Unit 8 Innate Immunity no figs

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Unit 8 Innate Immunity no figs Powered By Docstoc
					General or Nonspecific
Host Immune Defense
Innate versus Adaptive
Immunity: The Time Course of
an Infection
  Innate Mechanisms Designed to
         Prevent Infection

General barriers
   The more malnourished the host, the
   greater the susceptibility to infection
   Nutrient provide the building blocks for
   cell division, microbe destruction and
   tissue repair
–Acute-phase reactants
  During an acute infection,
  qualitative and quantitative
  changes in the host’s blood occur
  Bacteria induce macrophages to
  make interleukin 6 (IL-6)
   – The hepatocytes in the liver respond to
     IL-6 and produce acute phase,
     bacterial-specific proteins
– Examples of Acute Phase Reactants
   C-Reactive Protein (CRP) (a pentaxin)
    – Binds phosphorylcholine on bacterial surface
    – Activates complement
         Induces opsonization
         Membrane attack complex (MAC) is
         formed = cell lysis
   Serum amyloid protein (homologus to
   CRP, another pentaxin)
Mannose binding protein
 – Binds mannose on bacteria
 – Activates complement
      Induces opsonization
      Membrane attack complex (MAC) is
Iron redistribution – Release of
lactoferrin by neutrophils
 – Sequestered by host = hypoferremia
 – Uptake of iron by liver
  Thermal set point altered in
  Induced by pyrogens
   – Exogenous pyrogens
       Endotoxins of Gram negative bacteria
       NAM/NAG polymer of PTG
       Staphylococcal enterotoxin
       Group A streptococcal erythrogenic toxin
   –Endogenous pyrogens
      IL-1 (made by macrophages)
– Result of fever
   Stimulates leukocytes into action
   Enhances microbiostasis (growth
   inhibition) by decreasing availability
   of iron
   Enhances specific activity of the
   immune system
   Host cells protected from the effects
   of TNF-alpha
   – Postnatal protection = passive immunity
       IgG antibodies transferred
       transplacentally during pregnancy
       IgA antibodies transferred in colostrum
       in breast milk
   – Peripheral lymphoid organ follicles shrink
   – Thymus involutes
   – Homeostatic mechanisms fail
– Genetic factors
   Host temperature;
   Metabolic, physiologic, and anatomic
   Food preferences
   Major histocompatibility proteins
   (MHC class I/class II, class III)
   Racial factors (e.g. sick cell trait and
   resistance to malaria)
Physical barriers
– Skin - reasonably effective mechanical
   Keratin – water proofing
   Shedding/sloughing off
     – Fatty acids secreted by sebaceous glands (sebum)
     – Propionic acid (made by Propionibacteria – normal
     – Oleic acid (made by Gram positive flora, elgl
       Staphylococcus epidermidis)
   Washing activities
   Lymphoid tissue in the skin
Mucous membranes
Mucus secretions form a protective
covering that contains antibacterial
substances, such as lysozyme
Mucous surfaces contain specialized
cells called M cells
 –M cells endocytose pathogens and
  aids in antigen presentation to T and
  B cells by macrophages
 –B cells respond by synthesizing sIgA
  which is secreted across mucous
  membrane to the lumen -
– Respiratory system
   Inhalation of ~104 organisms/day
   Aerodynamic filtration deposits
   organisms onto mucosal surfaces, and
   Mucociliary blanket transports them away
   from the lungs
    – Hair and cilia or nasal cavity and tracheal
   Sneezing/coughing – expels saliva 
   washed to stomach
–Gastrointestinal tract and enzymes
  Stomach - gastric acid (pH 2-3)
  Small intestine - pancreatic
  enzymes, bile, intestinal enzymes,
  and secretory IgA
  Peristalsis and loss of columnar
  epithelial cells help eliminate
  pathogens (shedding/sloughing off
  every 2-5 days)
  Large intestine - normal microbiota
  may create unfavorable
  environment for colonization
–Genitourinary tract
  Unfavorable environment
   –Urine – low pH
   –Lactic acid in vagina produced by
    Doderleins bacilli in child-bearing years
   –Hypertonic kidney medulla
  Flushing action
  Length of urethra in males
  constitutes a distance barrier
–The eye
   Flushing action,
    –Hydrolysis of bond between NAM and
   Other antibacterial substances
   (sIgA, lactoferrin)
Chemical barriers
–Gastric juices
–Salivary glyco-proteins
– Oleic acid on the skin
– Urea
– Fibronectin
    Glycoprotein that reacts with bacteria to
    promote clearance, or with host cell
    receptors to prevent attachment
    Protects cell surfaces
– Hormones - affect inflammatory response
  and immune system activity; have cyclical
  effects on vaginal microbiota
– Beta-lysin
   Blood platelet product – disrups plasma
   membrane of Gram positive bacteria
   A catioinic polypeptide
   Examples of other cationic polypeptides:
   leukins, plakins, cecropins and phagocytin

– Interferons
   Respond to viruses and other inducing agents to
   reduce the spread of viruses to neighboring cells
   Three types: alpha, beta, gamma
     – Alpha and beta participate in innate IRs
     – Induced by dsRNA
– Effects of interferons:
   Acivation of endoribonuclease and
   protein kinase
    – Destruction of viral mRNA
    – Inhibition of protein synthesis (EF-2
   Upregulation of MHC class I
   Enhancement of Tcyt activity
   Activation of Natural Killer (NK) cells
Interferons have been used
clinically in treatment of several
– Papilloma virus
– Hepatitis B and C
– Some herpes infections
– Osteosarcoma
– Multiple myeloma
– Hodgkins disease
–Tumor necrosis factors (a and b)
–TNF alpha is released from
 monocytes or macrophages, natural
 killer cells or various lymphocytes
 mediate the inflammatory response,
 enhance phagocytosis
  TNF alpha = cachectin
–TNF beta is cytotoxic for tumor cells
  TNF beta = lymphotoxin
– Bacteriocins - plasmid-encoded
  antibacterial substances produced by
  the normal microbiota of the body
   Inhibits translation
   Inhibits energy production
   Lyse other bacteria
   Example: Colicin made be E. coli;
   Staphylococcin made by Staphylococcus
   Effect depends on bacteriocin type
– Cytokines – have a wide range of
  biological actions on eukaryotic cells
Biological Barriers
Normal indigenous microbiota may be
involved in the following ways:
 –Bacteriocin production (colicin by E.
  coli in large intestine)
 –Competition for space and nutrients
   Inhibition of colonization
–Prevention of pathogen attachment
–Influence on specific clearing
   Response to tissue injury through
   the release of chemical signals
   (inflammatory mediators –
   vasoactive and chemotactic factors)
   Vasodilation, increased capillary
   permeability, influx of phagocytic
Interaction of selectins (cell
adhesion molecules, e.g ICAM-1,
VCAM-1) on vascular endothelial
surface  with integrins (adhesion
receptors, e.g. LFA-1) on neutrophil
 – Promotes neutrophil extravasation
 – Integrins are activated by inflammatory
Rolling adhesion  Tight binding
(sticking)  Extravasation
(Diapedesis)  Migration to
injury site (chemotaxis) 
Pathogen encountered and
Involves neutralization and elimination of
the offending pathogen
 – Phagocytosis
 – Fibrin formation (walls off the inflamed area)
Characterized by redness (rubor), heat
(calor), pain (dolor), swelling (tumor),
and altered function (functio laesa)
 – Swelling = edema
     Infiltration of white blood cells
     Serum proteins = exudate (complement,
     antibody, CRP)
   Phagocytic cells arriving at the site
  of inflammation attack and
  phagocytize infecting organisms
   Recognition is mediated through
  surface receptors that allow them to
  attach nonspecifically to a variety of
    –LPS binding site
    –Hemagglutinin receptor
    –C3b receptor (CR1)
    –Mannose receptor
 – The use of opsonins in making bacteria more
   susceptible to phagocytosis
 – Examples of opsonins:
      Complement proteins (C3b, C4b)
May damage the pathogen by
respiratory burst (formation of
highly reactive, toxic oxygen
 –Singlet oxygen
 –Hydroxyl radicals
Phagosomes may fuse with
lysosomes and thereby hydrolyze
the invading organism
–Form phagolysosomes
–Enzymes include:
   Phospholipase A2
Gamma interferon and TNF induction of
reactive nitrogen intermediates (RNIs)
in phagocytes:
 – Secreted or formed in vacuoles:
      Nitric oxide (NO)
      Nitrite (NO2-)
      Nitrate (NO3-)
Biological Barrier: Mast Cells
      and Inflammation
     Activation and Physiological
   Effects of Preformed and Newly
        Synthesized Mast Cell
       Inflammatory Mediators
Preformed Inflammatory Mediators
Synthesized ahead of time and stored in
granules inside the cytopolasm
Released following stimulation with
bradykinin and substance P (from
damaged nerves)
 –   Histamine
 –   Heparin
 –   Enzymes (tryptase)
 –   Chemotactic factors
 –   (see figure for examples)
Newly Synthesized Mediators
Bradykinin binds mast cells
– Calcium influx  Degranulation
– Mast cell permeability changes 
  phospholipase A2 is activated
   Arichidonic Acid is released
    – Metabolized by two different pathways
         Cyclooxygenase pathway
         See figure for products of these pathways
Neutrophils also release
defensins, a family of broad
spectrum antimicrobial
 –Make PM more permeable
 –Ionic fluxes
 –Also affect enveloped viruses
Biological Barrier: Alternative
  Pathway of Complement
– Alternative pathway of complement
   Does not require antibodies
   Activates the terminal complement
   components which destroy bacteria by
   creating holes (pores) in the bacterial
   membrane - MAC
Biological Barrier: Cells of the
       Immune System
     The Reticuloendothelial
      Fixed Macrophages
Liver = Kupffer cells
Brain = microglial cells
Lung = alveolar macrophages
Lymph node = resident and recirculating
macrophages and dendritic cells
Synovium = synovial A cells
Kidney = mesangial phagocytes
Skin = Langerhans’ cells
Bone = Osteoclasts
             Circulating Cells
Blood monocytes and free macrophages
trafficking between tisues
Polymorphonuclear leukocytes (PMNLs)
– Basophils
– Eosinophils
– Neutrophils
– T cells
– B cells
– NK cells
Lymphoid Lineages Involved
in Non-Adaptive Responses
Lymphoid lineages involved in non-
adaptive immune responses
– Natural Killer cells (NK cells)
 g:d T cells
– CD5+ B cells (B-1 B cells)
Natural killer (NK) cells (aka large
granular lymphocytes – LGL)
    Defend host against virus-infected cells
    Kill sensitized targets
    Activated by IL-12, alpha-interferon and beta-
    MHC class I involved
     – Present  Negative signal overrides activity of
       killing receptors
Intraepithelial gamma:delta T cells
– A subset of T cells that are produced early
  during embryogenesis in waves
– Homogeneous T cell receptors within any
  epithelium location
– Do not recirculate
– May reorganize alterations on the
  surfaces of epithelial cells as a result of
– Exact function still unclear
CD5+ B cells (aka B-1 B cells)
– Also arise early in embryogenesis
– Limited rearrangement of V genes (Ab
  genes), mainly IgM
– Present as major lymphocyte in the
– Respond to polysaccharide antigens
  (TI-2 type – repeating subunit
– Exact function still debatable
– Once IgM is bound, can activate
Evasion of Phagocytic Destruction
Some microbes have evolved
mechanisms to avoid eradication by
phagocytic mechanisms
 – Inhibition of fusion phagosome with
    Mycobacterium tuberculosis
    M. leprae
    Legionella pneumophila
    Toxoplasma gondii
– Lyse phagosome  Released into
   Trypanosoma cruzi
   Listeria monocytogenes
   Shigella flexneri
– Exist in phagolysosome: Resistant
  to hydrolysis
   Mycobacterium leprae
   Leishmania spp.
   Salmonella typhimurium
 Defects in Intracellular Killing – A
predisposition to chronic infections
Inability to phagocytose and/or
destroy intracellular microorganisms
 – Associated with recurrent or chronic
   infections even though antibody may e
Chronic Granulomatous Disease
 – Chronic infections with catalase positive
 – NADPH oxidase defect
     Results in inability to produce hydrogen
     peroxide levels required for effective killing
Chediak-Higashi Syndrome
– Large lysosomes fail to fuse with
– Phagocytic cells fail to respons do
  chemotactic factors

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