Immunity to Infectious Disease Flashcards
Protective Immunity Based on Site of Infection
Extracellular:
Interstitial spaces, blood, lymph: complement cascade, phagocytosis, and Ab
Epithelial surfaces: antimicrobial peptides, Ab (especially IgA)
Intracellular:
Cytoplasmic: NK cells, cytotoxic T cells
Vesicular: T cell and NK cell dependent macrophage activation
Innate Defenses to Extracellular Bacterial Infection
Physical and physiologic barriers: skin, sebum, mucosal epithelial cells, mucus, mucous flow, fever
Enzymatic and protein effectors
Lysozyme, proteases, antimicrobial peptides (defensins), iron-sequestering proteins, complement (alternate & MBL paths)
Phagocytes (inflammation and phagocytosis)
Pro-inflammatory cytokine release (via TLR and PRR activation)
Phagocytosis & intraphagolysosomal killing
Innate opsonins: complement, collectins (conglutinin, mannose binding lectin, surfactant proteins A and D)
IFN-g activation of macrophage bactericidal activity [macrophage IL-12 activates NK cell release of IFN-g]
gdT cells and NKT cells: (restricted specificity for lipid and nonprotein antigens) early cytokine release to microbes in epithelia; cytotoxicity to infected or injured self cells
Complement Pathways
Alternative Pathway: induced by microbe
Classical Pathway: induced by Ab (IgG or IgM)
Lectin Pathway: induced by mannose binding lectin
C3a, C3b, and C5a
C3a = inflammation C3b = opsonization and phagocytosis C5a = inflammation
Antibody-Mediated Immunity to Extracellular Bacteria
Opsonization (promotion of phagocytosis)
IgG1, IgG3, and IgA via phagocyte FcR
Classical complement pathway via phagocyte CR3
Anti-toxin action (toxin neutralization, high affinity IgG)
Anti-adhesion activity (IgA at mucosal surfaces, some IgG)
Complement pathway-mediated lysis (gram-negative bacteria) IgM, IgG1, IgG3 (classical pathway) aggregated IgA (Alternate pathway )
ADCC (antibody-dependent cellular cytotoxicity)
IgG-mediated via phagocyte FcR
Ab Mediated Opsonization
Opsonization of microbe by IgG via binding of opsonized microbes to phagocyte Fc receptors, which signals activate phagocyte to induce phagocytosis and killing of ingested microbe
Ab Neutralization of Microbes/Toxins
Microbes attach in order to enter
If Ab: extracellular microbe, Ab blocks penetration through epithelial barrier
Vaccines: Ab at mucosal surfaces and prevent attachment and entering of microbe and infection of cells
Ab neutralization of toxins: Ab blocks binding of toxin to receptor; to get very high affinity Ab, may need multiple vaccines or boosters
Antigen-Specific Cell-Mediated Immunity to Intracellular Bacteria
TH1 (and Tc) release of IFN-g to activate macrophage killing of intravesicular microbes via Nitric oxide (NO) induction Increased ROI, digestive enzymes indoleamine 2,3 dioxygenase (IDO) induction (inhibits microbes by tryptophan depletion)
Tc killing of infected macrophages or intracellular bacteria via
Granzyme-mediated macrophage apoptosis
TNF-a and TNF-b-induced macrophage apoptosis
Granulysin-mediated direct bactericidal activity
Th1 Signals that Activate Macrophage Microbicidal Activity
T cell dependent pathway: macrophage presenting to CD8 cell, and share CD40 with CD40 ligand on T cell = full activation of all enhanced killing functions
IL-12 is released from macrophage and interacts with NK cells to produce INF gamma = get Ag specific TH1 cell and this causes more production of INF and CD40 ligand via the TH1
If you just get INF gamma without TH1 then you won’t get much killing
Once activated, macrophage pumps out all sorts of things and enzymes = if activated all the time would get inflammation
Autoimmune diseases: high levels of macrophage activation and inflammation/tissue damage
Cytotoxic CD8+ T cell Killing of Infected Macrophage
Phagocytosed microbes in vesicles and cytoplasm within the macrophage, which causes CD4 T cell to signal the macrophage via IFN-gamma to digest those microbes
If there is a viable microbe after this occurs, then the CD8 CTL will be signaled by the macrophage in order to kill the infected macrophage
Innate Immunity to Intracellular Viruses
Type 1 interferon (IFN-a, IFN-b, IFN-k)
induces DAI (dsRNA-activated inhibitor of translation)
increases MHC I expression
activates NK cells
NK cells:
kill virus-infected cells with decreased MHC 1 expression
NK cells release IFNg
Viruses: try to turn off MHC I to inhibit presentation and cytotoxic T cell killing; NK cells survey for self MHC I molecules
NK cell Recognition of Virally-Infected or Tumor Cells with Downregulated MHC I
When self MHC I is gone or lower levels than normal via viral inhibition, NK is turned on and kills the cell as an indication that the cell is infected
Antibody-Mediated Immunity to Viruses
Extracellular virions:
Ab “neutralization” of adherence & invasion
Classical Complement lysis of enveloped virions
Intracellular infection (viral antigens expressed on infected cell membrane):
ADCC by NK cells
Classical complement lysis of infected cell
IgA neutralization of intracellular virus (during IgA transcytosis of mucosal epithelial cells)
If viruses are enveloped: may be susceptible for Ab mediated killing
Antibody-Dependent Cellular Cytotoxicity (ADCC) vs. Virus-infected Cells
If you have anti-viral Ab, IgG, NK has Fc receptor and targets and binds the IgG to cause killing of Ab coated cell
ADCC: NK cells can not only recognize non-self MHC I, they can target Ab on cells that display viral Ag, even though complement cascade doesn’t normally work on self cells, you get such a high level you are able to kill the infected self cells
Specific Cell-Mediated Immunity To Virus Infection
CMI is essential for elimination of established intracellular virus infections
CD8+ Tc cytotoxicity
Perforin/granzyme/granulysin mediated apoptosis
FasL-Fas mediated apoptosis
Cytotoxic T cells have granules that are released in one way direction and damage infected cell membrane and then it causes apoptosis via Fas system
CD8+ Tc cytokine release
IFN-g (antiviral; MHC I stimulation)
TNF-b mediated apoptosis
Mechanism of Tc cell (CTL) Cytotoxicity
Virus infected target cell presented MHC I, which is bound to CD8
Granules with cytotoxic molecules, and once CD8 activated, the granules are released and causes damaged
Perforin: similar to C9 to complement pathway; polymerizes in cell membrane to form a pore and the granzymes activated caspase enzymes to induce apoptosis
One direction release with feedback mechs that prevent the T cell from killing itself
Immunity to Fungi
Filamentous molds & unicellular yeasts
Neutrophils readily kill nonpathogenic fungi and 37° C restricts their growth
TH1-mediated macrophage activation is required for immunity to many fungal pathogens
Granulomatous inflammation to fungal lung infection with Histoplasma or Coccidioides
DTH type skin reactions to fungal infection of hair, skin, nails (dematophytes = ringworm).
Immunity to Eukaryotic Parasites
Protozoa, helminths
CD8+ T cells and macrophages activated by TH1 cells control most protozoan parasites
Nitric oxide from activated macrophages kill parasites
CTL control intracytoplasmic protozoans
IgE mediates protection to helminth infections (intestinal worm-shaped parasites). [Helminths stimulate IL-4 from NK1.1+ T cells to promote TH2 responses.]
Elevated IgE and eosinophils mediate ADCC
IgE-sensitized mast cell degranulation
Antibody and complement are protective to purely extracellular parasites and to some extracellular stages of intracellular parasite life cycles
Extracellular Immune Mechanisms
Antibody-mediated phagocytosis, (IgG)
Antibody-mediated neutralization (anti-toxic or anti-adhesive action), (IgG, IgA)
Classical complement pathway-mediated opsonization or Lysis, (IgM, IgG)
ADCC (IgE) vs. large eukaryotic parasites (Ab Dependent Cellular Cytotoxicity = ADCC)
Intracellular Immune Mechanisms
CD4+ T-lymphocyte-activation of macrophage anti-microbial functions
CD8+ T lymphocyte-mediated cytotoxicity
ADCC (IgG, phagocytes, NK)
Harmful/Unregulated Innate Immune Responses
Sepsis
Systemic Inflammatory Response Syndrome (SIRS associated with a confirmed infectious process)
Septic Shock
Sepsis with hypotension (despite adequate fluid resuscitation) and multisystem organ failure
Pathogenesis of Septic Shock
Infectious triggers → cytokine and inflammatory mediator cascade, procoagulant state → cardiac dysfunction and microvascular injury, ischemic injury → hypotension and shock
Antigenic Variation
Multiple antigenic variants of microbe
Antigenic drift due to mutation
Antigenic shift due to genetic exchange
Sequential expression of antigenic variants via gene conversion (recombination)
Inhibition of Normal Immune Processes
Inhibitors of antigen processing/presentation
Suppressive cytokine analogs, cytokine receptor homologs, FcR homologs
Induction of immune cell apoptosis
Inhibition of adhesion molecule expression
Antagonize phagolysosome formation; escape from phagosome into cytoplasm, resistance to intracellular killing mechanisms
Anti-phagocytic, anti-complementary factors
Summary
Innate defenses protect against common “nonvirulent” microbes
Antibody, complement, and phagocytes protect mostly to extracellular pathogens and toxins (including extracellular phases of intracellular microbe infection)
Th1-activated macrophages protect against facultative intracellular pathogens
Cytotoxic T cells (CD8+ CTL) protect against intracellular pathogens and altered self cells
