-mediated immune response

Fig Cytotoxic T cell Perforin Granzymes TCR CD8 Class I MHC molecule Target cell Peptide antigen The killing action of cytotoxic T cells

Fig Cytotoxic T cell Perforin Granzymes TCR CD8 Class I MHC molecule Target cell Peptide antigen Pore The killing action of cytotoxic T cells

Fig Cytotoxic T cell Perforin Granzymes TCR CD8 Class I MHC molecule Target cell Peptide antigen Pore Released cytotoxic T cell Dying target cell ----A response to infected cells The killing action of cytotoxic T cells

Fig Antigen-presenting cell Endoplasmic reticulum of plasma cell Secreted antibody molecules Bacterium B cell Peptide antigen Class II MHC molecule TCR CD4 Helper T cell Activated helper T cell Cytokines Clone of memory B cells Clone of plasma cells 2 µm + B cell activation in the humoral immune response ----A response to extracellular pathogens

Fig Class of Immuno- globulin (Antibody) IgG (monomer) IgM (pentamer) J chain IgA (dimer) IgE (monomer) IgD (monomer) Trans- membrane region J chain Secretory component DistributionFunction First Ig class produced after initial exposure to antigen; then its concentration in the blood declines Promotes neutraliza- tion and cross- linking of antigens; very effective in complement system activation Present in secretions such as tears, saliva, mucus, and breast milk Only Ig class that crosses placenta, thus conferring passive immunity on fetus Triggers release from mast cells and basophils of hista- mine and other chemicals that cause allergic reactions Present primarily on surface of B cells that have not been exposed to antigens Acts as antigen receptor in the antigen-stimulated proliferation and differentiation of B cells (clonal selection) Most abundant Ig class in blood; also present in tissue fluids Promotes opsoniza- tion, neutralization, and cross-linking of antigens; less effec- tive in activation of complement system than IgM Provides localized defense of mucous membranes by cross-linking and neutralization of antigens Presence in breast milk confers passive immunity on nursing infant Present in blood at low concen- trations The five Ab, or immunoglobulin (Ig) classes

Fig a Distribution Class of Immuno- globulin (Antibody) IgM (pentamer) J chain First Ig class produced after initial exposure to antigen; then its concentration in the blood declines Promotes neutraliza- tion and cross- linking of antigens; very effective in complement system activation Function

Fig b DistributionFunction Class of Immuno- globulin (Antibody) IgG (monomer) Most abundant Ig class in blood; also present in tissue fluids Promotes opsoniza- tion, neutralization, and cross-linking of antigens; less effec- tive in activation of complement system than IgM Only Ig class that crosses placenta, thus conferring passive immunity on fetus

Fig c DistributionFunction Class of Immuno- globulin (Antibody) IgA (dimer) J chain Secretory component Present in secretions such as tears, saliva, mucus, and breast milk Provides localized defense of mucous membranes by cross-linking and neutralization of antigens Presence in breast milk confers passive immunity on nursing infant

Fig d DistributionFunction Class of Immuno- globulin (Antibody) IgE (monomer) Present in blood at low concen- trations Triggers release from mast cells and basophils of hista- mine and other chemicals that cause allergic reactions

Fig e DistributionFunction Class of Immuno- globulin (Antibody) IgD (monomer) Trans- membrane region Present primarily on surface of B cells that have not been exposed to antigens Acts as antigen receptor in the antigen-stimulated proliferation and differentiation of B cells (clonal selection)

Fig Viral neutralization Virus Opsonization Bacterium Macrophage Activation of complement system and pore formation Complement proteins Formation of membrane attack complex Flow of water and ions Pore Foreign cell Ab-mediated mechanisms of antigen disposal

Fig a Viral neutralization Virus

Fig b Opsonization Bacterium Macrophage

Fig c Activation of complement system and pore formation Complement proteins Formation of membrane attack complex Flow of water and ions Pore Foreign cell

Fig

Fig Allergen IgE Granule Mast cell Histamine Impact on public health hypersensitive : allergies Anaphylactic shock:epinephrine

Fig systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus multiple sclerosis Autoimmune diseases

Acquired immune system evasion by pathogens Inborn immunodeficiency –Severe combined immunodeficiency (SCID) – pneumonia and meningitis –Bone marrow and stem cell Antigenic variation Latency Herpes simplex viruses: typeI and II –Sensory neurons express relatively few MHCI molecules Attack on the immune system:HIV

Fig Weeks after infection Millions of parasites per mL of blood Antibodies to variant 1 appear Antibodies to variant 2 appear Antibodies to variant 3 appear Variant 3Variant 2Variant A change in epitope expression, which are called antigenic variation ---- sleeping sickness (trypanosomiasis)

Fig Latency Relative antibody concentration AIDS Helper T cell concentration in blood (cells/mm 3 ) Helper T cell concentration Relative HIV concentration Years after untreated infection