BMS150_PHL3-01_ImmuneIntro_Win2023 (1).pdf

Immunology I Introduction BMS 150 Week Objectives Elaborate on the major functions and characteristics of the immune system below: Recognition of foreign entities or damage Destruction/neutralization of pathogenic entities Recognition of self and tolera...

Immunology I Introduction BMS 150 Week Objectives Elaborate on the major functions and characteristics of the immune system below: Recognition of foreign entities or damage Destruction/neutralization of pathogenic entities Recognition of self and tolerance Specificity, memory, primary responses, and secondary responses Repair and regeneration Relate the clonal selection theory to the functions and characteristics of the adaptive immune system For lymphoid- and myeloid-derived leukocytes: Briefly describe their microscopic appearance and location Briefly describe their general function For lymphatic tissues: Distinguish between primary and secondary lymphoid organs Briefly describe the basic morphology, location, and function What is Immunology? Surprisingly hard to define: Many functions: § Protection from microbial pathogens § Protection from “foreign” cells that may have malignant potential § Detects damaged tissue and facilitates regeneration or repair of those tissues § Permits microflora to aid in Protection Provision of nutrients What is Immunology? (cont…) Surprisingly hard to define: Many components: § A wide diversity of cells derived from the bone marrow and that are relatively free to circulate through the body § Discrete, unique and widely-distributed lymphatic tissues § A wide diversity of molecular signals and effectors that are relatively free to circulate throughout the body Many disorders: § Allergy and autoimmune disease (immune-mediated diseases) § Acute and chronic inflammatory states (outside of immune- mediated diseases) § “Bystander” damage that happens when attacking a pathogen Overview of the Immune Response Most components of the immune system contribute to: 1. Recognizing foreign molecules, microbes, or cells 2. Destroying foreign molecules, microbes, or cells § Often by disrupting cell membranes, using free radicals to damage cellular components, or enzymatically catalyzing degradation of cellular components § That which cannot be destroyed is often isolated from the rest of the body 3. Communicating between these two activities Overview of the Immune Response Immune system has 2 major functional divisions: 1. Innate immunity - “1st line of defense” 2. Adaptive immunity - activated when innate defenses are breached (delayed) Overview of the Immune Response Immune system has 2 major functional divisions: Innate immunity - “1st line of defense” Features cellular and molecular effectors that are either: § Less specific – each cell or molecule recognizes a range of targets § Genetically “hard-wired” – cells and molecular effectors don’t change during the lifespan of the organism Adaptive immunity - activated when innate defenses are breached (delayed) Features cellular and molecular effectors that are: § Highly specific – each cell or molecule recognizes a particular target § Genetically “changeable” – cells and molecular effectors change their germline DNA to produce unique receptors/effectors during the lifespan of the organism Adaptive vs. Innate Immune Response Characteristic Innate Adaptive Response time Hours à days Days à 2 weeks Memory None Present Fixed responses with Response can improve in repeated exposures (to specificity and rapidity of antigen) response with repeated exposures Specificity Often recognizes Recognizes very specific “patterns” entities (majority of cases) Diversity Limited (though large) Extremely large number of repertoire of entities that entities can be recognized can be recognized and and neutralized/destroyed neutralized/destroyed Specificity – Adaptive Immunity Specificity: Recognition of a foreign molecule by high-affinity binding to a receptor § The affinity can increase as the receptor is modified over time § Receptors are generated by genetic recombination (gene shuffling) particular portions of the receptor Specificity – Adaptive Immunity Antigen § A substance that can bind to a receptor of the adaptive immune system § Receptors include B-cell and T-cell receptors § B-cell receptors can be released from a B-cell into the ECF à antibody Immunogen § A substance that can generate an adaptive immune response Specificity – Adaptive Immunity Epitope § The molecular entity that binds to the receptor § This antigen displays multiple different epitopes – note the different antibody affinities These were all produced by different B-lymphocytes Hapten § A substance that can bind to an antibody, but CANNOT generate an immune response § Often haptens are “too small” to activate the receptor Hallmarks of Adaptive Immunity Diversity: Vertebrate immune system can recognize ~1016 distinct antigens This is accomplished by sets of corresponding recognition molecules (receptors) on immune cells § B cell receptors (antibodies) § T cell receptors No two naïve T or B cells are activated by the same molecule Diversity is accomplished by randomly “shuffling” portions of genes for lymphocyte receptors and selecting receptors that: § Are functional § Do not recognize self Lymphocyte receptor repertoire: § the set of antigen (Ag) receptors in a given individual’s immune system Hallmarks of Adaptive Immunity Specificity & Diversity Clonal Selection Theory § Each lymphocyte bears a single type of receptor with a unique specificity § Receptor binding is required for cell activation § The differentiated effector cells derived from an activated lymphocyte bear receptors of identical specificity as the parent cell They are clones of the parent cell – exact genetic copies with the same receptor § Those lymphocytes bearing receptors for self molecules (i.e., endogenous antigens produced within the body) are destroyed at an early stage We select functional receptors that do not bind to self Hallmarks of Adaptive Immunity Specificity & Diversity: B cell Receptor Naïve B cells express Ab on their surface, where they are called B cell receptors Once activated, B cells secrete Abs into the blood (aka Immunoglobulins – Igs)  Hallmarks of Adaptive Immunity B cell Receptor Light chains (2) and heavy chain (2)—each with variable and constant regions § The variable regions are the portions that are “shuffled” and that can bind to antigen Some antigens can be bound by many different antibodies § Different epitopes on the same antigen Hallmarks of Adaptive Immunity B cell Receptor  Hallmarks of Adaptive Immunity B cell Receptor Antigens: Most antibodies bind to protein antigens – distinct sequences of amino acids § Recognized amino acid sequence can be either Continuous (aka linear), or Discontinuous (aka conformational) Antibodies can also bind to lipid, nucleic acid, and carbohydrate moieties § A wide range of molecules can be recognized Hallmarks of Adaptive Immunity Specificity & Diversity T cell Receptor Structurally very similar to the Fab portion of an Ab 2 chains: 1 alpha, 1 beta—each with a variable (V) region and a constant (C) region Best at recognizing protein antigens The T-cell receptor is never secreted – it always stays attached to the membrane Hallmarks of Adaptive Immunity T cell Receptor T-cell receptors only recognize antigen by close communication with molecules on other cells § This is known as antigen presentation § Complicated interaction that we will delve into later – T-cell receptors never bind to antigen “just floating around” dissolved in the ECF https://upload.wikimedia.org/wikipedia/commons/5/55/Activation_of_T_and_B_cells.png Hallmarks of Adaptive Immunity Memory: Exposure of the adaptive immune system to an antigen increases its ability to respond to the same or closely related antigen following re-exposure Secondary immune responses are generally: § Faster § Larger § Qualitatively different and often involve relatively high-affinity B-cell receptors How could you explain memory in the context of clonal selection theory? Hallmarks of Adaptive Immunity Memory: Hallmarks of Adaptive & Innate Immunity Self-Limiting: Both adaptive and innate immune responses are transient § The methods of downregulating the immune response differ greatly between the innate and adaptive immune system… but they can also interact Immune responses are tightly regulated and controlled § Control and down-regulation of the adaptive immune system is often quite specific, as is activation Self/Non-self Discrimination: The immune system must distinguish self from non-self § Immune responses to self can result in autoimmunity § Immunological unresponsiveness to self = tolerance Terms to know… Immature: A cell that has not reached a point where it can become activated – usually refers to cells of the adaptive immune system Naïve: A mature cell that has not yet been activated – always refers to the adaptive immune system Activated or Effector: A cell (or group of cells) that is currently an active participant in an immune response Anergic: A cell that responds to receptor binding by deactivation of the cell – it “goes to sleep” Clone: A group of effector T/B cells that express the same antigen receptor and are derived from the same parent cell Cells & Tissues of the Immune System Myeloid Cells Lymphoid Cells Primary Lymphoid Tissue Secondary Lymphoid Tissue  Cells & Tissues of the Immune System Hematopoietic Stem Cells Myeloid Cells Granulocytes Lymphoid Cells Neutrophils T cells Basophils B Cells Eosinophils NK Cells RBCs Mast Cells Dendritic Cells Platelets Monocytes Macrophages Dendritic Cells Sample Complete Blood Count (CBC) Myeloid Progenitor Cells Monocytes/Macrophages: Monocytes circulate in the blood & differentiate into macrophages upon migration into tissue (long-lived) Macrophages are phagocytic, and are the mature form of a monocyte Macrophages often produce soluble messengers that help orchestrate a wide range of adaptive and innate immune responses Present antigens to T cells Dendritic Cells: Resident in the body’s tissues During infection, recognizes infection and transports antigen to lymphoid organs Present antigens to T-cells - important in T cell activation during adaptive immune responses Myeloid Progenitor Cells Granulocytes: Neutrophils Phagocytic and enter sites of infection (short-lived) Die in infected tissues à form pus (purulent inflammation) Most numerous cellular component of innate immune system Eosinophils Defense against parasites Involved in hypersensitivity responses Basophils Along with mast cells, protect mucosal body surfaces & release histamine in hypersensitivity responses Also implicated in defense against parasites Mast Cells: Reside in all connective tissues – only resident granulocyte and have a unique role Orchestrate hypersensitivity responses (e.g. seasonal allergies), important in mucosal immune responses Myeloid Progenitor Cells Granulocytes: Neutrophils Phagocytic and enter sites of infection (short-lived) Die in infected tissues à form pus (purulent inflammation) Most numerous cellular component of innate immune system Eosinophils Defense against parasites Involved in hypersensitivity responses Basophils Along with mast cells, protect mucosal body surfaces & release histamine in hypersensitivity responses Also implicated in defense against parasites Mast Cells: Reside in all connective tissues – only resident granulocyte and have a unique role Orchestrate hypersensitivity responses (e.g. seasonal allergies), important in mucosal immune responses Lymphoid Progenitor B cells: Bone marrow derived Upon activation, differentiate into Ab-secreting plasma cells T Cells: Thymus-derived (though originate in bone marrow) Become either helper T cells (Th) or cytotoxic T lymphocytes (CTL) Helper T (Th) Cells: Activate other cells (macrophages, B cells) Cytotoxic T Cells (CTLs): Kill cells that express foreign molecules T and B lymphocytes look alike, each having receptors for specific antigen NK cells: Important in the innate immune system Lack antigen-specific receptors Kill infected & altered cells (e.g. malignant cells) “Adaptive” and “Innate” cells – a caveat Some texts artificially categorize immune cells as being “adaptive” or “innate” cells based on the specificity of the cell’s receptor/effector § In this categorization, only lymphocytes are “adaptive” immune cells However: § Dendritic cells and macrophages are absolutely key in presenting antigens to T-lymphocytes § Many “innate” immune cells produce cytokines that inform helper T-cells about how to “help” other immune cells § Certain subsets of helper T-cells are dedicated to ONLY aiding innate immune responses § Mast cells, neutrophils, eosinophils, and macrophages are important at helping to clear antigens that are bound by antibody Lymphoid Tissues Organized tissues where lymphocytes interact with non- lymphoid cells Important in initiation/maturation of adaptive immune responses 2 types of lymphoid tissues § Primary (central) lymphoid organs § Secondary (peripheral) lymphoid organs Primary Lymphoid Organs Where lymphocytes are generated and mature Includes bone marrow & thymus Both B and T cells are generated in the bone marrow B cells mature in the bone marrow Although additional maturation steps can occur in the spleen, it is not viewed as a primary lymphoid organ T cells mature in the thymus Once lymphocytes mature they leave primary lymphoid organs and are capable of responding to an antigen Secondary Lymphoid Organs Where adaptive immune responses are initiated—antigens and B/T Cell receptors encounter each other Exist to bring antigen and lymphocytes together Lymph nodes, spleen, and MALT Lymph nodes (LNs): Lie at junctions of lymphatic vessels Collect extracellular fluid (lymph) and return it to the blood (via lymphatics) Afferent lymphatics drain lymph and antigens from tissues, carrying it to the nodes where antigen is trapped Lymph Nodes Secondary Lymphoid Organs Spleen: Fist-sized organ located deep and lateral to the stomach “Filter for blood”—collects blood-borne antigens & also destroys aged RBCs B-cells in the spleen produce large quantities of antibodies and secrete them into the bloodstream Most B-cells undergo some degree of maturation in the spleen Organ is divided into red pulp & white pulp § Red pulp: Where old RBCs are destroyed § White pulp: Where lymphocytes surround arterioles entering organ Further subdivided into corona and periarteriolar lymphoid sheath (PALS) Secondary Lymphoid Organs Mucosa-associated lymphoid tissue (MALT): Includes gut- and bronchial- associated lymphoid tissues (GALT, BALT, etc…) Purpose is to collect Ag from mucosal surfaces Specialized lymphoid tissue at the body’s “wet” surfaces required due to large surface area, rich with potential pathogens GALT: Includes tonsils, adenoids, appendix and Peyer’s Patches (PP) PPs collect Ag from epithelial surfaces of GI tract via M cells PPs composed of distinct T and B cell areas