Defense against pathogens, possibilities of therapeutic affecting of the immune system

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Defense against pathogens, possibilities of
therapeutic affecting of the immune system

• Martin Liška

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Extracellular microorganisms

• Typically bacteria or parasites
• For defense against extracellular microbes and
  their toxins, specific humoral immune response is
  important

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Humoral immune response

• Recognition of antigen by specific Ig, bound i
  cell membrane of naive B lymphocyte
• The binding of antigen cross-links Ig receptors
  of specific B cells and then biochemical signal
  is delivered to the inside B cell a breakdown
  product of the complement protein C3 provides
  necessary second signal
• Clonal expansion of B cell and secretion of low
  levels of IgM

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Humoral immune response

• Protein antigens activate CD4 T helper cells
  after presentation of specific antigen
• T helper cells exprime CD40L on their surface and
  secrete cytokines ? proliferation and
  differentiation of antigen-specific B cells,
  isotype switching, affinity maturation

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Phases of humoral immune response
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Effector functions of antibodies

• Neutralization of microbes (incl.viruses) and
  their toxins
• Opsonization of microbec (binding to Fc receptors
  on phagocytes at the same time, stimulation of
  microbicidal activities of phagocytes)
• ADCC (Antibody-dependent cell-mediated
  cytotoxicity) IgG opsonized microb is destroyed
  by NK cells after its binding to IC
• Activation of the complement system (classical
  pathway)

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Defense against extracellular pathogens (bacteria
and unicellular parasites)

• a/ non-specific (innate) immune system
• - monocytes/macrophages, neutrophils, complement
  system, acute phase proteins (e.g.CRP)
• b/ specific (adaptive) immune system
• - antibodies (opsonization, neutralization)

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Defense against multicellular parasites

• Production of IgE ? coating and opsonization of
  parasites
• Activation of eosinophils - they recognize Fc
  regions of the bound IgE, then they are activated
  and release their granule contents, which kill
  the parasites
• Th2-lymphocytes support this type of immune
  response

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Intracellular microorganisms

• Initially non-specific immune response
  (ingestion by phagocytes)
• Some microorganisms are able to survive inside
  phagocytes (e.g. some bacteria, fungi,
  unicellular parasites, viruses) they survive
  inside phagosomes or enter the cytoplasm and
  multiply in this compartment
• The elimination of these microorganisms is the
  main function of T cells (specific cell-mediated
  response)

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Processing and presentation of antigen

• Professional antigen-presenting cells
  macrophages, dendritic cells, B lymphocytes (they
  express constitutionally class II MHC)
• a/ exogenous antigens e.g. bacterial,
  
  
• parasitic, viral (if they are ingested
  in IC or
• during the processing of infected
  cells)
• hydrolysed in endosomes to linear peptides ?
  
• presentation on the cell surface together with
  class II
• MHC to CD4 T lymphocytes

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Processing and presentation of antigen

• b/ endogenous antigens e.g. autoantigens,
• foreign antigens from i.c. parasites or
• tumorous antigens
• hydrolysed to peptides ? transportation into ER ?
  in Golgi complex they are associated with class I
  MHC ? presentation on the cell surface to CD8 T
  lymphocytes

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T cell-mediated immune response

• Presentation of peptides to naive T lymphocytes
  in peripheral lymphoid organs ? recognition of
  antigen by naive T lymphocytes
• At the same time, T lymphocytes receive
  additional signals from microbe or from innate
  immune reactions ? production of cytokines ?
  clonal expansion ? differentiation ? effector
  memory cells ? effector cells die after
  elimination of infection

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T cell-mediated immune response

• TCR (T cell receptor) T cell antigen-specific
  receptor
• - TCR recognizes (together with co-receptors -
  CD4 or CD8) the complex of antigen and MHC
• a signal is delivered into the cell through
  molecules associated with TCR and co-receptors
  (CD4 or CD8) after antigen recognition

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T cell-mediated immune response

• APC exposed to microbes or to cytokines produced
  as part of innate immune reactions to microbes
  express costimulators that are recognized by
  receptors on T cells and delivered necessary
  second signals for T cell activation
• Activated macrophages kill ingested bacteria by
  reactive oxygen intermediates, NO and lysosomal
  enzymes

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T cell-mediated immune response

• Naive CD4 T (helper) cells ? effector cells
  (activation of macrophages for killing of
  ingested microbes, activation of B cells for
  production of antibodie, activation of other
  cells)
• - Th1 lymphocytes production of IFN-g,
  activation of phagocytes, stimulation of
  production of opsonizing a complement binding
  antibodies support defense against i.c. microbes

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T cell-mediated immune response

• - Th2 lymphocytes production of IL-4 and IL-5,
  stimulation of IgE production, activation of
  eosinophils ( defense against multicellular
  parasites) they suppress defense reactions
  against i.c. microbes

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T cell-mediated immune response

• Naive CD8 T (cytotoxic) lymphocytes ? effector
  cells (killing of target cells, activation of
  macrophages)
• differentiation into CTL their function is
  killing of cells producing cytoplasmic microbial
  antigens
• Killing the cells mainly by induction of DNA
  fragmentation and induction of apoptosis

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Mechanisms of resistance of intracellular
microbes to cell-mediated immune response

• Inhibiting phagolysosome fusion
• Escaping from the vesicles of phagocytes
• Inhibiting the assembly of class I MHC-peptide
  complexes
• Production of inhibitory cytokines
• Production of decoy cytokine receptors

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Defense against intracellular pathogens (bacteria
and unicellular parasites)

• Intracellular bacteria (Mycobacteria, Listeria
  monocytogenes, Legionella pneumophila), parasites
  (Cryptococcus neoformans, Plasmodium falciparum),
  fungi (Leishmania, Trypanosoma cruzei)
• Specific immune response is necessary

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Anti-viral defense

• Viruses may bind to receptors on a wide variety
  of cells and are able to infect and replicate in
  the cytoplasm of these cells, which do not
  possess intrinsic mechanisms for destroying the
  viruses
• Some viruses can integrate viral DNA into host
  genome and viral proteins are produced in the
  infected cells (e.g. Retroviruses)

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Anti-viral defense

• a/ non-specific (innate) immune system
• - monocytes/macrophages, NK cells, interferons
  (IFN-g ? activation of macrophages, IFN-a ?
  antiviral activity, activation of NK cells)
• b/ specific (adaptive) immune system
• - T cells, antibodies (e.g. neutralization of
  viruses)

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Possibilities of therapeutic affecting of the
immune system

• Immunomodulation therapeutic approach to
  modulation of affected immune function
• Based on their effect, we can distinguish
  following immunomodulators
• immunostimulants
• immunosuppressives
• immunomodulators with the complex effect

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Immunostimulants

• They stimulate the immune system
• Methisoprinol (Isoprinosine) used for the
  treatment of severe or recurrent viral infections
  
• Cytokines IL-2 (anti-tumour therapy),
  colony-stimulating factors (e.g. treatment of
  severe granulocytopenia)

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Immunosuppressives

• They are used for the treatment of autoimmune or
  allergic diseases, in transplantology
• Corticosteroids anti-inflammatory,
  immunosuppressive effect
• Cytostatics, antimetabolites (cyclofosfamide,
  methotrexate, cyclosporine A) lymfocytotoxic
  effect
• Monoclonal antibodies antiCD3

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Immunomodulator with the complex effect

• Bacterial lysates (Broncho-Vaxom, Ribomunyl)
• Transferfactor
• Antihistamines esp. 3rd generation

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Substitution

• Typically substitution therapy with intravenous
  Ig (IVIG) in primary or secondary hypo- or
  agamaglobulinemia
• Life-long substitution
• IVIG 200-300 mg/kg every 3 weeks

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Active and passive immunization

• a/ active immunization
• immunization with vaccines made from killed or
  attenuated microorganisms or their products
• the immunity is long-lasting
• both B cell and T cell based immunity are
  activated
• injective, oral administration
• prophylactic procedure

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Active immunization

• DTP (diphtheria, pertussis, tetanus)
• H.influenzae
• N.meningitidis
• Pneumococci
• BCG
• MMR (measles, mumps, rubella)
• Poliomyelitis
• Hepatitis A,B

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Active and passive immunization

• b/ passive immunization
• provides humoral temporary (approximately 3
  weeks)
• prophylactic or therapeutic