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THE IMMUNE RESPONSES TO
EXTRACELLULAR PATHOGENS
PATHOGENS
Viruses, Bacteria, Fungi
Parasites
Unicellular protozoa
Multicellular worms
REQUIRES HIGH INITIAL DOSE FOR INFECTION
ESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS
HUMAN BODY
RESOURCE RICH ENVIRONMENT FOR PATHOGENS
DEFENSE MECHANISMS
Physical barriers/Innate immunity – STOP MOST INFECTIONS WITHOUT CALLING
Adaptive immunity
Diseases – Medical practice
DISEASE
Innate immunity fails to terminate infection
Activation of adaptive immunity
Successful evasion and subversion of the immune
system by pathogens
Pathogens have short generation time
Virus
3 hrs
3 hrs
Humans have longer generation time,
need a sophysticated protection system
Examples of extracellular bacteria
Distribution of mucosal tissues
Physical barriers separate the body from its
external environment
Movie: Mucosal immune tolerance and immune response
Five ways in which the commensal gut
microbiota benefit their human hosts
The structure of mucins gives mucus its
characteristic protective properties
Secretory immunoglobulins become attached to
the mucus, where they stand ready to bind
commensal and pathogenic organisms
Defensins disrupt microbial membranes
Gut-associated lymphoid tissues and lymphocytes
Epithelial cells contribute to
the defense of mucosal tissue
Uptake and transport of
antigens by M cells
Capture of antigens from the intestine by
dendritic cells
Lymphocytes activated in mucosal tissues return
to those tissues as effector cells
Homing of effector T cells to the gut is controlled
by adhesion molecules and chemokines
Mucosal infection engages the Th17 axis of
host defense
!
Th17 activation
Secretion of
chemokines
Production of
antimicrobial peptides
Infiltration of
phagocytes,
Cytokine secretion
Differentiation of
Th17 cells
The systemic and mucosal immune systems use
different strategies for coping with infections
Innate immune mechanisms establish a state of
inflammation at sites of infection
Immune defense involves recognition of pathogens
followed by their destruction
Phagocytosis and degradation of invading
microorganisms by a tissue macrophage
Neutrophils are stored in the bone marrow and move
in large numbers to sites of infection,
where they act and then die
Neutrophil extracellular traps
Exotoxins vs. endotoxin
Exotoxins – secreted by living bacteria
- Cytotoxicity of various mechanisms
- Inhibition of various cellular functions
Endotoxin – released by dying cells
- Cell wall – Gram (-) LPS
- Induction of cytokines
septic shock
Sepsis/Septicemia
TNF-α→platelet activating factor by
endothelial cells→clotting, blockage
restricts plasma leakage & spread of
infection
Infection of blood – Sepsis
Sysemic edema, decreased blood
volume, collapse of vessels
Disseminated intravascular
coagulation, multiple organ failure
Adaptive immune responses to extracellular microbes
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Mechanisms by which
antibodies combat infection
Many common diseases are caused by bacterial toxins
The four subclasses of IgG have different
and complementary functions.
Functions of Th17 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
MECHANISMS OF PROTECTION
INNATE IMMUNITY
Complement activation
Gram (+)
Gram (-)
peptidoglycan 
LPS

Mannose + MBL 
alternative pathway
alternative pathway
lectin pathway
Phagocytosis
Antibody and complement mediated opsonization
Inflammation
LPS
Peptidoglycan


TLR macrophage activation
TLR macrophage activation
ACQUIRED IMMUNITY
Humoral immune response
Targets: cell wall antigens and toxins
T-independent
T-dependent
 cell wall polysaccharide
 bacterial protein
 isotype switching
 affinity maturation
 memory B cells
Cellular Immune response: Th17 cells
Evasion mechanisms of extracellular bacteria
Proteins to increase adhesion
Bordetella pertussis
Inhibition of phagocytosis
Str. pneumoniae M protein, S. aureus coagulase enzyme - fibrin capsule
Antigenic variants
Neisseria gonorrhoeae (pilin)
Inhibition of complement-dependent cell lysis
Str. pyogenes
Sialic acid rich capsule inhibits activation of the alternative complement pathway
Some Gram-neg bacteria have a lipidA component that inhibits the MAC complex
Scavenging of reactive oxigen intermediates
Catalase positive staphylococci
Degradation of IgA antibodies
Neisseria, H. influenzae
Protective immunity against Streptococcus pneumoniae
is serotype-specific
Bacterial superantigens activate CD4 T cells by cross-linking
MHC class II molecules with α:β T-cell receptors and
CD28 co-stimulatory molecules in the absence
of antigenic peptides
Subversion of the immune system by extracellular bacteria
Superantigens of staphylococci – staphylococcal enterotoxins (SE)
PROFESSIONAL APC
2
2
1
1


– toxic shock syndrom toxin-1 (TSST-1)
Mimic specific antigen
Induce massive but ineffective T-cell activation and
proliferation in the absence of specific peptide
2 – 20% of CD4+ T-cells, which are not specific for
the bacteria but share V get activated and develop to
effector T-lymphocytes
Over production of cytokines – IL-1, IL-2, TNF-α
Systemic toxicity – shock
T cell
Suppression of adaptive immunity by
apoptosis
Evasion of IgA-mediated defense by staphylococcal
superantigen-like protein 7