The Innate System II: Interferon and the Complement Cascade Flashcards Preview

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Flashcards in The Innate System II: Interferon and the Complement Cascade Deck (31)
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summarize the antimicrobial serum agents


describe interferon alpha and interferon beta (type I)

  • type I interferons can be produced by almost any cell upon stimulation by a virus
  • act on neighboring uninfected cells 
  • inhibit transcription and translation of viral proteins


describe interferon gamma (type II)

  • produced by: TH1, CTLs (CD8+), NK cells
  • promotes NK cell activity
  • increases activity of macrophages
  • activates inducible nitric oxide synthase (iNOS):
    • relaxes smooth muscle, vasodilation
  • induces the production of antibodies
  • causes normal cells to increase expression of MHCI and MHCII
  • promotes adhesion and binding required for leukocyte migration
  • induces the expression of intrinsic defense factors with direct antiviral effects
  • respond to cancerous growth


describe granuloma formation by IFN-γ

  • body's way of dealing with a substance it cannot remove
  • infectious causes: tuberculosis, leprosy, histoplasmosis, cryptococcosis, blastomycosis, coccidiodomycosis and cat scratch disease
  • non-infectious causes: sarcoidosis, Crohn's disease
  • association between IFNγ and granulomas: IFNγ activates macrophages to kill intracellular organisms
  • IFNγ-induced granuloma formation:
    • activation of Th1 helper cells by macrophages
      • IL-1 and IL-12 by macrophages
    • Th1 helper cells aggregate around the macrophages
      • IFNγ release, which activates the macrophages 
    • repetitive action
  • finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection


describe the complement system (series of pro-enzymes)

  • 5% of serum globulin
  • consists of >20 serum glycoproteins synthesized principally by hepatocytes, but also monocytes, macrophages and epithelial cells
  • the complement system is important for the recruitment of inflammatory cells and the killing or opsonization of pathogens
  • many components ciruclate in the seurm as proenzymes (inactive); complement proteins are activated by cleavage (cascade reaction)
    • inactive precursors in blood: C2, C3, C4


name the 3 mechanisms that can enzymatically trigger the complement components, and what they all lead to

all lead to production of C3b

  • antibody-antigen (classical pathway)
  • microbial or non microbial foreign substances (alternative pathway)
  • mannose-binding lectin, MBL (lectin pathway)


describe the classical pathway

adaptive immunity

  • C1 binds to Ag-Ab complex
  • activated C1 cleaves C4 and C2
    • formation of C3 convertase
  • C3 is cleaved
  • C5 is cleaved
  • sequential binding of C5b, C6-C9


describe the alternative pathway

innate immunity

  • spontaneous cleavage of C3 based on multiple initiators
    • requires Factors B and D
  • formation of C3 convertase (less stable)
    • requires Properdin


describe the MBL pathway

innate immunity

  • mannan-binding lectin (MBL), an acute phase protein found in serum binds to carbohydrate residues on cells or pathogen surfaces
  • MBL-associated serine protease (MASP) binds to MBL
  • this complex cleaves C4 and C2 much like activated C1 (classical pathway)


summarize the 3 activation pathways (activator, C3-convertase, C5-convertase, MAC development)


describe the development of MAC

  • three pathways converge with activation of C5 convertase
  • C5b binds antigenic surface
  • MAC is formed on surface
    • C5 components: C5b, C6, C7, C8, C9
    • poly-C9: perforin-like molecule


summarize the functions of complement

complement has a role in both innate and adaptive immunity

  • cell lysis (C5b-C9)
    • Ab-dependent
    • Ab-independent
  • opsonization (C3b)
  • inflammation (C3a, C5a)
  • clearance of immune complexes (C3b)
  • viral neutralization (C3b, C5b-C9)


describe the CR1 complement cell receptor


describe the selected inhibitors of complement cascade


summarize the complement cascade inhibitors of the different pathways

  • inhibitors of alternative pathway:
    • factor H, factor I, DAF, MCP
  • inhibitors of classical/lectin pathways
    • Factor I, DAF, MCP, CR1, C1inh, C4bp
  • inhibitors of terminal common pathway
    • S protein, Clusterin, Factor J, HRF, CD59


describe the 2 types of complement deficiences

  • activator disorders: under-reactive system; more susceptible to infxns
  • inhibitor disorders: overreactive system


describe classical pathway component deficiencies (complement deficiencies of activators)

  • classical pathway component deficiencies (C1, C4, C2)
    • individuals are prone to immune complex disease
      • inability to clear circulating immune complexes
      • deposition in tissues and an associated inflammatory response
      • example: SLE, glomerulonephritis, vasculitis


describe MBL deficiency (complement deficiency of activator)

  • MBL deficiency
    • classically presents with recurrent pyogenic infxn in childhood
    • susceptibility to Saccharomyces cerevisiae, pneumococcal and Neisseria infxns


describe alternative pathway component deficiencies (complement deficiencies of activators)

  • alternative pathway component deficiencies (Properdin, factor B and factor D)
    • affected individuals are prone to pneumococcal and meningococcal infxns
    • Properdin deficiency: risk of overwhelming Neisseria infxn


describe C3 deficiency (complement deficiencies of activators)

  • C3 deficiency
    • C3 is required for opsonization
    • primary C3 deficiency tends to present in early life with overwhelming infxn with encapsulated organisms
    • there is also a tendency to connective tissue disease


describe MAC deficiences (complement deficiences of activators)

  • MAC deficiencies (C5-C9)
    • recurrent infxns
      • common infxn with Neisseria meningitidis


describe deficiency of C1-inhibitor (complement deficiences of inhibitors)

  • C1-inhibitor (C1-INH) regulates the classical pathway
    • deficiency results in angioedema (hereditary or acquired)
      • C2b accumulation: vasoactive


describe deficiency of DAF (complement deficiences of inhibitors)

  • DAF (decay acceleration factor)/CD55 and CD59
    • paroxysmal nocturnal hemoglobinuria (lysis of red blood cells)
    • caused by "continuous drilling"


summarize the diseases associated with complement deficiencies


describe complement genetics

  • most complement deficiencies follow AR inheritance
  • Properdin deficiency may be inherited as an X-linked trait
  • MBL deficiency can be both AD and AR
  • complement deficiencies can also be acquired
    • post-infxn


describe hereditary angioedema

  • rare syndrome characterized by episodic, nonpruritic, localized subcutaneous and submucosal swelling
    • laryngeal edema can precipitate fatal resp. obstruction
  • dysregulation of 3 different systems:
    • complement - classic (C1) and MBL (MASP-2) pathways
      • excessive activation of the complement due to mutation on C1inh results in high concentration of anaphylatoxins: C3a and C5a
    • coagulation: factor XI and XII leading to fibrin buildup
    • contact cascade: resulting in increased bradykinin levels leading to inflammation, coagulation and other body effects
  • there is an absence of urticaria (rash) that distinguishes HAE from an allergic reaction


summarize the problem in hereditary angioedema


describe assays for the classic pathway (laboratory testing)

  • assays for the classical pathway:
    • the hemolytic titration (CH50) assay: amount of patient serum required to lyse 50% of antibody-sensitized sheep erythrocytes
      • needs all complement molecules (C1-9) to function
    • ELISA
  • AH50 for the alternative pathway


describe the cascade defects/expected results for individuals components


list the diseases associated with decreased complement activity