Immunology Comprehensive Study

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hlwillson
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Immunology Comprehensive Study
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2010-08-17 16:05:18
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Immunology comprehensive exam study
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  1. T-cell general description
    • 1. No secreted form
    • 2. detects antigens from within cells using MHC Class molecules
    • 3. Matures in thymus
    • 4. No affinity maturation
    • 5. CD4 = TH1 and TH2; MHC Class II
    • 6. CD8 = cytotoxic; MHC Class I
  2. HLA-DM
    • MHC class II-like molecule
    • Catalyzes MHC class II CLIP removal
    • Catalyzes MHC class II peptide binding
    • Peptide editing
    • Does not bind peptide
    • Increased by IFN-γ
  3. HLA-DO
    • Does not bind peptides
    • Negative regulator of HLA-DM
    • Not increased by IFN- γ
  4. Pathogen evasion of MHC difficult because?
    • Polygenic
    • Polymorphic
  5. HLA genes
    • Human Leukocyte Antigen genes
    • MHC class I and class II genes in humans
  6. Polymorphism
    Within species variation at a gene locus
  7. Gene conversion
    Sequence of one gene replaced by sequence of a different gene
  8. Point mutations
    • Replacement substitutions that change an amino acid
    • Silent substitutions change codon but not amino acid
  9. Sequence motif
    Set of anchor residues that allow binding to a given MHC class I or class II allele
  10. Alloreactive
    Allogeneic T-cells that react to non-self MHC molecules
  11. Superantigens
    • Cause excessive production of T-cells
    • Bind MHC class II already bound to antigen
    • Bind TCR
    • Creates systemic shock
    • Suppresses adaptive immune response
  12. Superantigen Examples
    • SE - Staphylococcal enterotoxins
    • TSST - Toxic Shock Syndrome Toxins
  13. Four main tasks of the immune system
    • Immunological recognition
    • Immune effector functions
    • Immune regulation
    • Immunological memory
  14. Myeloid lineage cells
    • Common myeloid progenitor
    • Macrophages
    • Granulocytes
    • Mast Cells
    • Dendritic Cells
  15. Common myeloid progenitor
    • Macrophages
    • Granulocytes
    • Mast Cells
    • Dendritic Cells
  16. Macrophages
    • Innate system phagocyte
    • In most tissue
    • Mature form of monocytes
    • Induce inflammation
    • Secrete signal proteins
    • General scavengers
  17. Granulocytes
    • Neutrophils - innate system phagocytes
    • eosinophils - involved in allergic inflammation reactions
    • basophils - involved in allergic inflammation reactions
  18. Mast Cells
    • Differentiate inside tissues
    • Protect internal surfaces of body
    • respond to parasitic worms
    • cause allergic responses
  19. Dendritic cells
    • Antigen presenting cells (APC)
    • Phagocytic
    • Macropinocytosis
    • activate T-cells
  20. Lymphoid lineage
    • Both adaptive and innate immune systems
    • Common lymphoid progenitor
    • NK
    • Lymphocytes
    • B-cells
    • T-cells
  21. Common lymphoid progenitor
    • in bone marrow
    • creates antigen specific lymphocytes and NK cells
  22. NK cells
    • recognize and kill abnormal cells
    • innate immunity
  23. Lymphocytes
    • Naive lymphocytes
    • effector lymphocytes differentiate into B- and T- cells
  24. B-cells
    • Mature in bone marrow
    • enter bloodstream as naive mature B-cells
    • BCR
    • proliferate and differentiate into plasma cells
    • produce antibodies and immunoglobulins
    • can make memory cells
  25. T-cells
    • TCR
    • activated by antigen
    • proliferate/differentiate into effector T-lymphocytes
    • functions = cytotoxic, helper, regulatory
    • can make memory cells
  26. Central lympoid organs
    • bone marrow
    • thymus
    • generate lymphocytes
  27. Peripheral lymphoid organs
    • lymph nodes
    • spleen
    • mucosal lymphoid tissues
    • maintains mature lymphocytes and initiate adaptive responses
  28. PALS
    • periarteriolar lymphoid sheath
    • b-cells along follicles of spleen
  29. MALT
    mucosa-associated lymphoid tissue
  30. GALT
    • Gut-associated lymphoid tissue
    • M cells - microfold epithelia of Peyer's Patches in small intestines
  31. NALT
    Nasal-associated lympohoid tissue
  32. BALT
    • Bronchus-associated lymphoid tissue
    • overlaid by M cells
  33. Innate to Adaptive process
    • 1. Physical/chemical first defense barriers
    • 2. innate response cells
    • 3. macrophage secrete cytokines/ chemokines
    • 4. cytokines affect nearby cells
    • 5. chemokines attract cells out of blood
    • 6. inflammation
    • 7. Complement
    • 8. inflammation
  34. Three complement activation pathways
    • Classical
    • Lectin
    • Alternative
  35. Classical Complement Pathway
    • Initiated by binding of C1q to pathogen surface
    • C1q binds c-reactive protein
    • Binds antigen:antibody complexes
    • Natural antibodies can bind C1q and activate
    • C3 convertase = C4b2a
  36. Lectin Pathway of Complement activation
    • Initiates by binding carbohydrate binding proteins (CBPs) to carbohydrate arrays on pathogen surface
    • Homologous to classical pathway
    • Mannose binding Lectin (MBL) acts like C1q
    • C3 convertase = C2aC4b
  37. Alternative Pathway of Complement Activation
    • Initiated by binding spontaneously initiated C3 component to surface
    • C3 convertase = C3bBb
    • Does not depend on pathogen binding
    • Tickover
    • Acts as amplification loop for all three complement activation pathways
  38. PRR
    • Pattern recognition receptors
    • recognize PAMPs
    • includes: MBL, MMR, fMLP
  39. PAMPs
    • Pathogen associated molecular patterns
    • Include: lipoteichoic acid, lipopolysaccharides, unmethylated DNA
  40. MBL
    • Mannose binding lectin
    • free in plasma
    • initiates lectin complement pathway
    • binds phaogcytes
  41. MMR
    • Macrophage Mannose receptor
    • similar to MBL
  42. TLR
    • Toll-like receptors
    • 10 TLR genes
    • produce protein for PAMPs
    • limited repertoire
    • cell surface receptors
    • intracellular acting on endosome membranes (sense pathogen uptake)
  43. TLR-4
    • Detects common bacterial infections
    • on Macrophages
    • signal bacterial lypopolysaccharides (LPS)
    • Represents Toll pathway
  44. TLR-2
    Signals microbial constituents: lipoteichoic acid (LTS) (Gram +) and Lipoproteins (Gram -)
  45. TLR-3
    • signals DS - RNA
    • produces cytokine interferon
  46. Toll pathway
    • Initiates with TLR-4
    • CD-14 binds LPS
    • TLR-4:MD-2 complex targets binds CD-14:LPS complex
    • Causes transcript of factor NFκB
  47. NOD proteins
    • Present in cytosol
    • Similar to TLRs
    • NOD-1
    • NOD-2
    • Acts in addition to TLR if both present
    • Recognize bacterial cell-wall proteoglycans
    • Activates NFκB
  48. NOD-1
    • Binds breakdown of (-) bacteria: iE-DAP
    • Activates innate immunity
    • encoded in CARD 4 gene
  49. NOD-2
    • Binds muramyl dipeptide of (-) and (+) bacteria
    • induces α-defensins
    • CARD 15 gene
  50. NFκB activation
    • produces cytokines/chemokines
    • cell surface expression of co-stimulatory molecules
    • activates CD4 T-cells via MHC class II molecules
    • Initiates adaptive immune response
    • causes migration of APCs to lymph notes by cytokines (TNF- α)
  51. Adjuvants
    • vehicle used to enhance antigenicity
    • LPS co-injected with antigen to initiate co-stimulatory molecules necessary for adaptive memory response
  52. Cytokines
    • Secreted by activated macrophages
    • induce responses by autocrine, paracrine, endocrine receptor binding
    • hematopoietin family of groth homormones and innate and adaptive interleukins (IL)
    • TNF family of adaptive and innate
    • includes: IL-6, IL-1, IL-12, TNF- α
  53. Chemokine Description
    • chemoattractant cytokines recruit cells to infection
    • produced by phagocytes/dendritic cells
    • G-protein coupled receptors
    • CXCL8 typical of family
    • CC chemokines
    • CXC chemokines
  54. Chemokine Roles
    • Change conformation of leukocyte integrins adhesion molecules (extravasation)
    • Direct leukocyte by chemokine gradient in extracellular matrix (increases toward infection site)
  55. CC Chemokines
    • promote migration of monocytes, lymphocytes, others
    • 9 CC receptors (CCR 1-9)
    • Example: CCL 2 induces monocyte migration to tissues for maturation to macrophages
  56. CXC chemokines
    • expressed on different cell types
    • 6 CXC receptors (CXCR 1-6)
    • Example: CXCL 8 promotes migration of neutorphils
  57. fMLP peptide
    • bacterial product
    • acts like chemoattractant for neutrophils
  58. Cell adhesion molecules
    • Selectins
    • Integrins
    • ICAMs
  59. Selectins
    • cell adhsion molecule
    • leukocyte recruitment
    • membrane glycoprotein
    • lectin-like domain binds carbohydrates
    • binds fucosylated oligosaccharide ligands of leukocytes
  60. Integrins
    • cell adhesion molecule
    • binds ICAMs on endothelium to leukocytes
    • causes tighter binding
    • extravastion integrins: LFA-1, CR3
  61. ICAMs
    • intracellular adhesion molecules on endothelial tissue
    • binds to integrins on leukocytes
  62. Extravasation
    Exude from a vessel into tissues
  63. List the 4 steps of extravasation
    • 1. Selectins
    • 2. ICAMs
    • 3. Extravasation
    • 4. Leukocyte migration via chemokine gradient
  64. Extravasation step 1: selectins
    • P-selectin appears via cytokines, histamines, LPS produces E-selctin
    • recognizes leukocyte moiety allowing reversible vessel wall adhesion
  65. Extravasation step 2: ICAMs
    • leukocyte integrins LFA-1 and CR3
    • increases adhesion of neutorphil
    • bind proteoglycans to CXCL8 or chemokines causes conformational change
  66. Extravasation step 3: Extravasation
    • leukocyte crosses endothelial wall
    • diapedesis
  67. Extravasation step 4: Leukocyte migration
    • matrix associated chemokine gradient
    • CXCL8: recruits neutrophils first
    • CCL2: recruits monocytes second
  68. Cytokine Acute Phase response
    • stimulated by endogenous pyrogens (TNF-α, IL-1B, IL-6) and exogenous pyrogens (via TLR-4 signaling E2)
    • acts on hepatocytes
    • induces 2 acute-phase proteins: C-reactive, MBL
    • provides host with antibody like proteins with wide range pathogen specificity
    • increases circulating neutrophils = leukocytosis
  69. C-reactive proteins
    • cytokine acute phase protein
    • binds phosphocholine of LPS
    • Opsonizes
    • activates classical pathway via C1q binding
  70. MBL Proteins of acute-phase response
    • increased production during acute-phase repsonse
    • opsonin for monocytes which do not express MMR
  71. Interferons
    • proteins that interfere with viral replication
    • IFN- α
    • IFN- β
    • IFN- γ (indirectly induced by virus)
    • DS-RNA PAMPs recognized via TLR-3
    • Activate RIG-1, MDA-5
  72. STAT proteins
    • Janus-family tyrosine kinase induces transcription
    • Oligoadenylated synthetase
    • PKR kinase
    • Mx
  73. IFN-γ Production
    IL-12 + TNF-α stimulate NK cells to produce
  74. ITAMs
    immunoreceptor tyrosine-based activation motifs
  75. ILLs
    • innate-like lymphocytes
    • adaptive but act like innate
    • no clonal expansion
    • antigen receptors have decreased diversity due to few gene rearrangements
    • not via MHC molecules - recognize antigens as consequence of infections
  76. Natural antibodies
    • IgM
    • no somatic hypermutation
    • Low pathogen affinity
    • highly cross-reactive
    • binds some self molecules
    • not a consequence of infection
  77. Immunoglobulins (Ig)
    • antigen recognition molecules of B-cells
    • each B-cell produces 1 specific Ig
    • Secreted form = antibody
  78. BCR
    • B-cell receptors
    • membrane-bound Ig on B-cell surface
  79. Antibody description
    • secreted Ig
    • V-region = variable region antigen binds to
    • C-region = constant region (inserted into B-cell membrane in membrane form) defines Ig effector function
  80. TCR
    • T-cell receptors
    • V- and C-regions
    • bind pathogenic peptide fragments associated with MHC class I & II molecules on cell surfaces
  81. Ig 5 classes
    • IgM
    • IgD
    • IgG
    • IgA
    • IgE
  82. Ig structural description
    • 2 x heavy chains (H chains) both the same
    • 2 x light chains (L chains) both the same
    • H chain defines class
    • both H and L chains have V and C regions
    • Fab fragments
    • Fc fragments
  83. Ig L chains
    • λ
    • κ
    • *given antibody has one or the other - not both*
    • 2 Ig domains
  84. Ig H chain
    • denoted by lowercase Greek letter of each type (α, γ, δ , μ, ε)
    • defines Ig class
    • four Ig domains
  85. Fab fragments
    • Fragment Antigen Binding
    • corresponds to 2 identical arms of antibody: complete light chain, VH, CH1
    • antigen binding fragment of Ig
  86. Fc Fragment
    • Fragment crystallizable
    • Ig fragment with no antigen binding activity
    • functional differences
    • CH2 & CH3
  87. Fv
    • Fragment Variable
    • genetically engineered truncated Fab (V of H linked to V of L)
    • small size allows easy tissue penetration
    • potential tumor therapy
  88. Hapten
    partial antigen that cannot alone elicit antibody response but can combine with anti-hapten molecules to produce antibodies
  89. Ig Hv loops
    • Hv1
    • Hv2
    • Hv3 - most variable
    • * outer loops for antigen binding
  90. CDRs
    • complementarity determining regions
    • composed of combination of VH and VL region for specificity
  91. Combinatorial diversity
    generating different combinations of H and L-chains
  92. Antigenic determinant/ epitope
    • Structure recognized by antibody
    • conformational/discontinuous epitopes
    • continuous/linear epitopes
  93. TCR structure
    • TCRα
    • TCR β
    • form heterodimers similar to Ig Fab
  94. MHC class I molecules
    • polypeptide chains (α1 and α2) form peptide binding cleft/groove
    • α3 + β2-microglobulin resemble Ig-like domain
    • Bind preferentially to CD8 T-cells
    • displays peptides from intervesicular pathogens
    • binds peptide at endoplasmic reticulum
    • on most cells except non-nucleated cells
  95. MHC class II molecules
    • α1 +β1 = binding cleft
    • preferentially binds CD4 T-cells
    • displays peptide fragments from cystolic pathogens
    • normally on b-cells, dendritic cells, macrophages
    • stimulate b-cells, macrophages
  96. RSS
    • Recombination Signal Sequences
    • noncoding DNA adjacent to points of recombination that guide Ig gene rearrangement
  97. 12/23 Rule
    segment flanked by RSS with 12 bp spacer joins with one flanked by RSS with 23 bp spacer
  98. Ig repertoire diversity main processes
    • 1. combinatorial diversity
    • 2. Junctional diversity
    • 3. Different H- & L-chain combinations
    • 4. Somatic hypermutation
  99. P-nucleotides
    palindromic sequences added to ends of gene segments
  100. N-nucleotides
    • non-template encoded
    • added by TdT at SS-ends of coding DNA following hairpin cleavage
  101. Fc region 3 main effector functions
    • 1. Recognized by Fc receptors on immune effector cells
    • 2. binds complement and initiates compliment cascade
    • 3. delivers antibodies to places unreachable without using active transport
  102. Secondary diversification of antibody repertoire
    • only in activated B-cells
    • driven by antigen
    • 3 mechanisms
  103. 3 Mechanisms of secondary diversification of antibodies
    • 1. Somatic hypermutation
    • 2. Gene conversion
    • 3. Class switching (recombination)
    • all initiated by activation-induced cytidine deaminase (AID)
  104. Somatic hypermutation
    • induced by AID
    • introduces point mutations into V region of both chains
    • alters antigen affinity
    • causes affinity maturation
  105. Gene conversion
    • replaces blocks of gene sequence from V region with blocks from pseudogenes
    • induced by AID
  106. Class switching
    • induced by AID
    • involves C region only
    • replaces C μ with alternate isotype
    • also called isotype switching
    • irreversible DNA recombination
    • stimulated by Tcell cytokines or pahtogenic mitogenic signals
  107. Affinity maturation
    • clones have increased affinity for antigen than original BCR
    • selected preferentially for secretion
  108. R loops
    bubbles formed when RNA displaces non-template strand DNA
  109. antigen processing
    generation of peptides from intact antigen via modification of native protein
  110. antigen presentation
    display of peptide at cell surface by MHCs
  111. ABC
    • ATP-binding Cassette
    • mediates ATP-dependent transport
    • TAP 1
    • TAP 2
  112. immunoevasions
    • viral interference of antigen presentation of MHC I molecules
    • Targets TAP
    • Retains MHCI:Peptide complex in E.R.
    • dislocation by catalyzing degradation of newly formed MHC I molecules

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