Transcript Slayt 1

Immunity to bacteria
Antimicrobial Defenses for Infectious Agents
Neutrophils
Macrophages
Complement
NK cells
CD4 TH1-DTH
CD8-CTL
Antibody
Bacteria Intracellular Viruses Fungi Parasites
bacteria
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Barrier defenses of human body
Antibacterial Responses
“Protection is initiated on activation of innate
responses on a local basis and progress
to acute-phase and antigen specific
responses on a systemic scale”
major events in acute
inflamation
1. Expansion of capilaries to increase blood
flow (seen as blushing or a rash)
2. Increase in the permeability of the
microvasculature structure to allow
escape of fluid, plasma proteins, and
leukocytes from the circulation edema
3. Exit of leukocytes from the capillaries and
their accumulation at the site of injury
Bacterial components that activate
Protective Responses I
• Direct activation
– LPS
– Lipoteichoic acid
– Lipoarabinomannan
– Glycolipids and glycopeptides
– Polyanions
– N-Formyl peptides
Bacterial components that activate
Protective Responses II
• Chemotactic
– Peptidoglycan fragments
– Cell surface activation of alternative pathways
of complement (C3a, C5a)
Complement in antibacterial
response
• Alternative and Lectin pathways activated
by bacterial surfaces
• Classic pathway activated later by
antibody-antigen complexes
• Production of chemotactic and
anaphylotoxic proteins (C3a, C5a)
• Opsonization of bacteria (C3b)
• Promotion of killing of gram-negative
bacteria
• Activation of B cells (C3d)
Complement cascade
Neutrophil diapedesis in response to
inflamatory signals
Phagocytes & Phagocytosis
• PMNs, monocytes, and eosinophils are
the first cells to appear in response to
acute inflammation; they are followed later
by macrophages
Neutrophils
• major antibacterial response
• an increased number of neutrophils in the
blood, body fluids or tissue indicates:
“bacterial infection”
• “left shift”
Steps in Phagocytosis
• Attachment
– bacterial carbohydrates (lectins)
– receptor for opsonins
– fibronectin receptors
– Fc receptors
• Internalization (phagocytic vacuole)
• Digestion (phagosome)
Antibacterial compounds of the
phagolysosome I
• Oxygen-dependent compounds
– Hydrogen peroxide: NADPH oxidase
and NADH
– Superoxide
– Hydroxil radicals (OH)
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– Activated halides (Cl , I , Br ):
myeloperoxidase
– Nitrous oxide
Antibacterial compounds of the
phagolysosome II
• Oxygen-independent compounds
– Acids
– Lysosome (degrades bacterial
peptidoglycan)
– Lactoferrin (chelates iron)
– Defensin and other cationic proteins
(damage membranes)
– Proteases, elastase, cathepsin G
Phagocytosis & killing of bacteria
Macrophages in antibacterial
response
• Important antibacterial phagocytic cells
– Killing by oxygen-dependent and oxygenindependent mechanisms
– Production of IL-1, IL-6, and IL-12; TNF-a and
TNF-b, and interferon-a
– Activation of acute-phase and inflammatory
responses
– Presentation of antigen to CD4 T cell
Antibacterial responses
Acute-Phase Reactants
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a1-antitrypsin
a1-glycoprotein
Amyloid A & P
Antithrombin III
C-reactive protein
C1 esterase inhibitor
C3 complement
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Ceruloplasmin
Fibrinogen
Haptoglobulin
Orosomucoid
Plasminogen
Transferrin
Lypopolysaccharidebinding proteins
Specific Immune Responses to
Bacteria I
• Macrophages move to lymph nodes and
interact with CD4 T cells after ingestion of
bacteria
• initially: Macroph(APC).
CD4
TH0 cells
antigenic peptides + class II MHC
TCR + CD4, on TH0
Specific Immune Responses to
Bacteria II
• costimulatory signals from the interaction
of CD28 (T cells) B7 molecule
(macrophage)
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IL-1, IL-12
• TH0 produce IL-2, IFN-g and IL-4
• B cells produce IgM
• LPS and cell wall polysaccharides activate
B cells
Specific Immune Responses to
Bacteria III
• TH0
TH1
(IL-12 & IFN-g)
– activation of Macrophages, T cells, B cells
– important for intracellular infections
• CD4 TH2 T-cell response
– occur later
– initiated by the B cell presentation of antigen
– presentation to TH2 cell
(Ag + class II MHC)
– TH2 IL-4, IL-5, IL-6, IL-10
, Plasma-cells, memory cells
IgG
T cells in antibacterial response
• TH1 CD4 responses important for
intracellular bacterial infections
• TH2 CD4 response important for all
bacterial infections
• CD8 cytolytic T cells not very important
Antibody in antibacterial
response
• primary protection against extracellular
bacteria and reinfection
• Binding to surface structures of bacteria
(fimbriae,lipoteichoic acid, capsule)
– Blocking attachment
– Opsonization of bacteria for phagocytosis
– Promotion of complement action
– Promotion of clearence of bacteria
– Neutralization of toxins and toxic enzymes
Bacterial Immunopathogenesis
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“tissue and systemic damage”
IL-1, IL-6 and TNF-a life-threatening in
systemic infection
endotoxin
macrph. TNF-a in the blood
symptomes of sepsis
antibodies which share determinants with
human proteins post-streptococcal
glomerulonephritis and rheumatic fever
superantigens
STSS
Bacterial Evasion of Protective
Responses
1. the inhibition of phagocytosis and
intracellular killing in the phagocyte
2. inactivation of complement function
3. cleavage of IgA
4. intracellular growth (avoidance of
antibody)
5. change in bacterial antigenic
appearence