The Immune System

Biological mechanisms that defend an organism must be1. triggered by a stimulus upon injury or pathogen attack2. able to counteract the injury or invasion3. able to recognise foreign material, distinguish “self” from “non self”

Vertebrates have even more advanced immune systems that can4. recognise specific kinds of foreign material5. form a memory of previously encountered pathogens

These are classified as the Innate and Adaptive Immune Responses

Innate Immunity

Barriers exist for all external surfaces

Skin* cells are resistant to damage* physically difficult to penetrate* cells are constantly being replaced* coated with acidic secretions (pH 3-5)* sweat contains lysozyme which digest bacterial cell walls

Digestive Tract* saliva contains digestive enzymes* stomach contains hydrochloric acid and digestive enzymes

Innate Immunity

Respiratory and Urogenital tracts* mucous traps pathogens* cilia in the respiratory tract sweeps out mucous

Normal Flora* symbiotic microbes that normally live on our body* may prevent pathogens from seeking entry* usually beneficial

Blood Clotting* Platelets promote clotting to reinforces a breached surface

Innate Immunity

Barriers exist for all external surfaces

Barriers can be breached

Foreign invaders may enter * through damaged surfaces (eg. cuts to skin)* because they can survive in a harsh environment (eg. Hepatitis A through digestive tract)

Generic chemical signals produced by pathogens or damaged cells leads to a response from white blood cells, or leukocytes.

Innate Immunity

Hepatitis A Virus

Non-Specific Responders to Invasion

Neutrophils* phagocytose any foreign material at the invasion site* constitute 60-70% of all leukocytes

Macrophages* slower to arrive* larger and more effective at phagocytosis* release cytokines (WBC cytokine mediators are sometimes called interleukins)

Natural Killer (NK) Cells* attack virally infected or cancerous cells* release perforins that puncture membrane and burst cells

Innate Immunity

Innate Immunity

Aiding the Response

Complement* 20 types of protein* circulates blood and interstitial fluid

Complement System/Cascade* may attack the cell walls of bacterial or fungal cells (causing lysis)* may coat the foreign invader- “flagging” it for phagocytosis* stimulate the greater activity in phagocytes* recruit more leukocytes to the area

Innate Immunity

Managing the Response

Mast Cells* release histamine in response to complement activation* allergic (hypersensitivity) responses are caused by too much histamine being released

Inflammation* is initiated by histamine release and macrophage cytokine production* characterised by pain, heat, redness, swelling* symptoms are the result of increased blood flow and vascular permeability* the result is the greater recruitment of WBCs to the site of infection

Innate Immunity

Managing the Response

Fever* in addition to local inflammation a more extensive infection can trigger fever* leads to an elevated body temperature* increases the rate of phagocytosis* accelerates the actions of protein defenses* inhibits the growth of some pathogens.* speed up cellular repair by increasing the metabolic rate of cells

Fever is a broad response* it affects the whole body* severe, prolonged fever can damage host tissues.

Innate Immunity

Non-specific Viral Defense

Interferons* are proteins secreted by virally infected cells* signal healthy neighbouring cells to produce compounds that interfere with viral replication

Adaptive Immunity

When Innate Immunity Isn't Enough

Sometimes pathogens* exhibit resistance to innate immune mechanisms* multiply too rapidly to be overcome

Adaptive immune responses* target specific pathogens* are powerful and highly efficient

Adaptive Immunity

Identifying a Threat

Lymphocytes* are a special group of leukocytes* include B cells which develop in the bone marrow* include T cells which mature in the thymus* are found in the lymphatic system when they are not activated* each one expresses many receptor proteins on their cell surface

Recognition * Receptors recognise foreign material- typically a specific surface molecule on a pathogen* Recognition triggers lymphocyte activation* Any molecule that triggers this adaptive response is called an antigen

Adaptive Immunity

Receptor Specificity

Receptors* Possess a binding site that binds an antigen of a specific conformation* Any particular B or T cell will express receptors that bind a single antigen* In an individual vertebrate there are millions of lymphocytes each expressing receptors with a different binding site.

Question If only one, or a few, lymphocytes in an organism's body will recognise a specific antigen, how can these few cells mount an effective response?

B cell receptor T cell receptor

Adaptive Immunity: Clonal Selection

Generating the Responders

Clonal Selection * A lymphocyte receptor recognises an antigen * The lymphocyte undergoes rapid division* resulting in many daughter cells with identical receptors* Thus, only the cell with the correct receptor will be selected to produce clones.* The cells produced by clonal selection differentiate into different roles.

Exception: B cells must both recognise antigen and be activated by a helper T cell before being activated for division

Adaptive Immunity: Clonal Selection

NOTE: The clonal selection mechanism actually affects the lymphocyte receptors of both B cells and T cells

VCE textbooks only refer to clonal selection as a mechanism for generating antibody receptors in B cells.

Generating the Responders

Adaptive Immunity: Clonal Selection

B cell clones may differentiate into

B Plasma Cells* secrete antibodies into the blood, lymph, and interstitial fluid* these antibodies bind to the antigen (thereby coating the pathogen)* Humoral immunity refers to this process because it concerns the fluids, or “humors” of the body.

B Memory cells* do not participate in the immune attack* remain in the body * enable a more rapid response if the same antigen is encountered again

Adaptive Immunity

B Cell Receptors: Immunoglobulin Proteins

The antigen receptors of B cells belong to a family of proteins called immunoglobulins (Ig). Typically we refer to these as antibodies

Antibodies have* a Y shape* 2 identical, short chains* 2 identical long heavy chains

Classes* Antibodies come in different classes which have different effects* These include IgM, IgG, IgA, IgE

Each chain has both a constant region and a variable region. The variable regions contribute to the binding site.

Adaptive Immunity: Clonal Selection

T cell clones may differentiate into

T Helper Cells (TH)* activate B cells and the adaptive immune response* assist other WBCs in the immune response* release chemicals that can attract more WBCs to an infection site

Cytotoxic T Cells (TC)* destroy virally infected, or cancerous, host cells by apoptosis

T Memory Cells* do not participate in the immune attack* remain in the body * enable a more rapid response if the same antigen is encountered again

Cell-mediated immunity refers to T cells “mediating” an adaptive response

Adaptive Immunity

T Cell Receptors & MHC

T cell receptors can only recognise antigen that is “presented” by MHC marker molecules.

Found in most vertebrates, these marker molecules are encoded by a set of genes called the Major Histocompatibility Complex

MHC molecules are constantly in the process of binding short peptide fragments (8-10 amino acids) from the host cell and presenting them as antigen on the surface.

These peptide fragments come proteins the are digested in either the cytosol (MHC I) or in endocytic vesicles (MHC II)

Adaptive Immunity

MHC Presentation: Class I and Class II

* CD8 and CD4 refer to the receptors of TC cells and TH cells respectively

Adaptive Immunity

MHC Presentation: Class I and Class II

MHC Class I Molecules* are found on all nucleated cells* display peptide fragments* allow specific cytotoxic T cells to identify cells that are infected by intracellular microbes or viruses

MHC Class II molecules* are only expressed on professional Antigen Presenting Cells (APCs)* APCs travel to the lymph nodes to present their MHC-peptide structures* APCs include Dendritic cells, Macrophages, and B cells* Specific TH cells activate B cells via MHC II presentation

Dendritic cells

Thus, specific T cells can only be activated for clonal selection via TCR binding with an antigen

presenting MHC molecule (sometimes referred to as TCR MHC restriction). Once this has occurred, the adaptive immune response will properly begin.

Adaptive Immunity

T Cell Activation

Adaptive Immunity

Responding to Threat

APCs present antigen via MHC class II markers to T cells in lymph nodesT cells are activated and begin to divide and differentiate.

TC cell clones begin to attack infected cells expressing antigen via MHC class I markers

Memory T cell clones are generated

TH cell clones go looking for a B cell that has processed the same antigen

TH cells activate B cells via MHC II markers stimulating division

Memory B cell clones are generated

B plasma cell clones begin secreting antigen-specific antibodies

Antibodies bind antigen and coat (opsonise) the pathogen

Adaptive Immunity

Antibody Effects

Antibody binding may serve to* neutralise toxins (eg. Antivenoms)* prevent pathogens from binding at mucosal surfaces* increase vulnerability to phagocytes* activate complement* induce the release of cytoxic products from macrophages, NK cells, and eosinophils

Eosinophils

Thus the Adaptive Response also amplifies the Innate Response.

Adaptive Immunity

Measuring the Adaptive Immune Response

Antibody concentration reflects primary and secondary immune

responses to antigen

After first infection it takes about 2 weeks for antibodies to be generated

in significant levels.

After a second infection with the same antigen the adaptive immune response is swifter and more

pronounced.

Adaptive Immunity

Genetic Origins of Receptor Diversity

Question: Where does lymphocyte receptor diversity originate from?

Answer: Random DNA recombination of receptor genes in the lymphocytes as they develop in the bone marrow.

Question: Doesn't random recombination leads to the development of receptors that recognise self molecules?

Answer: Yes. When immature lymphocytes bind to normal self cells they either self-destruct or become permanently inactivated. It is estimated that as many as 90% of developing lymphocytes are eliminated this way before they can fully mature.