Janeway's Immunology

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Immune Responses to Pathogens

• Bacteria
• Viruses
• Fungi
• Parasites

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Different Phases of an Immune Response
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Natural Barriers to Infection
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Innate Responses to Extracellular Bacteria
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Bacteria that express mannose on their surface
may bind mannose -binding lectin
Opsonization and enhanced phagocytosis of the
bacteria
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Peptidoglycan in the cell wall activates the
alternative pathway of complement
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LPS in the cell wall activates the alternative
pathway of Complement in absence of Ab
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Immediate Responses to extracellular pathogens
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Toll-like receptors recognize specific properties
of pathogens
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Membrane attack complex lyses bacteria and
complement by-products participate in
inflammatory responses
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Tissue macrophage and dendritic cells are the
first leukocytes to encounter extracellular
pathogens
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Inflammatory mediators recruit leukocytes from
the blood into the tissues
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Intracellular vesicles of macrophage contain
multiple products to inhibit or kill bacteria
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Adaptive Immune Responses to Extracellular
Bacteria
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Adaptive Immune Responses to Extracellular
Bacteria

• Macrophage activation capable of causing tissue
  injury
• DTH to microbial protein antigens (PPD) of M.
  tuberculosis
• Persist for long periods and cause chronic
  antigenic stimulation and T cell macrophage
  activation
• May result in formation of granulomas surrounding
  the microbes
• Granulomatous inflammation
• May serve to localize and prevent spread of the
  microbes associated with severe functional
  impairment caused by tissue necrosis and fibrosis

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Functions of Antibodies
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Immunity to Intracellular Bacteria

• Innate
• Phagocytes and NK cells
• Pathogenic intracellular bacteria are resistant
  to degradation within phagocytes
• NK cells become activated by IL-12 produced by
  macrophage

• Adaptive
• Cell-mediated immunity
• Consists of 2 types of reactions-macrophage
  activation by the T cell-derived signals CD40
  ligand and IFN-?
• Lysis of infected cells by cytolytic T lymphocytes

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Cooperation of CD4 and CD8 T cells in defense
against intracellular microbes
CD4 helper T cell
CD8 cytotoxic T cell
CD40L
Killing of infected cell
MHC Class II
CD40
IFN-?
MHC Class I
Killing of bacteria in phagolysosome
Phagocytosed bacteria in vesicles cytoplasm
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Virus-infected cell
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Injurious Responses to Bacteria

• Septic shock syndrome characterized by
  circulatory collapse and disseminated
  intravascular coagulation
• Caused primarily by TNF-alpha

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Bacterial Superantigens

• Superantigens bind to class II MHC molecules on
  APCs
• At site away from peptide binding cleft
• Possess 2 binding sites for class II MHC molecules

• Stimulate large numbers of T cells but not all T
  cells
• Staph A produce enterotoxins (exotoxins) SEA,
  SEB, SEC, SED, and SEE, most common form of food
  poisoning
• TSST-1
• Most potent naturally occurring T cell mitogens
  known
• Enterotoxins bind to the V? region of the T cell
  receptor

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Viral Superantigens

• Viral gene products may also function as
  superantigens

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Mechanisms of Immune Evasion by Bacteria
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Immune Response to Viruses

• Innate Immunity
• Type I interferons
• NK Cells
• Natural Antibodies
• Specific Immunity
• B cell- and T cell-mediated

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1 2 3 4 5 6
7 8 9 10 11 12

Days after viral infection
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Action of IFN-a/b

• Activated by viral double-stranded RNA
• NK cell cytotoxicity is activated whenever the
  IFN-a/b cytokines are induced
• Increase expression of IL-12 receptors
• Stimulates the development of TH1 cells

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NK Cells

• Phylogenetically primitive CTLs that lack TCR for
  antigen recognition
• Antiviral Functions of NK cells
• Cytotoxicity activated by
• Arenaviruses (lymphocytic choriomeningitis
  virus),
• Herpesviruses (herpes simplex virus)
• Orthomyxoviruses (influenza virus)
• Picornaviruses (coxsackie virus)

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IL-12

• Induces NK cell IFN-g production
• Macrophage activation--gtkilling of microbes
• Contributes to preferential development of T
  helper type I cells (IFN-g-producing cells)
• Enhances the cytolytic functions of activated T
  lymphocytes (CTLs).

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Antibody-dependent cell mediated cytotoxicity
(ADCC)
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Antibody Response

• Immunological Discrimination B cells
• Neutralizing antibody responses against viruses
  prevent re-infection against the most important
  acute cytopathic human viruses, polio, measles,
  mumps
• In several model of infections, the absence of B
  cells or CD4 T helper cells (or both) results in
  impaired virus clearance and death
• Vesicular stomatitis virus (VSV) in mice

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Ways that Ig neutralizes viruses

• Inhibit attachment and uptake
• Bulky Ab can hinder adhesion
• Agglutinate viruses

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IgA Antibodies

• Largely secreted as dimers by plasma cells that
  underlie the mucosal epithelium

J-chain
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Secretory IgA
Lumen
Apical Recycling endosome
Epithelial Cell
nucleus
Poly-Ig receptor
Lamina Propria
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T cell-mediated responses to viruses
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Non-cytolytic viruses

• CTLs may be responsible for tissue injury
• i.e. LCMV infection in mice
• During some generalized infections with
  non-cytopathic viruses (LCMV) in mice and
  Hepatitis B or C in humans, all antigen-specific
  T cells may be deleted

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Role of TH cells in viral clearance
CD4 helper T cell
cytokines
CD40L
CD8 T cell
MHC Class II
CD40
Activation
MHC Class I
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Mechanism for degrading viral RNA
IFN-g/TNF-a
AAAAAAAAAAAAA
Pre-formed HBV RNA
endonuclease
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Immunological Memory

• Poorly understood
• Mediated by increased antibody levels
• Necessary, but also sufficient, to provide
  protection against cytopathic virus infections
• Transfer of memory antibodies from mother to
  offspring

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• CTL Memory
• Lack of transfer of T cell memory from mother to
  child, T cell receptor expression requires a
  learning process
• CTLs are induced and disappear rapidly
• CD8 T cell frequencies are low in a normal host

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Evasion of Immune Mechanisms

• Viruses capable of great antigenic variation
• Infect cells of the immune system, impairing
  their function
• Mimic cellular genes
• EBV protein BCRF1-an analog of cellular IL-10,
  similar to that of human IL-10

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Immune Responses to Fungi
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May live in extracellular tissue and within
phagocytes
1. Often occur in immunocompromised individuals
2. Immune responses often combinations of the
responses to extracellular and intracellular
bacteria
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Principal mediators of innate immunity against
fungi are neutrophils and macrophages.
Cell-mediated immunity is the major mechanism of
adaptive immunity against fungal infections TH1
responses are protective and TH2 responses are
detrimental to the host
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Immunity to Parasites

• Protozoas
• Helminths
• Ectoparasites (ticks and mites)
• Malaria infects more than 100 million people
  worldwide

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Innate Immunity to Parasites

• Primary response is phagocytosis
• Many parasites resistant to phagocytic killing
  and may replicate within macrophages

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Adaptive Immunity to Parasites

• Cell mediated immunity particularly macrophage
  activation by TH1 cell-derived cytokines