Immunology - Notes from Year 1 PDF

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IMMUNOLOGY    

Explain the importance of immunology for human health Outline the basic principles of immune responses, and the timescales in which they occur Define the terms antigen, antibody, B lymphocyte, T lymphocyte, primary and secondary immune response, innate and acquired immunity Outline the role of clonal selection in immune response

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Understand the roles of natural selection and the physical organization of the immune system in its function

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Immunology and human health Function: to identify and eliminate harmful microorganisms and substances like toxins  either by distinguishing ‘self’ from ‘non-self’ or by identifying ‘danger’ signals or both  has to strike balance between immunopathology (accidental damage to host) and clearing the pathogen. Problems if immune system malfunction: Persistent/fatal infection Transplant rejection Autoimmune disease Allergies Evolutionary ‘arms race’ between host and pathogen Both exert selection on each other  most polymorphic human genes (HLA, KIR) were selected by infectious diseases as they control the immune response Pathogen replicates faster (bacteria in minutes, viruses in hours and humans in years) Therefore, the host has to rely on a fast and effective immune response. Primary immune response timescale: innate  acquired 0-4 days: Type 1 interferon 0-6 days: Natural killer cells 2-12 days: Cytotoxic T lymphocytes After 4 days: Antibodies INNATE: early phase of the body’s response to pathogens characterized by non-specific mechanisms (barriers, acids, enzymes) and pattern recognition molecules that recognize repeating patterns of molecular structure (danger) on microorganism surfaces. It depends on pre-formed cells and is fast. No memory. Anatomical Barriers Skin - mechanical Mucus – traps microbes Cilia - propulsion on epithelia Physiological Barriers Low pH - acidity of stomach Lysozyme secretion - cleaves peptidoglycan layer of the bacterial cell wall) Interferons – group of proteins produced by virus-infected cells that induce a generalized antiviral state in nearby cells Antimicrobial peptides Complement proteins – group of serum proteins that circulate in an inactive state. They punch holes in bacteria by making membrane attack complexes, opsonization (enhance antigen phagocytosis as opsonins bind

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to both antigen and lymphocyte), chemotaxis (attracting neutrophils and macrophages by releasing anaphylatoxins) and agglutination (clumpling of antigen-bearing cells) Macrophages – engulfs pathogen  lysosome destroys them + releases cytokines which alert monocytes and other immune system cells (acts as a messenger between cells) Natural killer cells – destroys bacteria, parasites, virus-infected cells, cancer cells + release complement proteins which punch holes in bacteria Neutrophils (multilobed nucleus, stains with both acid and basic dyes) – release acute-phase proteins which destroy/inhibit microbe growth, direct microbes to phagocytes, give negative feedback on inflammation and stimulate coagulation factors so microbes can be trapped in blood clots. Purpose: buys time while acquired immune system mobilizes and stimulates acquired immune system through release of cytokines and complement proteins. Intracellular detection of viruses: pathogen-associated molecular patterns (PAMPs) are found on viruses  bind to receptors on the cell surface/cytoplasm (toll-like receptors, rig-I-like receptors, nucleotide binding domain, leu-rich repeat containing proteins, C-type lectin receptors) which vary according to cell type  elicits a signaling cascade which makes interferon type 1 and 3  make enzymes that degrade viral nucleic acids and retroviral restriction factors Acute phase inflammatory response to tissue damage: body temperature rises (fever) followed by production of proteins like C-reactive protein, serum-binding protein (bind to fungi and bacterial cell walls) and mannan-binding lectin (bind to mannose sugar molecules not found in mammalian cells to activate the complement cascade) by the liver = acute phase proteins. ACQUIRED: response of antigen-specific lymphocytes to foreign antigens. Magnitude increases with repeated exposure to the pathogen so products are highly specific to the potential pathogen. It depends on clonal selection, requires priming and is slow. Shows immunological memory. Capable of self-nonself recognition so the immune system only responds to foreign antigens. Antigens: molecules which react with antibodies or T cells but only some can react (immunogens) Antibody: immunoglobin molecules found in the blood stream, body fluids which bind to specific antigens and are part of the acquired component of the humoral immune response. Has a heavy and light chain. Constant region of the heavy chain on an antibody determines class and function. IgG (gamma globulin) – 75% of serum immunoglobulin, crosses placenta, long halflife (3 weeks), part of secondary immune response, has subclasses, involved in antibody-dependent cellular cytotoxicity in NK cells, can neutralize viruses, bivalent (2 binding sites) IgM – 10% of total, star-like shape with 10 binding sites, important in primary response, can activate the complement cascade, can bind to viruses to neutralize them, ‘first’ antibody produced IgA – found in body secretions like mucus, contains a secretory component that protects it from digestive enzymes and facilitates transport across the intestinal wall, prevents pathogens attaching to intestinal walls, four binding sites, involved in agglutination, secreted in milk as it can coat baby’s intestinal mucosa, cannot activate complements as constant region does not bind to C1. IgE – allergic response, binds to basophils and mast cells, triggers release of histamines, required for parasitic infections, causes anaphylactic shock IgD – antibody function not known, same heavy chain mRNA used to make IgM and IgD but spliced differently.

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Antibody recognizes an antigen because the antibody binding site fits perfectly with the epitope on the antigen  antigens are taken up by specialized APC (dendritic, macrophage and B lymphocyte) and transported from tissues to secondary lymphoid organs Antibodies and viruses Binds to virus to prevent attachment Opsonization: virus-Ab complex is phagocytosed by macrophages Complement-mediated lysis of enveloped viruses ADCC by NK cells Lymphocytes: mononuclear cells part of the leukocyte cell lineage  subdivided into thymus derived and bone marrow-derived cells with distinct surface molecules  precursors produced in haematopoietic tissue  express antigen receptors on surface to enable recognition Naïve lymphocytes: never encountered their specific antigen so have never responded, polyclonal Memory lymphocytes: products of an immune response enabling their specific receptor to remain the lymphocyte pool iFn the body Helper T-cell: supplies co-stimulatory signal to naïve B-cell and activates cytotoxic T cells and macrophages, express CD4 protein on surface, two chain (alpha and beta) antigen receptor (TCR) which binds digested antigen fragments TCR: recognizes complex of antigen peptide + human leukocyte antigens (major histocompatibility complex) which displays intracellular proteins on surface for immune surveillance Cytotoxic T-cell: destroyed virus-infected cells, cancer cells and transplant rejection by injecting lethal enzymes like perforin, express CD8 protein on surface, binds to antigens associated with MHC Class I B-cells: makes antibodies, acts as an APC and develops B memory cells, binds intact antigens on a surface immunoglobulin Dendritic cells: initiate immune response by activating virgin T cells Eosinophils: bilobed nucleus, granulated cytoplasm, stains with acid dye eosin red, phagocytic, secrete contents of eosinophilic granules that can damage parasite membranes. Basophils/mast cell: lobed nucleus, heavily granulated cytoplasm, stains with basic dye methylene blue, nonphagocytic, release pharmacologically active substances from granules that play a major role in allergic responses. Clonal diversity: random genetic recombinations in immunoglobulin genes or TCR genes  clone diversity of lymphocytes  specific to a different antigen  only lymphocytes that meet an antigen will proliferate and huge majority dies out  antigen binds to surface receptor on B or T cells  selective expansion of that clone  most die after function but some remain as memory cells Primary lymphoid organs: thymus and bone marrow Secondary lymphoid organs: lymph nodes, spleen, mucosa-associated lymphoid tissue Lymphocytes and APC recirculate through lymphatic vessels from tissues via lymph nodes or spleen into the blood  physical organization of immune system is important for function. EXAMPLES Skin has lymphatic vessels that drain into local lymph nodes Gut lymphoid tissue controls responses in intestinal tract Antigens in blood are taken to spleen Natural selection in the immune system reduces diversity whereas in Darwinian evolution, natural selection creates diversity

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Primary response: naïve lymphocytes are activated by antigen  few lymphocytes with the appropriate receptor remains as memory lymphocytes.  Secondary response: more effective than the primary response due to greater magnitude and more rapid onset.

IMMUNE CELLS AND ORGANS      

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Name the primary & secondary lymphoid organs and briefly differentiate between their functions Draw simple diagrams to illustrate the structure of the thymus, lymph node, spleen, Peyer’s patch, and indicate the changes that occur after stimulation by antigen. Outline the re-circulation of lymphocytes Explain the use of CD markers for discrimination between lymphocytes Compare and contrast phenotypic characteristics of B and T cells Give examples of antigen presenting cells and their locations

Primary lymphoid organs: where lymphocytes are produced  LYMPHOPOEISIS Provide appropriate microenvironments for the development and maturation of lymphocytes Lymphoid stem cells differentiate into mature functional lymphocytes Organs: bone marrow (where B and T cells are made) and thymus (T cells receive early training here)  Secondary lymphoid organs: where lymphocytes can interact with antigen, other lymphocytes and APCs. Organs: spleen, lymph nodes, mucosal associated lymphoid tissue (MALT) All have lymphoid follicles which are critical for the adaptive immune system to function  they are specialized regions of secondary lymphoid organs in which B cells percolate through a lattice of follicular dendritic cells that have captured opsonized antigen on their surface. B cells that encounter their cognate antigen and receive T cell help are rescued from death and these B cells undergo proliferation, somatic hypermutation and class switching. Follicular dendritic cells: express high levels of membrane receptors for antibody which allows efficient binding of antigen-antibody complexes All have high endothelial venules: B and T cells enter secondary lymphoid organs through HEVs from the blood  high endothelial venules is a special region in a small blood vessel where there are high endothelial cells (simple cuboidal epithelia rather than simple squamous epithelia like normal endothelium) with enough space in between for lymphocytes to pass through THYMUS:  Lies beneath the sternum in the middle of the chest Same level as the heart

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Pyramidal shape Divided into two lobes that separate at the body’s mid-line Consists of lymphocytes, a few macrophages and epithelio-reticular cells Can be divided into a central medulla and a peripheral cortex Made up of many lobules (each lobule has an outer cortex and inner medulla) separated by connective tissue septa (interlobular septum) called trabecula Thymic corpuscle (Hassall’s corpuscle): found in the medulla of the human thymus formed from concentric layers of degenerating epithelial cells Cortex: contains immature thymocytes Medulla: some thymocytes are selected from the cortex to become mature thymocytes in the medulla No change in thymus structure during infection Only a small % of cells leave the thymus into the peripheral T cell pool  lots of cell death Thymus atrophies with age: significant decrease in cortical and medullary cells and adipose tissue replace areas of active T cell production.  BONE MARROW Site of haematopoeisis + fat depot Foetus (all bones, liver/spleen, very cellular marrow)  Adult (mostly flat bones, vertebrae, Iliac bones, ribs, ends of long limb bones, marrow and fat) In the foetus, the liver is active prior to most bones becoming active sites of production  later life, active sites include spongy regions at the end of long bones, vertebral bones, sternum, ribs, flat bones of the cranium and pelvis. Bone marrow  stem cells + B lymphocytes (stem cells migrate towards thymus to become T lymphocytes) B cells: centripetal with stem cells under the bone, most mature phases found nearer the marrow centre

Longitudinal artery Venous sinuses

Longitudinal vein

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Lymphatic System: fluid drained from between tissue cells absorbed into the lymph (2-3L returned every day to circulation via superior vena cava) LYMPH NODE  1-15 mm across Round/Kidney shaped Structure: indentation at hilus where blood vessels enter and leave the node, lymph arrives through afferent vessels and leaves through efferent vessels at the hilus. Cortex = B cell area Paracortex = T cell area (separation between cell types is a general feature of secondary lymphoid tissue) Germinal centres: primary lymphoid follicles  secondary lymphoid follicles with a germinal centre containing macrophages, dendritic cells and some T cells that migrate from the paracortex  it is where B cells proliferate into antibody secreting plasma cells as macrophages and dendritic cells trap antigens and present them to B cells  B cells exit via the lymph  some become plasma cells in spleen or bone marrow to make antibodies whereas others recirculate through lymph and reenter secondary lymphoid organs to be restimulated by follicles. B and T cells can enter through the HEVs or through lymph BUT can only exit via the lymph Lymph enters node  percolates through holes in marginal sinus  goes through cortex, paracortex and medullary sinus  exits the node through efferent vessels How antigen enters the lymph nodes: 1. Dendritic cells are signaled to the node  bring antigen with them into the secondary lymphoid organs 2. Antigen opsonized by complement or antibodies can be carried by the lymph into the node  captured by follicular dendritic cells for display to B cells Lymph nodes are highly organized with specific areas for APCs, T lymphocytes and B lymphocytes  movement of immune system cells through the node is orchestrated by the up-and-down regulation of chemokine (chemoattractive cytokines) receptors and the localized production of chemokines that can be detected by these receptors (FDC produce chemokines, B cells and T cells up-regulate expression of the particular chemokine receptor) Function: lymph nodes are where lymphocytes find their cognate antigen, particulate antigens are removed from lymph by phagocytic cells (macrophages lining the walls of the marginal sinus) 

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SPLEEN

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longest dimension Located between an artery and a vein Function: blood filter Different to lymph nodes and Peyer’s patches as HEVs do not control what enters the spleen and everything in the blood can enter. No lymphatics to bring lymph into the spleen like Peyer’s patches. Blood enters splenic artery  diverted out to the marginal sinuses  percolates through the spleen body  naïve B cells and T cells are temporarily retained in different areas (periarteriolar lymphocyte sheath retains T cells to be activated by APCs and B cells are kept in the region between PALS and the marginal sinuses)  blood collects into the splenic vein Marginal sinuses: lined with macrophages that clean blood by phagocytosing cell debris and foreign invaders Red pulp: made of connective tissue and splenic sinuses filled with blood  general filter for blood by removing antigens and damaged RBC White pulp: lymphoid tissue  major initiator of responses to blood-borne antigens  stores platelets, RBC and blood that can be released into the blood stream in case of hemorrhagic shock Marginal zone: primary site of entry of B and T cells into the white pulp PALS: concentric areas of lymphoid tissue around the central arteriole Individuals without a spleen are more susceptible to infections with encapsulated bacteria as B cells that produce the antibody response to them are produced in the spleen. Encapsulated bacteria: outer covering made of polysaccharide which evades the complement system and prevents opsonization/phagocytosis  examples: streptococcus pneumonia and haemophilus influenza MUCOSA-ASSOCIATED LYMPHOID TISSUE  Mucosae and skin = physical barrier = large surface area = heavily defended by the immune system Aggregates of lymphoid tissue without a tough outer capsule Found especially in the lamina propria and sub-mucosal areas of the gastrointestinal, respiratory and genitorurinary tracts Example: tonsils, appendix, Peyer’s patches -

Peyer’s patches: patches of smooth cells embedded in the villi-covered cells that line the small intestine. About 200 in adults Have HEVs through which lymphocytes can enter from the blood + outgoing lymphatics that drain lymph away from these tissues Predominantly B lymphocytes Have germinal centres during immune responses Unlike lymph nodes, there are no incoming lymphatics  M cells specializes in transporting antigen from the interior of the small intestine into the tissues beneath the M cell by enclosing intestinal antigens in endosomes  endosomes are transported through the M cell to the other side into the tissue  lymph can drain the Peyer’s patches to take the intestinal antigens to lymph nodes as well Specificity of M cells: transport only the antigens that can bind to the molecules on the M cell surface as the rest pass through the intestine without binding to anything  not troublesome. Similarities with lymph nodes: HEVs to admit B and T cells + special areas to separate these cells Similarities with spleen: no incoming lymphatics + special areas to separate B and T cells CUTANEOUS IMMUNE SYSTEM  Innate immune response: keratinocytes release cytokines, macrophages engulf bacteria, B cell antibodies to neutralize infectious agents. Epidermal Langerhans cells: captures antigens that access the epidermis  migrates to lymph node  Langerhans cell differentiates into a dendritic cell  presents antigen to the appropriate T cell  -

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Recirculation of lymphocytes

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Problem: large number of B and T cells with different specificities but limited amounts of antigen  how does the body ensure the antigen meets the correct receptor?  Anatomical structure of the immune system + lymphocyte recirculation Traffic pattern of virgin and experienced lymphocytes are different. Virgin T cell Produced in the bone marrow Educated in the thymus When they emerge from the thymus, virgin T cells express cellular adhesion molecules on their surface which allow them to travel to secondary lymphoid organs. Examples: L-selectin which binds to GlyCAM-1 on HEVs of lymph nodes and Integrin (A4B7) which binds to MadCAM-1 on HEVs of Peyer’s patches and mesenteric lymph nodes (around intestines) In secondary lymphoid organs, virgin T cells pass by APCs in the T cell areas Those that do not find their cognate antigens reenter blood via lymph or directly (spleen) and recirculate every 12-24 hours. Can continue this for about 6 weeks before dying...