The Immune System
Overview: Reconnaissance, Recognition and Response
· Pathogens: infectious agents that cause disease
o An animal’s body offers nutrients, protection for growth and means of transportation
· Immune system: defense that allow an animal to avoid/limit infections
· Innate immunity: found in all animals
o Responses are active immediately upon infection and are the same whether or not the pathogen has been encountered previously
o Includes barrier defenses (skin), defenses that combat pathogens after they enter the body
· Acquired immunity: adaptive immunity
o Active after innate immune defenses take effect, develop more slowly
o Synthesis of proteins that inactive bacterial toxin, targeted killing of a virally infected body cell
43.1: Innate immunity: recognition and response rely on shared traits of pathogens
Innate Immunity of Invertebrates
· Invertebrates rely only innate immunity
o Insects rely on their exoskeleton as defense against infection
§ Lysozyme: enzyme that digest microbial cell walls
§ Low pH
§ Hemocyte: immune cells that circulate within the hemolymph, carry out
· Phagocytosis: ingestion and digestion of bacteria and other foreign substances
· Trigger production of chemicals that kill microbes/entrap parasites
· Antimicrobial peptides: inactivate/kill fungi and bacteria by disrupting their plasma membranes
o Insect immune cells secrete specialized recognition proteins, which bind to the macromolecules on invaders
Innate Immunity of Vertebrates
Barrier defenses
· Mammals
o Epithelial tissues block entry of pathogens – skin + mucous membranes lining the digestive, respiratory, urinary and reproductive tracts
§ Mucus: viscous fluid that enhances defenses by trapping microbes
· Ciliated epithelial cells sweep mucus and microbes upward, preventing infection of lungs
§ Saliva, ears, mucous secretions
· Saliva contains lysozyme
Cellular innate defenses
· Pathogens that get into the body encounter leukocytes (WBC)
· Toll-like receptor (TLR): recognizes fragments of molecules characteristic of a set of pathogens
o Recognition triggers a series of defenses, starting with phagocytosis
§ WBC engulfs the invading microbes, trapping them in a vacuole—fuses with a lysosome
· Neutrophils: most abundant phagocytic cells in the mammalian body; attracted by signals from infected tissues
· Macrophages: seen in spleen, lymph nodes; really large and can trap larger microbes
· Eosinophils: defend against multicellular invaders (parasitic worms); discharge destructive enzymes that damage invader
· Dendritic cells: populate tissues, stimulate development of acquired immunity against microbes
^The human lymphatic system
Made up of the lymphatic vessels, adenoids, tonsils, lymph nodes, spleen, Peyer’s patches and appendix
Antimicrobial Peptides and Proteins
· Interferons: proteins that provide innate defense against viral infections
o Virus-infected body cells secrete interferons, inducing uninfected cells to produce substances that inhibit viral reproduction
o Limit cell-to-cell spread of viruses, controlling viral infections like colds/flu
· Complement system: 30 proteins in blood plasma
o Circulate in an inactive state and are activated by substances on the surface of microbes
o Activation results in an influx of biochemical reactions leading to the lysis of invading cells
o Inflammation
Inflammatory Responses
· Inflammatory response: changes brought about by signaling molecules released upon injury
· Histamine: inflammatory signally molecule, stored in mast cells, connective tissues cells that store chemicals in granules fore secretion
o Histamine released by mast cells @ sites of damage triggers blood vessels to dilate and become more permeable
o Macrophages discharge additional signally molecules that promote blood flow to the injured site
o Increase in local blood supply causes redness and heat of inflammation
· Cycles of signaling and response transform the infection site
o Enhanced blood flow = antimicrobial proteins
o Activated complement proteins = release of histamine and help attract phagocytes
o Endothelial cells secrete signaling molecules = attract neutrophils and macrophages
o Pus: fluid rich in white blood cells, dead microbes and cell debris
· Major damage may lead to a response that’s systemic (throughout the whole body) – increased production of WBC
· Fever: systemic inflammatory response
o Pyrogens: released by macrophages, reset body’s thermostat to higher temp
o Fevers accelerate tissue repair by speeding up chemical reactions?
· Septic shock: life-threatening condition: high fever, low blood flow, low BP
Natural Killer cells
· Natural Killer (NK) Cells: help recognize and eliminate certain diseased cells
o Patrol body, attach to sick cells and release chemicals that lead to cell death
Innate Immune system evasion by pathogens
· Pathogens have evolved in order to avoid destruction by phagocytic cells
o Aren’t recognized by , prevent destruction, resistance to breakdown within lysosomes following phagocytosis (Tuberculosis)
43.2: Acquired Immunity: Lymphocyte receptors provide pathogen-specific recognition
Bunch of Vocab
· Lymphocyte: B cells and T cells, types of WBC, critical for acquired immune defense
· Thymus: an organ in the thoracic cavity above the heart that houses the T Cells
· B Cells: mature in the bone marrow
· B&T Cells recognize and inactivate foreign cells and molecules, contribute to
· Immunological memory: enhanced response to foreign molecule encountered previously
o responsible for the protection we obtain against chicken pox
o B&T cells only function in acquired immunity, but the two systems aren’t independent
§ Signally molecules of phagocytic cells set the stage for acquired immunity
§ Cytokines: proteins secreted by phagocytic cells that help recruit and activate lymphocytes
Acquired Immunity: An overview
· “Each B cell or T cell has on its surface many receptor proteins that can bind to particular foreign molecule. The receptor proteins on a single lymphocyte are all the same, but there are millions of lymphocytes in the body that differ in the foreign molecules that their receptors recognize. When an animal is infected, B and T cells with receptors that can recognize the microbe are activated […] B and T cells interact with fragments of microbes displayed on the surface of cells. Activated lymphocytes undergo cell division […] Some T cells assist in activated other lymphocytes. Other T cells detect and kill infected host cells. Specialized B cells secrete soluble receptor proteins that attack foreign molecules and cells” (936).
Antigen Recognition by Lymphocytes
· Antigen: a foreign molecule that is specifically recognized by lymphocytes and elicits a response
o Most are large molecules, either proteins or polysaccharides
o Some are toxins secreted by bacteria
· B and T cells recognize antigens using their antigen-specific receptors embedded in their plasma membranes
· A single B or T cell has about 100,000 antigen receptors on its surface
o Sometimes B cells give rise to plasma cells that secrete a soluble form of the antigen receptor, the antibody or immunoglobulin (Ig).
· Epitope: antigenic determinant, a small accessible portion of an antigen
· All of the receptors on a single lymphocyte recognize the same epitope; each of the body’s lymphocytes displays specificity for a particular epitope
Antigen Receptors of B cells and T cells
· B cell receptor for an antigen is a Y-shaped molecule consisting of four polypeptide chains
o Two identical heavy chains
o Two identical light chains
o With two disulfide bridges linking the chains together
o The light and heavy chains have a constant (C) region: amino acid sequences vary little among the receptors, includes the cytoplasmic tail and transmembrane region of the heavy chain and all the disulfide bridges
o Variable (V) region: two tips of the Y shape, amino acid sequence varies from one B cell to the other
o Antibodies have the same overall recognition as B cell receptors except they lack the transmembrane region and cytoplasmic tail
· T cell receptor: consists of two different polypeptide chains: a chain and b chain, linked by disulfide bridge
o Have as many features as the B cell receptors
o Tip of the molecule = V region: antigen binding site
o Rest of the molecule = C region
· B cell receptors recognize and bind to an intact antigen whether it is free or bound to a pathogen ; T cell receptors bind only to antigen fragments that are displayed on the surface of host cells
· Major histocompatibility complex (MHC): genes in a group , produces a host cell protein that can present an antigen fragment to a T cell receptor
The Role of the MHC
· Antigen presentation: display of the antigen fragment on the cell surface
o By MHC proteins either activates immune responses against the antigen or target destruction of the infected cell
· Class I MHC molecules:
o found in almost all cells of the body
o bind to peptide fragments of foreign antigens synthesized within cells
o recognized by cytotoxic T cells (kill by toxic gene products)
· Class II MHC molecules: made by just a few cell types—dendritic cells, macrophages, B cells
o bind to antigen fragments derived from foreign materials that have internalized through phagocytosis/endocytosis
o antigen-presenting cells: dendritic cells, macrophages and B cells because of their key role in displaying internalized antigens
o recognized by cytotoxic T cells and helper T cells: a group of T cells that assist both B cells and cytotoxic T cells
Lymphocyte Development
· Major properties of acquired immune system
o Diversity of receptors ensures that new pathogens are recognized as foreign
o Ability to recognize vast numbers of foreign molecules coexist with a lack of reactivity against body’s own molecules
o Response to antigen that has been encountered previously is stronger (immunological memory)
Generation of Lymphocyte Diversity by Gene rearrangement
· Differences in amino acid sequences of V regions make antigen receptors extremely different
· Each person has 1 million + different B cells and 10 million + different T cells
· Understanding the origin of receptor diversity
o Immunoglobulin (Ig) gene that encodes the light chain of secreted antibodies and membrane-bound B cell receptors
§ Joins randomly selected V and J gene segments
§ Undergoes transcription, splicing and translation
Origin of Self-Tolerance
· Lymphocytes mature in the bone marrow of thymus; tested for self-reactivity
o The ones that try to destroy the body’s own cell are destroyed by apoptosis or rendered nonfunctional
o Body lacks mature lymphocytes that react against its own components
Amplifying Lymphocytes by Clonal Slection
· It is rare for an antigen to encounter a lymphocyte with a specific for that antigen; acquired immune response is effective because of the changes in cell number and behavior triggered by the binding of the antigen to the lymphocyte
· Binding of an antigen receptor
o B cells or T cells amplify by dividing many times, forming two different types of clones
§ Effector cells: short lived, attack antigen and any pathogens producing the antigen
§ Memory cells: long lived, less numerous, bear receptors specific for the antigen
o Clonal selection: proliferation of a lymphocyte into a clone of cells in response to binding an antigen
§ The presentation of an antigen to specific receptors on a lymphocyte leads to repeated rounds of cell division
§ Result? Clonal population of thousands of cells, specific to that antigen
· Primary immune response: first exposure to an antigen, peaks about 10-17 days after initial exposure
o B cells generate plasma cells, antibody secreting effector cells
o T cells activated to their effector forms (helper cells and cytotoxic cells)
· Secondary immune response: repeated exposure to the same antigen, faster response and of greater magnitude
o Relies on the reservoir of T and B memory cells generated after the initial exposure
§ Long-lived cells = provide immunological memory that can span many decades
43.3: Acquired immunity defends against infection of body cells and fluids
Overview
· Humoral immune response: activation and clonal selection of effector B cells- which secrete antibodies that circulate in the blood and lymph
· Cell-mediated immune response: activation and clonal selection of cytotoxic T cells- which identify and destroy target cells
Helper T Cells: Response to nearly all antigens
· Helper T cells are activated by encounters with antigen-presenting cells
· Cell proliferates after interacting with antigen fragments displayed by antigen-presenting cells
· Activated helper T cells secrete cytokines that stimulate activation of nearby B cells and cytotoxic T cells
· CD4: protein found on the surface of most helper T cells, binds to class II MHC molecule
o Keep the helper T cell and antigen-presenting cell joined
· Dendritic cells are particularly important in triggering primary immune response
o Serve as messengers, capture antigens, migrate to the lymphoid tissues
Cytotoxic T Cells: Response to Infected Cells
· Effector cells in cell-mediated immune response
· Require signaling from helper T cells to become active, as well as interaction with an anti-gen presenting cell
· CD8: protein found on most cytotoxic T cells, enhances interaction between target cell and T cell
· Destruction involves the secretion of proteins that cause cell rupture and cell death
o Exposes pathogen to circulating antibodies
· Dendritic cell can present fragments from a wide variety of protein antigens, whereas B cells only present only to the antigen to which it binds
Antibody classes
· Monoclonal antibodies: prepared from a single clone of B cells grown in culture – identical and specific for the same epitope on an antigen – useful for tagging specific molecules
The Role of Antibodies in Immunity
· Neutralization: antibodies bind to the surface proteins of a virus or bacterium, blocking the pathogen’s ability to infect a host cell
· Opsonization: antibodies bound to antigens present readily recognized structure for macrophages and increase phagocytosis
· Complement: proteins increase the effectiveness of antibody directed attacks on bacteria