Concepts in immunity



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Immunology Review – Quiz 1
CONCEPTS IN IMMUNITY

  • Background

    • Goal of immune system: battle infection

    • Leukocytes: interact as network to attack microorganisms

    • Microbes can be intracellular (invade cells) or extracellular (grow on tissues)

    • Host defense mechanisms

      • External defenses (e.g. physical barriers)

      • Innate immunity: non-specific molecules/cells

      • Adaptive immunity: specific molecules/cells

  • Components of the immune system

    • Leukocytes:

      • 3 types of lymphocytes (B, T, large granular lymphocyte)

      • myeloid derived cells (monocytes/macrophages, granulocytes)




  • Hematopoietic stem cells

    • Hematopoietic cells derived from common stem cell in bone marrow

    • Self-renewing

    • Differentiate in response to cytokines, other signals

  • Important definitions

    • Antigen: reacts with antibodies (foreign pathogen/particle)

    • Immunogen: antigen that induces immune response (e.g. protein, na, carb, lipid)

    • Hapten: small molecule that can’t induce Ig alone (e.g. penicillin); can if attached to larger protein

    • Passive immunity: established by transfer of Ig or lymphocytes (provided to patients)

    • Active immunity: result of host cells’ response to antigen (e.g. vaccination)

    • Humoral immunity: mediated by Ig

    • Cellular immunity: mediated by cells

    • Specific immunity: protects against specific antigen that elicits response

    • Non-specific immunity: protects against many types of antigens (usually related)

    • Immunological memory/secondary response: specific response to previously-encountered antigen

    • Cytokines: small proteins that signal between cells

      • Membrane-bound or soluble

      • Autocrine or paracrine

      • Bind to specific receptors

      • Know: IL-1,2,4,5,10,12; TNF-alpha, beta; IFN-alpha/beta, gamma; chemokines

    • CD: cluster designation for cell suface molecules (see CD chart)

  • Immune receptors: recognizing danger

    • Pattern recognition receptors

      • Bind to patterns on microorganisms and their products

      • Macrophages, DCs, epithelial cells, etc.

      • Nonspecific (bind to similar molecules on diff organisms)

      • Innate

    • Immunoglobulin (Ig)

      • One specific antigen

      • B cells

    • T cell receptors (TCR)

      • One specific peptide and MHC

      • T cells

    • Fc receptors (FcR)

      • Bind to Ig

      • Allow cells to use specificity of Ig to direct function

      • NK, macrophage, PMN, Eos, mast cells

  • Innate immunity: first cells to respond

    • Mechanisms present prior to infection

    • Sentinels that find infection near site of entry

    • Acute phase proteins/complement, macrophages, PMNs, NK cells, epithelial/endothelial cells

  • Phases of immune response -----------------------------------

    • Recognition of antigen

    • Activation of immune cells

    • Clonal expansion

    • Effector phase

    • Decline after antigen is cleared

    • Memory cells




  • Antigen presentation: recognizing pathogen presence

    • Antigen-presenting cells (APCs): macrophages, B cell, dendritic cell

    • Small peptides presented with MHCs on APC surface

    • T cells recognize specific MHC-peptide complex with TCR

  • Major histocompatibility complex (MHC)

    • Bind small proteins and present them to TCR

    • Class I: all nucleated cells; present internal proteins

    • Class II: on APCs; present external proteins

  • Adaptive immunity: specific response

    • Lymphocytes with highly specific receptors (Ig, TCR)

    • Specificity

    • Memory

  • Clonal selection

    • Lymphocytes exist in pools of clones

      • Each clone specific for single antigen

    • Clone activates when bound to antigen  divides a lot

      • Differentiation to effector cells, memory cells

  • Receptor cross-linking

    • Must trigger several antigen-specific receptors at once to get cell response

    • Receptors localize near each other to bind to antigen on cell surface, bringing signaling molecules close together  response

    • Ig can be use to mimic this process

  • Two signals for immune cell activation

    • Prevents inappropriate activation

    • 1: via immune receptor (Ig, TCR)

    • 2: via costimulatory signal (general signal induced by presence of pathogen)

  • Antibodies: response to remove pathogen; humoral

    • Made by plasma cells (from B cells)

    • Multiple sites for same antigen

    • 2 heavy chains, 2 light chains

    • Fab portion: antigen binding

    • Fc portion: effector region

    • 5 classes: Ig-M,D,G,A,E

  • T cells: response to remove pathogen; cell-mediated

    • Lymphocytes, develop in thymus

    • Specific TCR

    • Activate humoral response

    • 3 types

      • cytotoxic (CTL): CD8, cytokines

      • helper (Th): CD4, lots of cytokines

        • Th1: interact with macrophages, inflammation, development of CTLs

        • Th2: interact with B cells, promote Ig making

        • Th17: autoimmunity, inflammation

      • regulatory (Treg): suppress T cell activity in periphery, prevent autoimmunity

  • Immunological memory

    • On second exposure to antigen, response is faster and more effective

    • Antigen-specific memory lymphocytes in higher numbers, easier to activate

  • Lymphoid tissue and trafficking: linking antigens and lymphocytes

    • Primary lymphoid tissue: where lymphocytes develop (marrow, thymus)

    • Secondary lymphoid tissue: where mature lymphocytes reside (spleen, nodes, tonsils, etc.)

    • DCs pick up antigens in periphery and bring to node via lymphatic drainage

    • DCs present antigen to lymphocyte in node

  • Tolerance: avoiding immune response to “self” antigens

    • Removes/inhibits lymphocyte receptors for normal proteins

  • What to know:

    • Cells of immune system

    • Antigen

    • Key cytokines and CDs

    • Adaptive versus innate immunity

    • Clonal selection and expansion

    • Antigen presentation

    • 2-signal system

    • Immunological memory

    • Lymphoid organs



INNATE IMMUNITY

  • External defenses

    • Physical barriers: microbes must pass skin/epithelial cells actively or passively

    • Secretions: sweat, tears, saliva, gastric fluid have antimicrobial substances

    • Microbial products/competition: non-pathogenic bacteria (commensals) on epithelial surfaces

  • Soluble molecules: mediate protection against microbes before adaptive immunity develops

    • Complement

      • 20 interdependent proteins

      • sequential activation  inflammation, attract neutrophils (chemotaxis), help attach microbes to phagocytes (opsonization), kill microbe

      • activation is direct by microbes (alternative path) or by Ig bound to antigen (classical path)

    • Acute phase proteins

      • Plasma proteins

      • Innate defense against microbes (esp bacteria)

      • Limit tissue damage cause by disease/infections

      • Maximize activation of complement, opsonization

      • Produced in liver in response to microbe or cytokines (IL-1/6, TNF-alpha/gamma)



    • Interferons (IFN)

      • Protect against viral infections (interfere with replication)

      • Signaling molecules btwn cells

      • Type I (alpha, beta): made by lots of cells; inhibit protein synth in infected cells

      • Type II (gamma): leukocytes (Th1, NK); regulates Th1 response, increases phagocytosis and antigen presentation

    • Collectins: carb binding proteins; act as opsonins (help macrophage destroy microbe)

    • Peptide antibiotics: produced by lots of cells (e.g. epithelial, phagocytic)

  • Innate immunity cellular receptors/pattern recognition receptors

    • Innate immune cells have receptors to recognize pathogens

    • Germ-line encoded  no gene rearrangements for expression

    • No memory response

    • Activation of receptors  costimulation (signal 2) of lymphocytes

    • Types (one cell can have many types)

      • Mannose receptors

        • On macrophages, DCs, endothelial

        • Bind to mannosyl/fucosyl carbs  eat microbe  peptides on MHC  T and B response

      • CD14

        • On macrophages

        • Binds LPS on gram neg bacteria

        • Helps destroy microbes, induce secretion of cytokines that trigger adaptive immunity

      • Scavenger receptors

        • On macrophages

        • Recognize carbs, lipids in bacteria and yeast cell walls

      • Toll-like receptors (TLR)

        • Cell surface or vesicles

        • Recognize patterns on multiple pathogens  signal presence of pathogen  expression of costimulatory molecules and cytokines needed for adaptive response

        • NODs are similar to TLR but in cytoplasm (involved in Crohn’s disease)




    • Innate versus adaptive immune receptors -----------------------




  • Macrophages

    • Aka phagocytes; eat particles and dying cells

    • Derived from monocytes in blood

    • Differentiate in different tissues (mononuclear phag system)

      • Kupffer—liver

      • Mesangial—kidney

      • Alveolar—lungs

      • Microglial—brain

    • Secrete cytokines to activate immune cells

    • Can be activated to kill bacteria

    • Phagocytosis -------------------------------------------------------------------

      • Attraction to site of infection via chemotaxic signals MDP, C

      • Interaction with microbe for easier ingestion (opsonization)

        • Mannose, C, Fc receptors

      • Ingestion/endocytosis (invagination of membrane)

      • Fusion of phagosome and lysosome (microtubules)

      • Killing ingested material (O2 dependent/independent)

        • Reactive O2 intermediates (ROI)

        • Nitric oxide (NO)

        • Lysosomal proteases

        • Upregulated by IFN-gamma

      • Digested pieces released  inflammation, recruit PMNs

    • Activation of macrophages to (can interchange based on stimuli):

      • Pro-inflammatory (classical): kill microbes through phag

      • Wound-healing: produce ECM, alter cytokine production, suppress lymphocyte expansion

      • Regulatory (anti-inflammatory)





  • Dendritic cells

    • Immature DCs sit in tissues and phagocytose particles to sample environment

    • Mature when encounter microbe signal (via TLR or TNF-alpha)  upregulate MHCI/II on surface  can’t phag anymore, move to nodes to present to T cells, activate antigen-specific T cells

    • Subtypes for different T cell types

    • Different names for DCs

      • Langerhans (LH)—skin

      • Interdigitating (IDC)—lymph node T cell areas

      • Follicular dendritic cells (FDC)—B cell follicles of lymph tissues

    • Possible immunotherapy

  • Neutrophils/polymorphonuclear cells (PMN)

    • Major leukocyte in the blood

    • Granules with enzymes that kill bacteria

    • Short life span (hours/days)

    • Have Fc receptors

    • Move through blood till they get signal to move to tissue: selectin on endothelial cells

      • Inflammation induces selectin expression

        • E.g due to TNF-alpha from macrophage

      • PMNs slow down and roll ----------------------------

        • Sensitive to inflammation signals (C5a, LPS)  causes PMN to upregulate integrins on surface  bind to ICAMS on endothelium  move into tissue by chemotaxis due to chemokine gradients  move to infection and kill microbe

  • Natural killer (NK, LGL) cells

    • In many tissues and blood

    • Make and release cytokines (inc IFN-gamma, TNF-alpha, GM-CSF) for virus and tumor killing, activating macrophages

    • Can kill cells

      • Perforin granules

      • Fas-Fas ligand

      • TNF (cytokine) release

    • No TCR or Ig

    • Express Fc receptors

    • Help with antibody dependent cellular cytotoxicity (ADCC)

    • NK activating receptors bind to molecules on stressed/tumor/virus-infected cells

      • Turns on NK killing and cytokine production

    • NK inhibitory receptors bind to MHCI and shut of NK to protect normal cells

      • Tumor/virus-infected cells sometimes dec MHCI to avoid T cells, but then NK can kill them

  • Mast cells (CT) and basophils (circulation)

    • Fc receptors for IgE

    • Triggered by specific antigens

    • Degranulate when activated  release pharmacological mediators

      • Histamine: vasodilation, vascular permeability

      • Cytokines

        • TNF-alpha, IL-8/5: attract neutrophils, eosinophils

        • platelet activating factor: attract basophils

  • Eosinophils

    • Production induced by IL-5 in marrow

    • Granules involved in inflammation

    • Attack parasites that can’t be phagocytosed with major basic protein

    • Related to allergies

  • Platelets

    • Release mediators that activate complement  attraction of leukocytes

    • Granules with chemokines, growth factors

  • Interaction between innate immune cells: network

    • Macrophages make cytokines (TNFalpha)  activates its own IL-12 production, recruits PMNs

    • IL-12  NK cells make IFN-gamma  makes macrophages better killers, upregulates IL-2 receptors on NK so they proliferate

    • TNF-alpha, IFN-gamma, IL-12 also activate T cell immunity!!

  • Resistance to innate immunity

    • Organisms can become resistant to phag, ROS, complement, antimicrobial peptide

  • Innate versus adaptive immunity

    • Innate cells/molecules often present at infection site when it occurs

    • Innate works rapidly acute inflammation

    • Adaptive takes longer and is highly specific for the microbe’s antigens

    • Adaptive system shows memory so next response is more rapid

    • Adaptive is specific, but doesn’t know “bad” from “good/benign” – innate system decides whether to attack

  • What to know

    • Know the different levels of innate immune defense: physical, soluble molecules, cells

    • Know the characteristics of the different cells of the innate immune system

    • Characteristics and function of innate immune receptors

    • Functions of immature and mature dendritic cells.

    • Role of class I in NK cell recognition

    • Understand the differences between innate and adaptive immunity

    • Understand the role of innate defenses in activating adaptive immune defenses



ANTIBODIES/IMMUNOGLOBULINS

  • Basics

    • Antigen due to vaccination/infection  inc Ig specific to it

      • Plasma, extravascular spaces, secretions

    • Glycoproteins

    • Bind antigens with high specificity, affinity

    • Made by B cells

    • 5 classes: G, A, M, D, E

  • Basic structure

    • 4 polypeptide chain unit covalently bonded

      • 2 identical light (L) chains

        • 2 kinds: kappa κ, lambda λ

      • 2 identical heavy (H) chains

        • 5 kinds (define Ig classes): M--µ. D--δ. G--γ. E--ε. A--α

      • L bound to H via disulfide and non-covalent hydrophobic/hydrophilic interactions

    • Symmetrical: allelic exclusion – inhibition of the other Ig genes in the B cell making a specific Ig

    • L and H have disulfide loop every 90 aa’s

      •  polypeptide loop domains of 110 aa’s

        • VH, VL, CH1, CH2, CH3 domains each with diff function

        • VH + VL: binding site for antigen

        • CH2-CH2: complement fixation

      • Characteristic of Ig superfamily

    • Fab fragment: N-term half of H chain and all of L chain

      • Antigen binding site: N quarter of H and N half of L

        • Binds to antigenic determinant

        • Variable region of Ig

      • Constant regions CH1

        • All Ig of same class/subclass have same aa sequence in constant regions

    • Fc region: C-term half of H chain

      • Constant regions CH2, CH3

      • Determines effector function of Ig

        • Combines Ig with complement

        • Binds to certain types of cells at FcR

      • Fc receptors (FcR)

        • Many types of cells

          • IgG FcR: monocytes, granulocytes, lymphocytes (not RBC)

          • IgA FcR: monocytes, granulocytes (esp mucosal)

          • IgE FcR: mast cells, basophils (involved in degranulation)

    • Antibody valence, affinity, avidity

      • Valence: max number antigenic determinants Ig can interact with

        • E.g. 2 Fab sites can bind to 2 molecules antigen or 2 identical site on same antigen

      • Affinity: tightness of bond between Ig binding aite and antigenic determinant

        • Kd, dissociation constant (higher = more likely to dissociate)

      • Avidity: combined effect of valence and affinity

        • Higher valence  higher affinity due to more bond sites

  • Antigens: fits in Ig pocket via non-covalent bonding

    • Innate system recognizes molecule patterns common to microbes

    • Adaptive system recognizes specific antigens on a microbe

    • Protein, lipid, carb, na

    • Ig binds to native antigen (how it is in nature)

    • Must be unique enough to induce immune response

      • Often several diff antigenic determinants (epitopes) per antigen  multideterminant

        • Ig binds to this (can have multiple diff Ig’s if determinant is non-identical)

        • Protein: 3-6 aa’s; Carb: 5-6 sugar molecules

          • Carbs tend to have repeating sugar units  several identical determinants

  • Antibody classes (isotypes)

    • IgG

      • 150kD (small, so gets into tissues)

      • vascular, extravascular, and secretions

      • most abundant Ig in blood

      • most immunity for blood borne microbes

      • crosses placenta  passive immunity to fetus

      • 4 subclasses with diff H chain sequences (1-4)

        • bind to diff FcR

      • long half-life  good protection

        • FcRn binds to IgG at low pH when IgG gets to endosome and recycles it

      • Requires help to activate complement

    • IgM

      • 900kD (big!)  mostly in vascular space/serum, not tissue

      • First Ig expressed on B cell

        • Normal 4-chain unit

      • Also soluble in blood

        • 5 5-chain units held together

        • J chain causes polymerization

      • Activates complement well (on its own)

      • 10 binding sites per molecule  high overall avidity

        • important since IgM is first in immune response; must act until IgG is ready

    • IgA

      • Vascular

        • 170kD

        • normal 4-chain unit

      • Also major Ig in secretions (colostrum, milk, saliva)

        • also has secretory component (SC) and joining chain (J chain)

          • SC: transepithelial transport, protection from degradation

          • J chain: holds units together via disulfides

        • 420kD dimer

        • made locally by plasma cells in mammary and salivary glands and resp, GI, GU tracts  transported through epithelial cells to lumen

      • Defense against microbes at mucosal surfaces

      • 2 subclasses

    • IgD

      • Low quantities vascular

      • Antigen receptor on B cells

        • Naïve B cells have IgM and IgD for the same antigen

        • Antigens internalized when bound  presented on surface to T cell  T cell signals B to proliferate and become plasma cell  plasma makes lots of Ig

    • IgE

      • Very low quantities vascular

      • Acute inflammation

      • Protection from worm infections

      • Allergies, hay fever, asthma (hypersensitivity)

      • Mast cells with IgE

        • Antigen binds  mast cells releases histamine

  • Allotypes and idiotypes

    • Allotypes

      • Genetic markers on Ig’s that differ between individuals

      • Often single aa differences on L or H chain

      •  immunogenic when injected into individual that doesn’t have the allotype

      • don’t affect function of Ig

    • Idotypes

      • Unique antigenic determinants in the antigen binding site

      • Ig’s can be made against them when injected into other animals

      • Each B cell clone expresses same idotype (produces single type of Ig)

  • IgM versus IgG

    • Neutralizing virus/toxins: IgM is better since it has 10 binding sites

    • Wider distribution: IgG, since it’s smaller and can get into tissues

    • Long-term protection: IgG due to long half-life

    • Interaction with innate components: IgM can activate complement on its own, IgG requires 2 molecules

  • What to know

    • Know the different antibody isotypes and subclasses.

    • Be able to describe antibody structure and know how this relates to different functions

    • Know where different antibody isotypes are found

    • Understand the basic nature of an antigen and its epitope (what is recognized)

    • Understand the unique features of each isotype that relate to its specific function

    • Know the differences between isotypes, allotypes and idiotypes



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