Organs of the Immune System and Lymphatics PDF

Section 5: Organs of the Immune System and Lymphatics Relevant Readings: Please refer to Canvas (eLearning).  Outline Organs Overview Primary Lymphoid Organs – Thymus - Organization, Size Change over time – Bone Marrow Lymphatic System Secondary Lymp...

Section 5: Organs of the Immune System and Lymphatics Relevant Readings: Please refer to Canvas (eLearning).  Outline Organs Overview Primary Lymphoid Organs – Thymus - Organization, Size Change over time – Bone Marrow Lymphatic System Secondary Lymphoid Organs – Lymphoid Follicles (Present in 2nd Lymphoid Organs) – Lymph Nodes – Spleen – GALT Immune Organ Phylogeny  Organs of Immune System Primary organs - where lymphocytes reach functional maturity ‒ Bone Marrow, Thymus (in humans, mice) Secondary organs - where mature lymphocytes interact with antigens ‒ Lymph nodes, spleen, MALT, GALT Lymphatic system - network of vessels that collects fluid (lymph) that has escaped into tissues from the circulatory system and returns it back into the blood  Primary Lymphoid Organs Also called generative organs The location where lymphocytes first express antigen receptors and attain functional maturity Bone Marrow - Site of generation of all circulating blood cells in adults – Site of early B cell (immature lymphocyte) maturation – Preferential niche of plasma and memory T cells Thymus - Location of T cell maturation – Cortex contains a thick collection of mostly immature thymocytes  Thymus The thymus is a bi-lobed organ where each lobe is divided into lobules, separated by trabeculae Purpose: Generate T cell repertoire that will protect from infection Thymocytes of thymus undergo gene rearrangement ‒ Produces enormous diversity of TCR ‒ Most fail to recognize MHC-Ag complexes; Some are capable of mounting immune response to self ‒ >95% thymocytes die by apoptosis Role of thymus can be studied in thymectomized mice or nude mice with  DiGeorge’s Syndrome patients - Caused by extracellular or intracellular pathogens? Thymus Location Thymus: Basic Histology Thymus: T Cell Development Thymus: T Cell Development Thymus: Change Over Time  Bone Marrow Site of hematopoiesis and B cell maturation Bone marrow B cells generate 90% of Immunoglobulin G and A (antibody isotypes) in plasma B cell development occurs in … ‒ Bursa of Fabricus in birds ‒ Fetal spleen → ileal peyer’s patch in sheep and cattle ‒ Appendix in rabbits Bone Marrow: B Cell Development Bone Marrow: B Cell Development  Lymphatic System: Movement of Lymph As blood travels under pressure, plasma seeps through thin capillary walls into surrounding tissues Up to 2.9 liters of interstitial fluid is generated in adults per day, which bathes tissues and cells Fluid eventually returns to blood ‒ If fluid does not return back to the blood, then swelling (edema) can occur, which can be life threatening  Lymphatic System: Movement of Lymph cont. Most fluid is returned back to the blood through walls of the venules and the remainder passes through primary lymphatic vessels - Cells (e.g., Macs, DCs, lymphocytes) can also pass through thin wall Thoracic duct empties into left subclavian vein (largest lymphatic vessel) Muscle contractions help move the lymph in a unidirectional path  Lymphatic System - Unidirectional Movement Fluid seeps out of blood plasma Thoracic Duct empties Now called interstitial fluid; lymph into left subclavian Tissues and cells are bathed vein back to blood Fluid, now called lymph, flows from Most returned through the walls tiny tubes into larger collecting of venules vessels called lymphatic vessels Remainder enters network of thin-walled tubes called primary lymphatic vessels  Lymphatic System Macrophages, lymphocytes, and dendritic cells, and other immune cells gain entry to lymph/tissues Since lymphatic system drains all tissues, when foreign antigens enter tissues, it is eventually picked up by the lymph Lymph is carried to organized lymphatic tissues such as lymph nodes In sum: Lymph serves as a means of carrying lymphocytes and antigens from connective tissues to lymphoid Lymphatic System → Lymph Node Secondary Lymphoid Organs Locations where mature lymphocytes interact with antigens Includes spleen, lymph nodes, Mucosa- Associated Lymph Tissue (MALT), & Gut- Associated Lymph Tissue (GALT) All of these include lymphoid follicles - collections of lymphoid and non-lymphoid cells surrounded by draining lymphatic capillaries Most organized: lymph node + spleen ‒ Contain distinct B- and T-cell regions and fibrous capsules in addition to lymphoid  Lymphoid Follicles (Present in 2nd Lymphoid Organs) Primary follicle - contains follicular dendritic cells and resting B cells. Before activation. No germinal center (GC). Secondary follicle - packed circular ring of B cells surrounding GC which contains rapidly dividing B-cells, non- dividing B-cells, Follicular T Helper Cells (TFH), Follicular DCs, Macs. After activation. Secondary Follicle gc = Germinal Center m = Mantle Video: The Germinal Center Reaction  Lymph Node Encapsulated bean-shaped structures Full of lymphocytes, dendritic cells, macrophages First organized lymphoid structure to encounter antigens entering tissue spaces Antigens become trapped for antigen presentation Cortex - B cells, Follicular DCs, Follicular T cells, and Macrophages (primary and secondary follicles) Paracortex - B- and T- cells and DCs (MHCII) Medulla - sparse lymphocytes, Ab-secreting Lymph Node Basic Diagram Afferent lymphatic vessels Efferent lymphatic vessel  Lymph Node: Antigen Migration Within the paracortex, the antigen gets trapped. – DCs internalize, process, and express in MHCII to Th cells. – Soluble antigen binds to BCR specific to antigen. B- and T- cells begin forming foci (clonal colony specific to antigen) – (4-6 days): Some plasma cells are produced. (4-7 days) Some B- and TFH cells  Lymph Nodes: High Endothelial Venules Efferent (outgoing) lymph vessel has antibodies and 50x lymphocytes – Mostly from migration of blood-borne lymphocytes – Some due to proliferation Blood-borne lymphocytes migrate through post capillary venules using high endothelial venules (HEV) – Migration of cells through HEV is called extravasation  Spleen Large oval structure in left abdominal cavity Plays major role in mounting immune responses to blood-borne antigens Blood-borne antigens and lymphocytes arrive through splenic artery Spleen is surrounded by capsule with projections (trabeculae) extending into interior – Red pulp (mostly RBCs and macrophages) and white pulp (lymphocytes) are separated by a marginal zone – Within the white pulp, the PeriArteriolar Spleen Diagram  Spleen: Antigen Migration Antigen enters through splenic artery → empties in marginal zone In marginal zone, antigen trapped by DCs, then processed. DCs move to PALS, where they present MHCII-Ag → T cell activation Loss of spleen results in increase of bacterial sepsis in children  Gut-Associated Lymphoid Tissue (GALT) M cells: Separate internal and external environment Intraepithelial cells Video: Immunology in GALT (nature) GALT Diagram GALT: Antigen Migration GALT: Antigen Migration Immune Organs: Phylogeny Human Immune Organs Overview  Section 6: Adaptive Immune Response Relevant Readings: Please refer to Canvas (eLearning).  Outline Adaptive Immune Response Overview ‒ Qualities ‒ Antigen Roles ‒ Lymphocytes - B, T Signalling Overview T Cell Activation - How ‒ Receptor Types ‒ Effector Functions - Cell-Mediated, Humoral ‒ Subtypes ‒ Regulation B Cell Activation - How ‒ Antibodies Primary vs. Secondary Response Functions ‒ Clonal Selection Theory Humoral vs. Cell-Mediated Immunity Review Immune Dysfunction  Stages of the Adaptive Immune Response Recognitio Activation Effector Decline Memory n Phase Antigen Clonal Antigen Immun Some Detecti Expansi Remov e Immune on on al; Cell Cells of B and Immun Apopto Remain T cells e sis For Cells Repeat Work Exposure 0 7 1 >3 4 0 Days After Exposure  Principle Facets of the Adaptive Immune Response Specificity: Different microorganisms mediate specific responses Diversity: Immune system is capable of responding to large numbers of microbes Memory: Able to recall previous encounters with antigens- leads to faster, stronger responses to future encounters with the same microbe Optimization: Able to specialize attacks for distinct microorganisms Self-limiting: Capable of starting and stopping an attack of a new microorganism Safe to Self: Does not accidentally attack self- tissues  Antigens Antigens - anything that elicits an immune response Usually foreign – Except in autoimmune diseases (e.g. Multiple Sclerosis and Rheumatoid Arthritis) Antigens can be: – high-molecular weight compounds (>5 kDa) – low molecular weight compounds  Immune Cells of the Adaptive Immune Response B cell T-helper T-cytolytic TCR cellCD4 TCR cell CD8 B cell with Ag - T cell with T -cell T cell with T - cell binding receptor receptor (TCR) and receptor and (antibody). CD4 marker. CD8 marker. Mature in Bone Mature in Mature in Marrow Thymus Thymus.  Lymphocytes Major cells of the immune system – T cells, B cells, and NK cells (Natural Killer Cells; Outdated term: null cells-recent term innate lymphoid cell) Stem cells differentiate into B and T lymphocytes in the bone marrow – Are blocked from exiting G0 cell cycle phase until they are activated by binding of specific antigen onto lymphocyte surface receptors – After activation, replication continues as lymphocytes circulate and enter lymphoid tissue – Some activated cells form memory cells that do not immediately replicate, but will do so later when the host is reexposed to an antigen Immune Cell Division Metabolism TCA cycle Glutamine Glucose Lymphocyte Morphology Change  B Lymphocytes Mature in bone marrow Circulate in blood Can settle in lymphoid organs After maturation and activation some become plasma cells that secrete large volumes of antibodies  T Lymphocytes Mature in thymus, after which they (naive T lymphocyte) can: ‒ remain in thymus (most migrate out) ‒ circulate in blood ‒ reside in lymphoid tissue Like B cells, T cells require antigen binding to surface receptors (i.e. TCR) for activation and replication; Unlike B cells, antigen must be presented to T cells by APC in the context of MHC Activated T cells produce cytokines (proteins that have effects on other cells), -Can also undergo changes in cell surface proteins, or up-regulate cytolytic/cytotoxic molecules Types: CD4+, CD8+, and Treg BCR/TCR Required For Activation *CD4 and CD8 associate with αβ T-cell receptors, forming TCR complex  Signaling Overview - Background for Activation  T Cell Activation T cells have a membrane bound T cell receptor (TCR) The TCR recognizes a peptide when it is bound to a MHC molecule on an APC In addition to peptide + MHC, naïve T cells also require interaction with other molecules on the surface of APCs known as co-stimulators. These activation steps help prevent T T Cell Activation CD4:CD8 ratio in peripheral CD4 vs. CD8 Activation TCR complex Immunoglobulin folds ITAM: Immunoreceptor tyrosine based activation motif TCR sub-Types: Demographics in Peripheral Blood  Naïve T cells require co- stimulation for Activation or Anergy Occurs If no co-stimulation: Anergy Figure 11-4 p. 365 Figure 11-7 p.  Antibody Basic Diagram Antibod y activity Biological activity (binding compleme nt) Adaptive (Inducible) - Effector Function Cell- Humoral Mediated Phagocyti Infected c cell; cells MHCI capture Presentati microbes; on MHCII Presentati Helper T cells Cytotoxic T on activate cells kill Virally- phagocytic cells infected/ to kill microbes Cancerous Cells B cell B cells produce T T antibodies that prevent h c infection and eliminate The Kiss of Death T Cell Subtypes  CD4 (Th) Cell Subtypes: Commonly Produced Chemicals TH1: IFNγ => intracellular pathogens TH2: IL-4 => extracellular pathogens TH17: IL-17 => extracellular pathogens (fungi) T Follicular Helpers => important in humoral immunity and B cell development in germinal centers (in lymphoid follicles)  T Cell Regulation CTLA4 - competes with CD28 Cytokine Signaling Suppressors Include: – Immunomodulatory cytokines (e.g. IL- 10) – PD-1 ligands (Programmed cell Death-1) – Regulatory T cells (Tregs) Apoptosis in the absence of continued TCR stimulation  Regulatory T cells Basic goal of the immune system is not only defense against infectious microorganisms, BUT also tolerance to self. Regulatory T cells (Tregs) play an active role in tolerance In the absence of Tregs, autoimmune diseases develop Tregs require TCR stimulation for activation; however, instead of promoting an immune response, they  Types of Regulatory T Cells TR1 ‒ Isolation via: Culturing CD4+ T cells in presence of IL-10, antigen ‒ Suppression: Produces IL-10, TGF-β, and IL-5 Th3 ‒ Isolation via: Low dose oral antigen ‒ Suppression: Produces TGF-β and IL-10 CD8+ Tregs ‒ Suppression mechanism varies between systems CD4-CD8- Tregs ‒ Suppression is Contact-dependent Naturally occurring CD4+CD25+ Tregs ‒ Constitute 5-10% and 2-4% of peripheral CD4+ T cells in mice and humans respectively ‒ Possess the transcription factor Foxp3  Common Features of Immune Receptor-Ligand Interactions Aggregation due to ligand binding enhance ligand binding Kd Cell-cell interactions rely on a binding affinity to maintain contact over long periods of time Extended contact facilitates signal transduction and exchange of cytokine signals Cytoskeletal reorganization may occur upon extended binding  Naïve T cells require co- stimulation for Activation or Anergy Occurs If no co-stimulation: Anergy Figure 11-4 p. 365 Figure 11-7 p.  nTregs Constitutively expressing CD25 (IL2 receptor alpha chain) The IL2 R serves as an ”IL2 sink”, removing IL2 from the system and inhibiting the expansion of T cells Pancreas IL2 Treg B Cell Activation Leads to Antibodies (Effector function) CD4 B Cell B Cell Activation: T- Dependent B Cell Activation: T- Independent 1  B Cell Activation: T- Independent 2 ITAMs present on CD21, Igα/Igβ (CD79α/β)  Antibodies (Ab) Soluble glycoproteins that bind antigens with high specificity and affinity Five major isotypes of antibodies are known: ‒ IgG - the most abundant immunoglobulin in the blood; present as a monomer ‒ IgM - the first Ab produced in response to an infection; present as a pentamer ‒ IgA - The major immunoglobulin in external secretions (milk, saliva, etc.);  Humoral Response to Antigens Primary antibody response ‒ Peaks between 10-17 days ‒ Mostly IgM ‒ Antibody levels increase then decline Secondary response: (memory) ‒ Is more rapid (peaks in 2-7 days) ‒ Mainly IgG ‒ Results in higher levels of antibody ‒ Antibody persists longer than in the primary response (years...think of vaccination) Humoral Response: Primary vs. Secondary Humoral Response: Primary vs. Secondary Humoral Response: Naïve vs. Memory  Antibody Functions Neutralization of virus infectivity. ‒ Viruses treated with specific Ab lose their ability to infect cells in vitro and to infect animals Neutralization of toxins Opsonization - Coating of bacteria with Ab or Ab+complement increases rate of phagocytosis Activation of complement Antibody Dependent Cell Cytotoxicity (ADCC) Antibody Functions  Antibody Specificity Theories Selective theory ‒ proposed that immune cells expressed a variety of receptors (side chain receptors) that could react and neutralize infectious agents. Once the infectious agent bound the cell, it would cause more receptors to be made and released. Receptor specificity was predetermined – later refined into the clonal selection theory Instructional theory ‒ Ehrlich’s Side Chain Theory (Selective)  Clonal Selection Theory Antibody Diversity produced via gene rearrangement in B cells during development Receptors on the cell surface recognize a specific antigen (all B cell receptors on a given B cell are identical – antigen committed) Recognition of the antigen stimulates maturation and proliferation of Ab producing and memory cells Antibody Selection, B Cell Activation (conceptually similar in T Cell-Mediated, Humoral Immunity Review Cell-Mediated, Humoral Immunity Review: Another Look Where Does the Action Take place?  Immune Dysfunction Allergies and asthma (hypersensitivity) Graft rejection and graft versus host disease (GVHD) Autoimmune diseases Immunodeficiency  Allergies and Asthma Some substances such as plant pollen or food induce hypersensitivity ‒ Seen when immunizing dogs w/ Jellyfish toxin Physalia Phylaxis vs anaphylaxis IgE binding to allergen causes release of histamines ‒ Irritation, Inflammation, Dermatitis (hives), sneezing, asthma  Asthma Caused by inflammation of the lungs, which are caused by changes in the environment or infections 20 million in US; 12 million/yr experience allergy attacks; 5000 die/yr in US, which has doubled in 20 yrs Asthma attacks account for 1/3 of emergency room visits Asthma/allergy cost 20 billion in lost How Allergies Occur  Graft Rejection and GVHD Basic function of immune system is distinction between self and foreign - great in cancer, but not great in transplantation Graft rejection occurs when immune system views transplanted tissues as foreign and attempts to eliminate them Graft versus host disease (GVHD) occurs when transplanted material contains immune function  Autoimmunity Occurs when tolerance mechanisms break down - immune system damages self tissues Multiple sclerosis - Attack on myelin sheaths protecting nerve cells in Central Nervous System Crohn’s disease - Attack on intestinal cells Rheumatoid arthritis - Attack on joints Autoimmunity Cases in the US (2018) Total U.S. Population: 326 million Multiple sclerosis: 300,000 Rheumatoid arthritis: 1.3 million Type 1 diabetes: 1.25 million w/ disease, 40,000 new cases/year Systemic Lupus Erythematosis (SLE): 250,000 Autoimmune Histology  Immunodeficiency Any deficiency in the immune response (primary or secondary) May go unnoticed depending on which part of immune system or how much of the immune system is affected Severe Combined ImmunoDeficiency (SCID) - Rare genetic disease that causes lack of B and T Cells. Can result in death because of infection in youth if undetected Acquired Immune Deficiency Syndrome (AIDS) - Results from infection with retrovirus HIV, causing destruction of CD4+ Th cells are destroyed. ~37 million infected