Oral Immunology - 0523 - L9 10

  1. Local immune response
    • Macrophages secrete cytokines, dilate local blood vessels.
    • Leukocytes recruited as a result of increased expression of adhesion molecules
    • Leukocytes extravasate at site of infection
    • Blood clotting in microvessels
  2. Cytokines that cause fever
    IL-1b (induces the production of IL-6), TNF-a, IL-6
  3. Cytokines and chemokines by macrophages
    IL-1b: Activates vascular endothelium & lymphocytes; Local tissue destruction; Increases access of effector

    TNF-a: Activates vascular endothelium and increases vascular permeability; increased entry of lgG, complement, and cells to tissues; increased fluid drainage to lymph nodes

    IL-6: Lymphocyte activation; Increased antibody production

    CXCL8: Chemotactic factor recruits neutrophils, basophils, and T cells to site of infection

    IL-12: Activates NK cells; Induces the differentiation into TH1 cells
  4. The adaptive (acquired) system is based on ________ of lymphocytes bearing ________, and has memory.
    • clonal selection
    • Ag-specific repertoire
  5. MHC Class I vs. MHC class II
    • on all cells except RBCs
    • on all antigen presenting cells
  6. Generation of diversity in BCR and TCR:
    V(D)J recombination (aka. Somatic gene recombination) by enzymes, mainly RAG1&2 (recombination activating genes)
  7. The adaptive immune system is induced when an infection has overwhelmed the _________.
    innate immune mechanisms
  8. T cells that mature in the _____ enter the bloodstream, reach the peripheral lymphoid organs, and recirculate via the lymphatics between the blood and peripheral LNs.

    To participate in the adaptive immune response T cells must ____________. They then differentiate into ________, capable of ________.
    • thymus
    • encounter their specific Ag, presented to them as MHC-peptide complex on antigen presenting cells (APCs)
    • Effector T cells
    • removing the Ag
  9. __________ are called Naïve T cells
    Mature recirculating T cells that have not encountered their specific Ag
  10. T Cells
    • comprise the cell-mediated arm of the adaptive immune system.
    • must dock with an APC that bears the correct Ag peptide presented by an MHC molecule.
    • function only in the context of intimate cell-cell contacts.
  11. T cells function:
    • helper functions, such as control of Ab responses via contacts with APCs and B cells
    • cytolytic functions, i.e. recognition and lysis of virally infected cells (requiring cell-cell contact)
  12. CMI reactions occur in response to:
    • Viruses
    • Intracellular bacteria
    • Fungal infections
    • Parasitic infections
    • Tumor immunity
    • Allograft rejection
  13. Activated functions of myeloid cells in innate and adaptive immunity
    Dendritic cell - Ag uptake in peripheral sites; Ag presentation

    Macrophage - Ag presentation; Phagocytosis & activation of bactericidal mechanisms

    Neutrophil - Phagocytosis & activation of bactericidal mechanisms

    Eosinophil - Killing of antibody-coated parasites

    Basophil - augmentation of anti-parasitic immunity; Promotion of allergic responses

    Mast cell - Release of granules containing histamine and active agents
  14. APCs
    • Dendritic cells - low MHC expression when immature
    • macrophages - low MHC but induced quickly
    • B cells - constant high MHC expression
  15. _________ are immature DCs that take up Ag in the skin, migrate to LNs to present foreign Ag to T cells.
    Can transfer Ag to ________, too.
    In LNs, LCs differentiate into DCs that can no longer ingest Ag (no more phagocytosis), but have _________ activity, enhancing activation of naive T cells.
    • Langerhans cells
    • resident DCs
    • co-stimulatory (B7)
  16. Examples of co-stimulatory molecules
    • B7 (7.1/7.2; CD80/CD86), DC -> CD28, T, enhance, naive
    • B7 (7.1/7.2; CD80/CD86), DC -> CTLA-4 (CD152), T, inhibitory, upregulated in activated T cell, thus down-regulate T cell proliferation, binds more avidly than CD28
    • CD40 (B) -> CD40L (T), enhance
  17. APC deliver three kinds of signals to naive T cells
    • Activation: Ag presentation, carried by MHC II, binds to TCR and CD4 (binds to MHC II)
    • Survival: B7.1/7.2 - CD28
    • Differentiation: cytokines bind
  18. CD28-dependent co-stimulation induces expression of T cell growth factor (IL-2) and its high affinity receptor (CD25)
    • Naive T cells only have IL-2R β,γ chains w/ moderate affinity w/ IL-2.
    • Activation of T cells induces expression of IL-2R α chain or CD25.
    • Binding of this high affinity receptor by IL-2 leads to T cell proliferation.
  19. Effector T cells can respond to target cell ______ co-stimulation signal.

    activated T cells proliferate and differentiate w/ the action of IL-2 to form effector T cells
  20. The roles of effector T cells in cell-mediated and humoral immune responses
    • CD8 cytotoxic T cells - Kill virus-infected cells
    • CD4 TH1 cells - Activate infected macrophages; Help B cells' Ab production; IFN-γ
    • CD4 TH2 cells - Help B cells' Ab production, esp IgE; against parasites; IL-4,5,13
    • CD4 TH17 cells - Enhance neutrophil response; Promote barrier integrity (skin, intestine); fungi; IL-17,22
    • CD4 regulatory T cells (various types) - Suppress T-cell responses; TGF-β, IL-10
    • TFH cells - Help B cells' Ab production and lsotype switching; found in follicular centers; IL-21
  21. Naive T cells encounter antigen during their recirculation through peripheral lymphoid organs
    • T cells enter lymph node cortex from blood via high endothelial venules (HEVs)
    • T cells not activated by Ag presented by dendritic cells exit LN via cortical sinuses
    • T cells activated by Ag presented by dendritic cells start to proliferate and lose the ability to exit LN
    • Activated T cells differentiate to effector cells and exit LN
  22. Dendritic cells reside in ________ when immature. They take up ____ and migrate to ________ via _______. Mature dendritic cells activate _________ thus initiate ________.
    • peripheral tissue
    • Ag
    • regional LN
    • lymphatic vessels
    • naive T cells
    • Adaptive immune response
  23. Lymphocyte entry into a lymph node from the blood
    • Rolling - selectins; naive T cells have CCR7
    • Activation - chemokines, CCL21; activated T cells lose CCR7 and acquire CCR9
    • Adhesion - integrins, LFA-1
    • Diapedesis - chemokines, CCL21, CXL12
  24. Activation of naive and effector T cells by antigen
    • Activate naive T cells:
    • - Dendritic cell takes up Ag, presents it
    • - Naive T cell recognizes Ag
    • - Binding, enhanced by costimulatory molecules like B7 (dendritic) and CD28 (T)
    • - T cells activated
    • Activate naive B cells:
    • - naive B APC binds to effector T cells, enhanced by CD40L (T) - CD40 (B) binding
    • - B cells activated
    • Activation of effector T cells at site of infection
  25. TCR complex
    • made up of variable Ag-recognition proteins and invariant signaling proteins
    • ITAM (Immunoreceptor Tyrosine-based Activation Motif) - intracellular signaling component of both TCR and CD3
    • Ag-binding TCRα:β heterodimer
    • 4 signaling chains (2 ε, 1 γ, & 1δ) collectively called CD3; required for the expression of TCRα:β and for signaling.
    • A homodimer of ζ associated w/ TCRα:β.
    • Each CD3 chain has one ITAM, ζ chain has three.
  26. BCR
    • cell-surface Ig for Ag binding
    • non-specific Igα and Igβ (together linked to the heavy chain) both of which contains intracellular signaling tail, ITAM signaling proteins
  27. ITAMs recruit signaling proteins that have ______ domains, which connect to _______.
    • tandem SH2
    • kinase domain
  28. Cell adhesion molecules of the Ig-super-family stabilize interactions between APCs : T cells
    • ICAM-1/2/3 : LFA-1
    • CD58 : CD2
  29. Transient adhesive interactions between T cells and Ag-presenting cells are stabilized by specific antigen recognition
    • ICAM-1:LFA-1 loose binding initially
    • Ag-specific binding of TCR signals LFA-1 for conformational change
    • ICAM-1:LFA-1 binding strengthened
  30. The area of contact between an effector T cell and another cell forms ____________.
    • an immunological synapse
    • outer ring - pSMAC (supramolecular adhesion complex); LFA-1:ICAM-1, etc.
    • inner ring - cSMAC; TCR, CD4, etc.
  31. Tc action
    • collision and non-specific binding w/ target cell
    • specific binding -> redistribution of cytoplasmic matter and cytoskeleton
    • release of granules at site of contact
  32. Activation of T cells changes the expression of several cell-surface molecules
    • CD45RA -> CD45RO
    • L-selectin disappears
    • VLA-4 appears
    • CD4, TCR stay
    • LFA-1, CD2, CD44 increase
  33. TH1 action
    • secretion IFN-γ or binding to APCs containing microbes
    • APCs secrete IL-12
    • IL-12 converts naive CD4 T cell to TH1
    • activated TH1 secrets IFN-γ, activating macrophage killing
  34. TH2 actions
    • binds B cell, secrete IgG & IgE (enhanced by IL-4)
    • - IgE -> degranulation of mast cells
    • secrete IL-5, activates eosinophil against parasite
    • secrete IL-5, IL-13, alternative activation of macrophage -> suppression of inflammation
  35. CTL-mediated cell lysis
    • exocytosis of granzymes, perphorin -> endocytosis -> perforin-dependent entry of granzymes -> caspases activated, leading to apoptosis
    • FasL on CTL binds to Fas on target cell -> apoptosis activated
  36. Cytotoxic effector proteins released from cytotoxic T cells
    • Perforin - helps delivering
    • Granzymes & Granulysin - activate apoptosis
  37. Critical cytokines for CD4 T cells differentiation
    • TH1 - IFN-γ
    • TH2 - IL-4
  38. B cell Development
    • Derive from hematopoietic stem cells in the bone marrow.
    • Rearrangement of the heavy-chain locus.
    • The pre-B-cell receptor tests for successful production of a complete heavy chain and signals for the transition from pro-B cell to pre-B cell.
    • Pre-B-cell receptor signaling inhibits further heavy chain locus rearrangement and enforces allelic exclusion.
    • Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin.
    • Immature B cells are tested for autoreactivity before they leave the bone marrow.
  39. Gene segments for light and heavy chains
    • Leader, Variable, (Diversity), Joining, Constant
    • D is only for heavy chain
    • All have multiple functional segments except κ light chain only has 1 Constant.
  40. The early stages of B-cell development are dependent on ________.
    • bone marrow stromal cells
    • stromal cells release CXCL12
    • FLT3 of multipotent stem cell binds to FLT3 ligand on stromal cells
    • stromal cells release IL-7, binds to IL-7 receptors on common lymphoid progenitor, which develops through pro- and pre-B-cell stages
    • pre-B cell puts IgM on the surface, becomes immature B cell
  41. Transcription factors during early stages of B-cell development:
    • ikaros - functioning throughout
    • Pax5 - from the beginning of pro-B cell on
  42. The development of a B-lineage cell vs. the rearrangement of Ig genes
    • early pro-B: H chain, D-J
    • late pro-B: H chain, V-DJ
    • Pre-B: L chain, V-J
  43. Suface Ig on B cells
    • immature - IgM
    • mature - IgD and IgM
  44. The development of a B-lineage cell vs. protein expression
    • RAG-1/2 - during time of rearrangement
    • lambda5 - surrogate light-chain; disappears at the end of pre-B
    • Iga/b - throughout B cell development
    • CD19 - from late pro-B on
    • IL-7R - growth factor receptor; mid-stem to mid pre-B
  45. Genes can be recombined contains sequence called
    • recombination signal sequence (RSS)
    • RAG-1/2 randomly pick two segments, cleave off RSS, and the remaining segments are eventually connected w/ the help of many proteins, including TdT
  46. Selective expansion of TH1 leads to ______ & production of ________;
    Selective expansion of TH2 provides ________ (especially production of ________).
    • cell mediated immunity
    • opsonizing Ab classes (IgG)

    • humoral immunity
    • IgM, IgA & IgE
  47. CD-4 T cells' fate-speficying and secreting cytokines
    • TH1: by IFN-γ, IL12. Produce IFN-γ
    • TH2: by IL-4. Produce IL-4, IL-5, IL-13
    • TH17: by TGF-β, IL-6, IL-23. Produce IL-17, IL-22
    • TFH: by IL-6. Produce IL-21
    • iTReg: by TGF-β, IL-2. Produce TGF-γ, IL-10.
  48. Blocking of _______ can induce Th1
    Blocking of _______ can induce Th2
    • IL-4
    • IFN-γ
  49. The subsets of CD4 T cells each produce cytokines that can negatively regulate the development or effector activity of other subsets
    • TReg produces TGF-b, inhibits TH1 & TH2
    • TH2 produces IL-4, inhibits TH1 & TH17
    • TH1 produces IFN-c, inhibits TH2 & TH17
  50. Transcription factors for
    • T-bet
    • GATA-3
  51. TH1 vs. TH2 ____ can affect disease outcome
  52. Intracellular parasites (Mycobacterium leprae & M.
    tuberculosis) – macrophage vesicles
  53. Tuberculoid leprosy – Predominantly ___ response (_______): __________.
    • TH1
    • little Ab production
    • survival with few bacteria, but inflammatory skin and peripheral nerve damage
  54. Lepromatous leprosy – Predominantly ____ response (): _________.
    • TH2
    • Mainly humoral response
    • Ab cannot reach the intracellular bacteria in macrophages; gross tissue destruction; fatal
  55. _______ are critical for keeping the immune response in check:
    X-linked _____ mutation in humans – multiorgan autoimmunity
    _____ - mouse model; autoimmunity
    • Tregs
    • FoxP3
    • IPEX
  56. Course of acute infection that is cleared by adaptive immune response
    • 1. Establishment of infection: from entry of microbes to threshold Ag level (to activate adaptive response) is reached; microbe level increases.
    • 2. Induction of adaptive immune response: microbe level keeps rising until the peak.
    • 3. Adaptive immune response: in effect; microbe level decreases until cleared.
    • 4. Immunological memory
  57. Both the ____ and the ______ of Ab increase with repeated immunization.
    • affinity
    • amount
    • isotype switch IgM -> IgG
    • stronger effect on IgG than IgM [seemingly]
  58. secondary Ab response from memory B cells is distinct from generation of primary response
    • higher frequency of Ag-specific B cells
    • IgG, IgA vs. IgM>IgG
    • high affinity
    • high somatic hypermutation (discuss later)
  59. Function of Ab isotypes
    • IgG
    • - Opsonization
    • - classical pathway of complement activation
    • - Ab-dependent cytoxicity of NK and macrophages
    • - neonatal immunity via gut and placenta
    • - feedback inhibition of B activation
    • IgM
    • - classical pathway of complement activation
    • - surface Ab-receptor for naive B cells
    • IgA
    • - mucosal immunity - GI & respiratory tracts
    • IgE
    • - Ab-dependent cytotoxicity of eosinophils - parasites
    • - mast cell degranulation (immediate hypersensitivity)
    • IgD
    • - surface Ab-receptor for naive B cells
  60. Different cytokines induce switching to different antibody classes
    • IL-4 induces IgG1, IgE
    • IFN-γ induces IgG3, IgG2a
    • TGF-β induces IgG2b, IgA
    • IL-21 induces IgG3, IgG1, IgA
  61. Specialized function
    Activate complement system
    • IgG1
    • IgM and IgG3
    • IgG1,2,3,4 and IgA
  62. IgA is transported across epithelium as _______ and diffuses into extravascular sites as _______.
    • dimer
    • monomer
  63. IgG2 can act as opsonin in presence of an FcR of appropriate allotype in ~ 50% of whites
  64. Effector functions of Ab
    • neutralize microbes and toxin
    • macrophage - opsonization and phagocytosis
    • NK - Ab-dependent cytolytoxicity
    • Complement activation - C1q
    • - Lysis of microbes
    • - phagocytosis of opsonized microbes
    • - inflammation
  65. Bound Ab is distinguishable from free Ig by _______:
    • its state of aggregation
    • Free Ig does not cross link FcR on macrophages, no action
    • Bound Ig aggregate and causes FcR crosslink, activates macrophage, phagocytose and kill.
  66. IgG ADCC
    • antibody dependent cell-mediated cytotoxicity, through which Ab-coated target cells can be killed by NK cells
    • Fc region of IgG binds to FcγRIII (CD16) on NK
    • Crosslink
    • NK activate and cause apoptosis of the target cell
  67. IgE ADCC
    • multivalen Ag cross-link IgE
    • activates mast cells
    • rapid release granule contents, inflammatory mediators
  68. thymus independent antigens
    Response of bacterial Ags with intrinsic ability to activate B cells do not require T cell help
  69. TI-1 antigens: At high concentrations, these molecules cause ______, regardless of their ______. Also called ___. E.g. LPS which binds LPS binding protein and CD14, and associates with TLR4 of B cells.
    • proliferation and differentiation of most B cells
    • Ag-specificity
    • B cell mitogens
  70. High concentration of TI-1 Ag causes __________.
    polycolonal B cell activation and nonspecific Ab response
  71. Low concentration of TI-1 Ag causes __________.
    TL-1 Ag-specific Ab response
  72. TI-2 antigens
    consist of molecules such as bacterial capsular polysaccharides that have repetitive structures
  73. Whereas TI-1 Ags can activate _________, TI-2 Ags can _________.
    • both immature and mature B cells
    • only activate mature B cells
  74. Response to TI-2 Ags occur predominantly in _______ B cells (aka _____).
    • a subclass of B cells called B-1
    • CD5 B cells
  75. TI-2 Ag induce _________ production. However, with help from _______, B cells _________.
    • IgM
    • DCs and cytokines such as BAFF
    • switch their class of Ig to IgG
  76. Antibody neutralization of toxins
    • Toxin binds to membrane receptor
    • endocytosis
    • Toxin dissociates, poisons the cell
    • Ab binds to toxin and block its binding to the host cell
  77. Cell receptor for Ab
    • NK -> IgG1: FcγRIII (CD16), low affinity
    • mast cell -> IgE: FcεRI, high affinity
  78. The major class of Ab present in the lumen of the gut is _____________, the transcytosis of which is facilitated by ________.
    • secretory dimeric IgA
    • pIgR (polyIg)
  79. Secretary Component (SC)
    • binds part of the Fc of IgA containing binding site for FcαRI, so that FcαRI cannot bind IgA
    • Protects the Ab from proteolytic cleavage
    • Binds mucins in mucus – “glues” IgA to mucus layer
  80. Neonatal Humoral Protection
    • Fetus – passive IgG; only Ab isotype in fetus
    • FcRn (neonatal)
    • - Placental IgG transport from mother to fetus
    • - Neonatal transporation - Transports IgG from gut lumen of neonate into circulation
    • - Adult recyle - gut, liver & epithelium of adults – endocytose and recycle IgG to blood, prevents excretion from the body
    • Colostrum – IgG, IgA
Card Set
Oral Immunology - 0523 - L9 10
Oral Immunology - 0523 - L9, 10