IMMUNITY Chapter 35

IMMUNE SYSTEM Immune System ◦ Enables an animal to avoid or limit many infections ◦ 2 types of immunity  Innate  Non specific responses to pathogens  Consists of external barriers plus internal cellular and chemical defenses  Adaptive  Develops after exposure to agents  Requires a very specific response to pathogens

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

Innate Barrier Defenses Barriers at body surfaces ◦ Intact skin ◦ Mucus membranes  Traps and allows removal of microbes  Prevents colonization ◦ Lysozyme  Break down bacterial cell walls  Tear / Saliva ◦ Low pH

Barriers at Body Surface

Innate Cellular Defenses Nonspecific Responses ◦ Lymph nodes ◦ Types of phagocytic cells  Neutrophills  Circulate in the blood  Attracted by signals from infected tissues  Macrophages  Found throughout the body

 Dendritic cells  Stimulate development of adaptive immunity in cells that contact the environment  Eosinophils  Discharge destructive enzymes beneath mucus surfaces  Natural Killer cells (NK)  Circulate through body and detect abnormal cells  Release chemicals leading to cell death  Inhibit the spread of virally infected or cancerous cells Innate Cellular Defenses

Antimicrobial Peptides and Proteins ◦ pathogen recognition triggers release of peptides and proteins that attack pathogens or impede their reproduction  Interferons  provide innate defense, interfering with viruses and helping activate macrophages  Complement system  consists of about 30 proteins that are activated by substances on microbe surfaces ◦ Activation can lead to lysis of invading cells Innate Cellular Defenses

neutrophil mast cell T lymphocyte B lymphocyte basophileosinophil NK cell Cells Involved in Immune Responses

dendritic cell macrophage

Chemical Weapons in Immunity

Inflammatory Response ◦ Purpose  Destroys invaders  removes debris  promotes healing ◦ Mast cells release histamine  Enhanced blood flow to the site helps deliver antimicrobial peptides  This results in an accumulation of pus, a fluid rich in white blood cells, dead pathogens, and cell debris from damaged tissues Innate Cellular Defenses

Pathogen Splinter Macro- phage Capillary Neutrophil Red blood cells Mast cell Signaling molecules 1 Histamines and cytokines released. Capillaries dilate.

Pathogen Splinter Macro- phage Capillary Neutrophil Red blood cells Mast cell Signaling molecules 1 Histamines and cytokines released. Capillaries dilate. Movement of fluid Antimicrobial peptides enter tissue. Neutrophils are recruited. 2

Pathogen Splinter Macro- phage Capillary Neutrophil Red blood cells Mast cell Signaling molecules 1 Histamines and cytokines released. Capillaries dilate. Movement of fluid 2 Antimicrobial peptides enter tissue. Neutrophils are recruited. Phagocytosis 3 Neutrophils digest pathogens and cell debris. Tissue heals.

Adaptive Immunity The adaptive response relies ◦ Lymphocytes  mature in the thymus  T cells  mature in the bone marrow  B cells ◦ white blood cells

Antigen receptors Mature B cell Mature T cell

Antigens ◦ substances that can elicit a response from a B or T cell Recognition occurs when a B or T cell binds to an antigen, via an antigen receptor Epitope ◦ accessible part of an antigen that binds to an antigen receptor

Antigen Recognition by B Cells and Antibodies Each B cell antigen receptor is a Y-shaped molecule The constant (C) regions of the chains vary little among B cells, whereas the variable (V) regions differ greatly

Antigen- binding site B cell antigen receptor Disulfide bridge Light chain Antigen- binding site Variable regions Constant regions Transmembrane regions Plasma membrane Heavy chains Cytoplasm of B cell B cell V V C C C C V V

Binding of a B cell antigen receptor to an antigen is an early step in B cell activation This gives rise to cells that secrete a soluble form of the protein called an antibody or immunoglobulin (Ig) Secreted antibodies are similar to B cell receptors but are not membrane bound The antibodies, rather than B cells themselves, defend against pathogens

Animation: Antibodies Right click slide / Select play

5 Classes of Immunoglobulins IgG ◦ found in blood plasma ◦ all body fluids ◦ smallest but most common ◦ primary and secondary response IgA ◦ found in your nose, digestive tract, ears, eyes ◦ protects mucous membranes  saliva, mucus tears, breast milk

5 Classes of Immunoglobulins IgM ◦ found in the blood and lymph ◦ used to fight a new infection ◦ causes clumping of antigens, transfusion reactions IgE ◦ found in your lungs, skin ◦ responsible for allergic reactions IgD ◦ found in your stomach, chest ◦ very small amount

5 Classes of Immunoglobulins IgG, IgD, and IgEIgAIgM

Antigen- receptor Antibody B cell Antigen Epitope Pathogen (a) B cell antigen receptors and antibodies Antibody C Antibody A Antibody B Antigen (b) Antigen receptor specificity

Each T cell receptor consists of two different polypeptide chains (called  and  ) The tips of the chain form a variable (V) region; the rest is a constant (C) region The V regions of the a and b chains together form an antigen-binding site Antigen Recognition by T Cells

Antigen- binding site T cell antigen receptor Disulfide bridge T cell Cytoplasm of T cell  chain  chain Variable regions Constant regions Transmembrane region Plasma membrane VV CC

In infected cells, antigens are cleaved into smaller peptides by enzymes T cells bind only to antigen fragments displayed or presented on a host cell ◦ MHC (major histocompatibility complex)  MHC molecules bind and transport the antigen fragments to the cell surface, a process called antigen presentation This interaction is necessary for the T cell to participate in the adaptive immune response Antigen Recognition by T Cells

Host cell Displayed antigen fragment MHC molecule Antigen fragment Pathogen T cell T cell antigen receptor

B Cell and T Cell Development The adaptive immune system has four major characteristics ◦ Diversity of lymphocytes and receptors ◦ Self-tolerance; lack of reactivity against an animal’s own molecules ◦ Proliferation of B and T cells after activation ◦ Immunological memory

Generation of B and T Cell Diversity By combining variable elements, the immune system assembles a diverse variety of antigen receptors The capacity to generate diversity is built into the structure of Ig genes Many different chains can be produced from the same gene by rearrangement of the DNA Rearranged DNA is transcribed and translated and the antigen receptor formed

DNA of undifferentiated B cell V 39 V 38 V 40 V 37 J5J5 J4J4 J3J3 J2J2 J1J1 Intron DNA of differentiated B cell pre-mRNA Transcription of permanently rearranged, functional gene Recombination deletes DNA between randomly selected V segment and J segment Functional gene C V 39 V 38 V 37 J5J5 Intron C C V 39 J5J5 21

pre-mRNA Intron C V 39 J5J5 mRNA RNA processing C Cap V 39 J5J5 Poly-A tail Translation Light-chain polypeptide Variable region Constant region B cell Antigen receptor V C V V V V C C C C 43

Proliferation of B Cells and T Cells In the body only a tiny fraction of antigen receptors are specific for a given epitope In the lymph nodes, an antigen is exposed to a steady stream of lymphocytes until a match is made This binding of a mature lymphocyte to an antigen initiates events that activate the lymphocyte

Once activated, a B or T cell undergoes multiple cell divisions to produce a clone of identical cells (called clonal selection) Two types of clones are produced ◦ effector cells  short lived  act immediately against the antigen ◦ memory cells  long lived  can give rise to effector cells if the same antigen is encountered again Proliferation of B Cells and T Cells

Animation: Role of B Cells Right click slide / Select play

Immunological memory is responsible for long-term protections against diseases, due to a prior infection primary immune response ◦ first exposure to a specific antigen represents the selected B and T cells give rise to their effector forms and memory forms secondary immune response ◦ memory cells facilitate a faster, stronger, and longer response Immunological memory can span many decades Immunological Memory

Primary and Secondary Immune Response

humoral immune response ◦ antibodies help neutralize or eliminate toxins and pathogens in the blood and lymph cell-mediated immune response ◦ specialized T cells destroy infected host cells Humoral vs Cell-Mediated

Helper T Cells: A Response to Nearly All Antigens A type of T cell called a helper T cell triggers both the humoral and cell-mediated immune responses ◦ Antigen-presenting cells are recognized by the helper T cells ◦ Signals are then exchanged between the two cells ◦ The helper T cell is activated, proliferates, and forms a clone of helper T cells, which then activate the appropriate B cells

Animation: Helper T Cells Right click slide / Select play

Antigen- presenting cell Antigen fragment Class II MHC molecule Accessory protein (CD4) Antigen receptor Helper T cell Pathogen Cytokines B cell Cytotoxic T cell Cell-mediated immunity Humoral immunity

Cytotoxic T Cells: A Response to Infected Cells Cytotoxic T cells ◦ effector cells in the cell-mediated immune response ◦ recognize fragments of foreign proteins produced by infected cells ◦ secretes proteins that disrupt the membranes of target cells and trigger apoptosis

Animation: Cytotoxic T Cells Right click slide / Select play

Antigen fragment Class I MHC molecule Accessory protein Antigen receptor Cytotoxic T cell Infected cell 1

Antigen fragment Class I MHC molecule Accessory protein Antigen receptor Cytotoxic T cell Infected cell 1 Pore 2 Perforin Granzymes

Antigen fragment Class I MHC molecule Accessory protein Antigen receptor Cytotoxic T cell Infected cell 1 Pore 2 Perforin Granzymes Released cytotoxic T cell Dying infected cell 3

B Cells and Antibodies: A Response to Extracellular Pathogens The humoral response is characterized by secretion of antibodies by clonally selected B cells Activation of B cells involves helper T cells and proteins on the surface of pathogens In response to cytokines from helper T cells and an antigen, a B cell proliferates and differentiates into memory B cells and antibody-secreting effector cells called plasma cells

Helper T cell Antigen fragments Pathogen CD4 Antigen- presenting cell Antigen receptor 1 MHC

Helper T cell Antigen fragments Pathogen CD4 Antigen- presenting cell Antigen receptor MHC B cell Cytokines Activated helper T cell 2 1

Helper T cell Antigen fragments Pathogen CD4 Antigen- presenting cell Antigen receptor MHC B cell Cytokines Activated helper T cell Plasma cells Secreted antibodies Memory B cells

Antibodies do not kill pathogens; instead, they mark pathogens for destruction In neutralization, antibodies bind to viral surface proteins, preventing infection of a host cell Antibodies may also bind to toxins in body fluids and prevent them from entering body cells Antigen-antibody complexes may bind to a complement protein ◦ A cascade of subsequent events leads to formation of a pore in the membrane of the foreign cell, leading to its lysis

Animation: Immunology

B cell Helper T cell Antigen- presenting cell Engulfed by Antigen (1st exposure) Humoral (antibody-mediated) immune response Cell-mediated immune response Key Stimulates Gives rise to Cytotoxic T cell Memory helper T cell Memory cytotoxic T cells Memory B cells Antigen (2nd exposure) Active cytotoxic T cells Defend against intracellular pathogens and cancer Defend against extracellular pathogens Plasma cells Secreted antibodies

Autoimmune Disorders Immune system makes antibodies against self antigens Grave’s disease ◦ hyperthyroidism Myasthenia gravis ◦ body produces antibodies that prevent muscles from receiving message from nerve cell Type I Diabetes Celiacs ◦ Villi becomes damaged due to gluten

Active and Passive Immunization Active immunity ◦ occurs naturally when a pathogen infects the body ◦ induced when antigens are introduced into the body in vaccines Passive immunity ◦ provides immediate, short-term protection ◦ naturally when antibodies cross the placenta from mother to fetus or pass from mother to infant in breast milk ◦ conferred artificially by injecting antibodies into a nonimmune person