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  1. IL-1beta function in inflammation when released from macrophages?
    • Local effects:
    • Activates vascular endothelium
    • Activates lymphocytes
    • Local tissue destruction
    • Increases access of effector cells
    • Systemic Effects:
    • Fever
    • Production of IL-6
  2. TNF-alpha function in inflammation when released from macrophages?
    • Local effects
    • Activates vascular endothelium and increases vascular permeability.
    • Leads to increased entry of IgG, complement, and cells to tissues
    • Increased fluid drainage to lymph nodes
    • Systemic Effects
    • Fever
    • Mobilization of Metabolites
    • Shock
  3. IL-6 function in inflammation when released from macrophages?
    • Local Effects
    • Lymphocyte activation
    • Increased anitibody production
    • Systemic effects
    • Fever
    • Induces acute-phase protein production by hepatocytes
  4. CXCL8 function in inflammation when released from macrophages?
    Chemotactic factor; recruits neutrophils, basophils, and T cells to site of infection
  5. IL-12 function in inflammation when released from macrophages?
    • Activates NK cells
    • Induces the differentiation of CD4 T cells into TH1 cells
  6. TLR-3
    RIG-1 & MDA-5
    • recognize dsRNA and induce the expression of Type 1 interferons which inhibit viral replecation and spreading
    • TLR-3 in endosomes
    • RIG-1 and MDA-5 in the cytosol
  7. IFN-alpha and -beta
    • Induce resistance to viarl replication in all cells
    • Increase MHC class I expression and antigen presentation in all cells
    • Activate dendritic cells and macrophages
    • Activate NK cells to kill virus-infected cells
  8. NK cells
    • develop in the bone marrow
    • activate in response to type 1 interferons
    • failure to express normal levels of MHC class 1 molecules triggers kill
  9. Classical Pathway Activators
    • IgM
    • IgG (IgG3>IgG1>IgG2>>IgG4); bound Ig
    • Apoptotic cells
    • Oxidized LDL
    • BINDS C1q
  10. Alternative Pathway activators
    • Whatever causes C3 to undergo conformational change to expose internal thiolester
    • Repeating Polysaccharides
    • Endotoxin
    • Virally infected cells
    • Yeast cell walls
    • IgA complexes
    • Lectin Pathway Activators
    • Mannose-containing microbial carbohydrates
    • Agalactosyl IgG
  11. Complement Receptor in opsonization
    CR1 (CD35)
    • Ligand: C3b;C4b
    • Expressed in RBC, PMN, monocytes, B cells, FDC, Kupffer cells, glomerular podocytes
    • Biological Effects: Removal of Immune Complexes (IC), phogocytosis, antigen presentation
  12. Complement Receptor in Opsonization
    CR2 (CD21)
    • Ligand: C3d,g
    • Sites of Expression: B-cells, thymocytes, FDC
    • Biological Effects: B cell co-activator, antigen presentation
  13. Complement Receptor in Opsonization
    CR3 (CD11b/CD18)
    • Ligand: C3bi
    • Sites of Expression: PMN, monocytes
    • Biological Effects: Phagocytosis
  14. Complement Receptor in Opsonization
    CR4 (CD11c/CD18)
    • Ligand: C3bi
    • Sites of Expression: PMN, monocytes
    • Biological Effects: Phagocytosis
  15. Anaphylatoxins
    • N-terminal fragments of C3, C4, C5
    • C5a is most potent
    • Bind to GPCR
    • Effects: chemotaxis, cytokine production, coagulation
  16. C1 esterase inhibitor
    • inhibits the protease activity of C1r and C1s
    • deficiency leads to hereditary angioedema
  17. Regulators of Complement Activation (RCA)
    Co-Factor Activity
    • Cleave C3 and C4 in the presence of Factor I
    • Factor H; fluid phase; AP
    • C4 binding protein; fluid; CP
    • Membrane Co-Factor Protein (CD46); cell surface, all pathways
    • CR1(CD35); cell surface; all pathways
  18. RCA factors Decay acceleration activity
    • Disrupt the association of C3 with C2a or Bb
    • Factor H; fluid phase; AP
    • C4 binding protein; fluid; CP
    • Decay Accelerating Factor (CD55); cell surface, all pathways
    • CR1(CD35); cell surface; all pathways
  19. Vitronectin
    Binds C5b-7 trimer and turns it hydrophilic, preventing membrane insertion
  20. Clusterin
    Prevents any C5b-9 that forms from binding to cells
  21. CD59
    • binds C8 in C5b-8 complex and prevents the sebsequent incorporation and polymerization of C9
    • attached to the cell surface by a glycophosphotidyl-inositol
  22. Isotypes (constant region of Ig)
    • Distinct forms of Ig light or heavy chains present in all members of a species
    • determine class of immunoglobulin
    • determined by constant region of the heavy chains
  23. Allotypes (constant region of Ig)
    different forms of the Ig C-region which can vary among members of the same species and are inherited in an allelic manner
  24. Idiotypes (Ids) (variable region)
    • unique VH and VL combination from all other antibodies, except antibodies from the same B cell founder clones
    • serves as a clonal marker for an Ig molecule and for the B cell that originally made it.
  25. IgM properties
    • T1/2: 5 days
    • Complement fixation: Yes
  26. IgG properties
    • Serum conc: 12-14 mg/ml
    • Source for fetus/newborn: crosses placenta
    • T1/2: 23 days
    • Complement fixation: Yes
  27. IgA properties
    Source for fetus: Milk
  28. FcRn
    • deliver maternal IgG across placenta
    • regulate IgG levels in the body via recycling
  29. poly-Ig receptor
    deliver IgA to mucosal surface
  30. HLA Class 1 presents antigens from? Using what molecules?
    • Cytosolic
    • Proteasome complex containing LMP
    • TAP transports peptide into ER
  31. Cross-presentation pathway
    Allows Pro APC to sense infections/tumors in other cell types (via extracellular compartment) and load peptide onto MHC class 1
  32. HLA class II, presents antigens from what compartment? Function of Invariant chain (CD74), MIIC, DM molecules?
    • Extracellular
    • Invariant chain: occludes class II groove, cleaved by CLIP
    • MIIC: compartment where processed antigen fragments meet class II/CLIP complex
    • DM molecules: replace CIP with anitgenic peptides
  33. CD1
    • class I-like beta2m-associated molecules
    • present non-processed, non-peptidic (lipid/glycolipid) antigens
    • antigens are loaded onto CD1 grooves in endocytic compartments, like class II MIIC compartments
    • Role in response to M. tuberculosis
  34. Class II genes
    • DP
    • DQ
    • DR
  35. Class I genes
    • B
    • C
    • A
  36. CD is linked to what genes
    HLA-DQ2 > HLA-DQ8
  37. What do MIC proteins do?
    • Upregulated under pro-inflammatory conditions due to IFNgamma upregulation
    • Activate intraepithelial T lymphocytes via NKG2D receptors
  38. Major gene associtation for Type 1 Diabetes? in Caucasions?
    • HLA-DQ8 > HLA-DQ2
    • DR3-DR-2 & DR4-DQ8 class II haplotypes
  39. Cytokine needed for DP cell development
  40. Cytokine needed for CD4 T cell/CD4 Treg development
    Pep/HLA CII
  41. Cytokine needed for iNK T cell development
  42. Cytokine needed for CD8 T cell development
    Pep/HLA CI
  43. What's the role of pTalpha subunit
    • Signal successful rearrangement of TCR beta protein
    • Allow DN to DP and RAG re-expression for TCRalpha locus
  44. Three Signals for T cell
    • Signal 1: TCR
    • Signal 2: CD28 (or ICOS)
    • Signal 3: cytokine receptor
  45. T cell/APC adhesion molecules
    • LFA-1 (CD11/CD18) --- ICAM1 (CD54)
    • ICAM ---- LFA-1
    • VLA-4 ---- VCAM
    • CD2 ----- LFA-3
  46. Which CD is the IL-2 receptor?
  47. Signal 3, transcription factor, and Cytokine produced by Th1
    • S 3: IL-12
    • TF: T-bet
    • cytokine produced: gamma-IFN
  48. Signal 3, transcription factor, and Cytokine produced by Th2
    • S3: IL-4, IL-25
    • TF: GATA3
    • cytokine produced: IL-4, IL-5, IL-13
  49. Signal 3, transcription factor, and Cytokine produced by Th17.
    • S3: IL-1, IL-6, TGF-beta
    • TF: ROR
    • cytokine produced: IL-17
  50. Signal 3, transcription factor, and Cytokine produced by Treg
    • S3: none
    • TF: GATA3
    • cytokine produced: IL-6, IL-10
  51. Signal 3, transcription factor, and Cytokine produced by Tfh
    • S3: IL-6, IL-21
    • TF: ?
    • cytokine produced: IL-21
  52. CDs unique to B cells
    CD19, CD20, CD22
  53. Surrogate light chain components
    VpreB and delta5
  54. What B cell stage expresses CD34
    Stem cell
  55. What B cell differentiation stage expresses CD79 and CD20
  56. Mutations in what cause immunodeficiency disease?
    Ig-Mu, Pre-BCR, and CD-79
  57. What can be used to immunophenotype B cell tumors
    Flow cytometry, immunohistochemistry
  58. Rituximab is what?
    • anti-CD20 drug, depletes B-cells
    • used in B-cell tumors, autoimmunity
  59. Stats:
    • WBC: 4000-11000
    • lymphocytes: 1000-4000 (15-40% of WBC)
  60. What allows naive lyphocytes to enter lymph nodes?
    L-selectin (CD62L)
  61. Most important ligand/addressin pair on effector lymphocytes
    • Ligand: VLA4
    • Addressin: VCAM1
  62. B cell:
    Signal 1-3
    • Signal 1: BCR is triggered
    • Signal 2: CD40 is activated by CD-40 on T cells
    • signal 3: cytokines
  63. What engages CD28 on T cells (Signal 2)
    CD 80/86 or (B7-1 and B7-2)
  64. Function of AID
    key enzyme for somatic mutation and class switching.
  65. Memory B cells
    • Class-switched, no IgD
    • High affinity & quick to fire
    • Located in marginal sinus (spleen) and sub-capsular sinus (lymph nodes)
    • Increased in frequency
  66. Plasma Cells
    • Secrete Ig (lack membrane Ig)
    • Located in splenic Red Pulp and Medullary cords in lymph nodes
    • Long lived in bone marrow
  67. CTLA4Ig (abatacept)
    • CD40-CD40L or CD80/CD86 – CD28 interactions
    • used to tx autoimmunity, such as rheumetoid arthritis
  68. Hyper IgM syndrome
    • mutations in CD40L or CD40
    • presents with high levels of IgM
    • also in patients deficient in AID
  69. CVID (common variable immunodeficiency)
    Lack ICOS and therefore cannot for a germinal center
  70. Pre-B cell tumors give rise to what?
    • Acute lymphoblastic leukemia
    • highest prevelance in children
  71. Mature B cell tumors give rise to what?
    Chronic Lymphocytic Leukemia (CD5+)
  72. Germinal Center B cell tumors give rise to what?
    Diffuse Large B cell Lymphoma
  73. Plasma cell tumors give rise to what?
    • Multiple Myeloma
    • most common bone tumor
  74. In BCR signaling, the phosphorylated ITAM motifs in the CD79 recruit what tyrosine kinase
  75. In BCR signaling, the tyrosine kinase Syk activates what key intermediate?
    BTK (bruton's tyrosine kinase)
  76. Bruton's Disease
    • Mutated BTK
    • reduced B cellas with normal amount of Pre-B cells
    • Reduced Ig (serum)
  77. BTK activates what intermediate? To generate what?
    • PLCgamma2
    • generates IP3 and DAG
  78. Antigen coated with C3d activates what?
    CD21 =>phosphorylates CD19 and amplifies Signal 1
  79. CD32 and CD22 activate what?
    phosphatases that inhibit B cell activation
  80. TI-1
    • T cell independent ligands (LPS)
    • Trigger B cells polyclonally
    • Engage a TLR
    • Differentiates B cell into an IgM secreting cell
    • TI antigen response lacks class switching, affinity maturation and memory.
  81. TI-2
    • T cell independent ligands are polymeric antigens that cross-link specific BCRs
    • Ex; several bacterial polysaccharides, Flagellin,Ficoll,Dextran
    • Marginal Zone B cells and primitive B-1 Be cells (express CD5)
  82. What drugs target Calcineurin?
    Cyclosporin & FK506
  83. IgG important facts
    • Mol weight: 150,000
    • Serum: 12 mg/ml
    • Major sites: Intravascular and Extravascular
    • T1/2: 23 days
    • crosses the placenta
    • Binds FcR and thus Induces ADCC
    • Neutralizes toxins
    • Present in milk
    • Anti-viral
    • Anti-bacterial
  84. IgA properties
    • J & S chain
    • Major sites: Intravascular and SECRETIONS
    • Present in milk
    • Anti-viral
    • Anti-bacterial (Lysozome)
    • Agglutinator
  85. IgM key properties
    • J chain
    • Major sites: Mostly Intravascular
    • Agglutinator
    • Fix Complements
  86. Agglutination is used in what tests?
    • Coombs Test: Assaying for Anti-RBC antibodies using by using agglutination
    • ABO Blood group typing
    • cold/warm agglutinations
  87. Which complements act as anaphylatoxins?
    • C3a & C5a
    • induce inflammation
  88. Which IgG binds the best to complement?
  89. What is the most common immunodeficiency disease and its frequency?
    • Selective IgA deficiency
    • 1:500
  90. CTLA-4 (T cell)
    Binds B7-1 and B7-2 with more affinity than CD28 (Blocks Signal 2)
  91. Fas (T cell)
    mediates a cell death signal when fasl is encountered
  92. PD-1 (T cell)
    limits T cell activation
  93. Antigenic Drift
    Hemagglutinin protein of an influenza virus mutates amino acids that are structurally adjacent to critical attachment structures until antibodies no longer bind
  94. Antigenic Shift
    Recombination b/t two distinct forms of the influenza virus
  95. Characteristics of a good vaccine
    Image Upload 1
  96. Prozone
    When Ab > Ag in antigen-antibody precipitation tests
  97. Post Zone
    When Ab < Ag in antigen-antibody precipitation tests
  98. Turbidimetry
    measure of the reduction of light intensity as a consequence of the absorption, reflection and scattering
  99. Nephelometry
    measures the light that is scattered at a particular angle from the incedent light where the detector is placed
  100. azathioprine
    Anti-rejection drug that Inhibits DNA synthesis
  101. Cyclosporine
    Anti-rejection drug that binds to cyclophilin and blocks calcineurin and inhibits cytokine broduction
  102. Tacrolimus
    Anti-rejection drug that binds FKBP-12 and blocks calcineurin and inhibits cytokine broduction
  103. IL-2 receptor-specific monoclonal antibody
    Binds IL-2 receptor chain and blocks it from binding.
  104. What cytokine produced by T lymphocytes activates NK cells and macrophages to kill tumor cells and can also induce apoptosis?
    IFN-alpha (TNF-alpha also induces apoptosis)
  105. Rituximab for tumor therapy
    • Anti-CD20
    • CD20 is expressed on all B cells
    • Chronic lymphocytic leukemia (CLL)
    • Modest efficacy when given alone; better efficacywhen combined with chemotherapy (fludarabineand cyclophosphamide)
    • Mode of action not known, but believed to be via ADCC
  106. Trastuzumab for tumor therapy
    Antibody to human epidermal growth factor receptor (Her2)Her2 is over-expressed on some breast cancers.Her2 is associated with elevated proliferation and angiogenesis.Modest efficacy when given alone; best when combined with chemotherapy.Mode of action believed to be by inhibiting production of angiogeneic factors by breast cancercells and by promoting ADCC
  107. Bevacizumab for Tumor Therapy
    • Anti-vascular endothelial growth factor (VEGF) antibody
    • FDA-approved for first-line treatment of colorectal cancer.
    • Inhibits angiogenesis.
  108. Ipilimumab for Tumor Therapy (know this one!)
    • Anti-CTLA-4
    • First new drug approved by FDA in over a decade for treating melanoma.
    • First randomized phase 3 trial in melanoma ever to show improved patient survival.
    • Unique kinetics that can require months to years to produce regression.
    • Acts to block inhibitory receptors (CTLA-4) on T cells. Takes “brakes” off of T cells while allowing “accelerator” to remain activated.
  109. Function of TGF-β, IL-10, and indoleaminedioxygenase (IDO) as tumor-derived immunosuppressive and anti-inflammatory molecules
    suppress immune responses locally and promote generation of T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs).
  110. Function of Soluble FasL as a tumor-derived immunosuppressive and anti-inflammatory molecule
    • released from tumor cells.
    • Blocks Fas-FasL interactions thatare used by immune cells to induce apoptosis of tumor cells.
  111. Role of FasL in tumor "counter-attack"
    Induces apoptosis of activated T cells
  112. Role of PD-L1
    engages PD-1 on T-cells and inhibits T cell proliferation and induces apoptosis
  113. 2 bacteria that do not Gram stain
    • T. pallidium
    • M. Tuberculosis
  114. Tetanus as an exotoxin producing pathogen
    • Neurotoxin
    • made in small quantities so that it doesn't stimulate an immune response
  115. Diphtheria as an exotoxin producing pathogen
    • Transmitted via repiratory secrections
    • toxin kills epithelial cells in the throat and leads to the formation of a pseudomembrane => swelling in the airway
  116. Cholera as an exotoxin producing pathogen
    • causes massive diarrhea
    • bacteria stay in the gut lumen and don't invade past the epithelium
  117. Function of Type 1 interferon?
    interfere with viral production in fresh? cells.
  118. Omenn Syndrome
    • Mutation in RAG 1/2
    • severe immunodeficiency
    • WBC normal, differences in %
  119. Most common Bare Lymphocyte Syndrome that results in no MHC class I
    No TAP
  120. Most common Bare Lymphocyte Syndrome that results in no MHC class II
    Inactivation of transcription complex of which CIITA is the master regulator.
  121. What is the function of AIRE
    Transcription factor that forces tissue specific antigens to be expressed in the thymus.
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