General or Nonspecific Host Immune Defense Mechanisms

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• General or Nonspecific Host Immune Defense
  Mechanisms

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• Innate versus Adaptive Immunity The Time Course
  of an Infection

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Innate Mechanisms Designed to Prevent Infection

• General
• Physical
• Chemical
• Biological

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• General barriers
• Nutrition
• The more malnourished the host, the greater the
  susceptibility to infection
• Nutrient provide the building blocks for cell
  division, microbe destruction and tissue repair

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• Acute-phase reactants
• During an acute infection, qualitative and
  quantitative changes in the hosts 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

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• 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)

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• Mannose binding protein
• Binds mannose on bacteria
• Activates complement
• Induces opsonization
• Membrane attack complex (MAC) is formed
• Iron redistribution Release of lactoferrin by
  neutrophils
• Sequestered by host hypoferremia
• Uptake of iron by liver

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• Fever
• Thermal set point altered in hypothalamus
• 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)
• TNF-alpha
• IL-6

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• 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

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• Age
• Young
• Postnatal protection passive immunity
• IgG antibodies transferred transplacentally
  during pregnancy
• IgA antibodies transferred in colostrum in breast
  milk
• Elderly
• Peripheral lymphoid organ follicles shrink
• Thymus involutes
• Homeostatic mechanisms fail

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• Genetic factors
• Host temperature
• Metabolic, physiologic, and anatomic differences
• Food preferences
• Major histocompatibility proteins (MHC class
  I/class II, class III)
• Racial factors (e.g. sick cell trait and
  resistance to malaria)

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• Physical barriers
• Skin - reasonably effective mechanical barrier
• Keratin water proofing
• Shedding/sloughing off
• Dry
• Acidic
• Fatty acids secreted by sebaceous glands (sebum)
• Propionic acid (made by Propionibacteria normal
  flora)
• Oleic acid (made by Gram positive flora, elgl
  Staphylococcus epidermidis)
• Washing activities
• Epidermis/Dermis
• Lymphoid tissue in the skin

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• 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 -
  NEUTRALIZATION

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• 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
  epithelium
• Sneezing/coughing expels saliva ? washed to
  stomach

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• 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

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• 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

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• The eye
• Flushing action,
• Lysozyme
• Hydrolysis of bond between NAM and NAG
• Other antibacterial substances (sIgA, lactoferrin)

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• Chemical barriers
• Gastric juices
• Salivary glyco-proteins
• Lysozyme

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• 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
• Corticosteroids
• Estrogen

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• 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

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• Effects of interferons
• Acivation of endoribonuclease and protein kinase
• Destruction of viral mRNA
• Inhibition of protein synthesis (EF-2
  phosphorylation)
• Upregulation of MHC class I
• Enhancement of Tcyt activity
• Activation of Natural Killer (NK) cells

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• Interferons have been used clinically in
  treatment of several diseases
• Papilloma virus
• Hepatitis B and C
• Some herpes infections
• Osteosarcoma
• Multiple myeloma
• Hodgkins disease

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• 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

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• 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

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• Biological Barriers

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• 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 mechanisms

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• Inflammation
• Response to tissue injury through the release of
  chemical signals (inflammatory mediators
  vasoactive and chemotactic factors)
• Histamine
• Serotonin
• Bradykinin
• Prostaglandins
• Vasodilation, increased capillary permeability,
  influx of phagocytic cells

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• 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 surface
• Promotes neutrophil extravasation
• Integrins are activated by inflammatory mediators

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• Rolling adhesion ? Tight binding (sticking) ?
  Extravasation (Diapedesis) ? Migration to injury
  site (chemotaxis) ? Pathogen encountered and
  phagocytosed

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• 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)

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• Phagocytosis
• 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 organisms
• LPS binding site
• Hemagglutinin receptor
• C3b receptor (CR1)
• Mannose receptor

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• Opsonization
• The use of opsonins in making bacteria more
  susceptible to phagocytosis
• Examples of opsonins
• Antibodies
• Complement proteins (C3b, C4b)
• Fibronectin

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• May damage the pathogen by respiratory burst
  (formation of highly reactive, toxic oxygen
  products)
• Superoxides
• Peroxides
• Hypochlorous
• Singlet oxygen
• Hydroxyl radicals

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• Phagosomes may fuse with lysosomes and thereby
  hydrolyze the invading organism
• Form phagolysosomes
• Enzymes include
• DNAse
• RNAse
• Phospholipase A2
• Proteases

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• Gamma interferon and TNF induction of reactive
  nitrogen intermediates (RNIs) in phagocytes
• Secreted or formed in vacuoles
• Nitric oxide (NO)
• Nitrite (NO2-)
• Nitrate (NO3-)

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Biological Barrier Mast Cells and Inflammation

• Activation and Physiological Effects of Preformed
  and Newly Synthesized Mast Cell Inflammatory
  Mediators

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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)

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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
• Lipooxygenase
• See figure for products of these pathways

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• Neutrophils also release defensins, a family of
  broad spectrum antimicrobial peptides
• Make PM more permeable
• Ionic fluxes
• Also affect enveloped viruses

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Biological Barrier Alternative Pathway of
Complement Activation
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• Complement
• Alternative pathway of complement activation
• Does not require antibodies
• Immediate
• Activates the terminal complement components
  which destroy bacteria by creating holes (pores)
  in the bacterial membrane - MAC

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Biological Barrier Cells of the Immune System

• The Reticuloendothelial System

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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

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Circulating Cells

• Blood monocytes and free macrophages trafficking
  between tisues
• Polymorphonuclear leukocytes (PMNLs)
• Basophils
• Eosinophils
• Neutrophils
• Lymphocytes
• T cells
• B cells
• NK cells

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Lymphoid Lineages Involved in Non-Adaptive
Responses
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• Lymphoid lineages involved in non-adaptive immune
  responses
• Natural Killer cells (NK cells)
• gd T cells
• CD5 B cells (B-1 B cells)

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• 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-interferon
• MHC class I involved
• Present ? Negative signal overrides activity of
  killing receptors

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• Intraepithelial gammadelta T cells (gd)
• 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 infection
• Exact function still unclear

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• 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 peritoneum
• Respond to polysaccharide antigens (TI-2 type
  repeating subunit structure)
• Exact function still debatable
• Once IgM is bound, can activate complement

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Evasion of Phagocytic Destruction

• Some microbes have evolved mechanisms to avoid
  eradication by phagocytic mechanisms
• Inhibition of fusion phagosome with lysosome
• Mycobacterium tuberculosis
• M. leprae
• Legionella pneumophila
• Toxoplasma gondii

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• Lyse phagosome ? Released into cytsol
• Trypanosoma cruzi
• Listeria monocytogenes
• Shigella flexneri
• Exist in phagolysosome Resistant to hydrolysis
• Mycobacterium leprae
• Leishmania spp.
• Salmonella typhimurium

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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 present
• Chronic Granulomatous Disease (CGD)
• Chronic infections with catalase positive
  microbes
• NADPH oxidase defect
• Results in inability to produce hydrogen peroxide
  levels required for effective killing

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• Chediak-Higashi Syndrome
• Large lysosomes fail to fuse with phagosomes
• Phagocytic cells fail to respons do chemotactic
  factors