Transcript Lipoteichoic acid contaminant

Defenses
Against Infection
1. Innate responses (humoral and cellular)
2. Immunity to intracellular pathogens
NK cells, control of Th1/Th2 responses
3. Immunity to extracellular pathogens
and toxins
4. Immunological Memory
5. Introduction to Evasion of Host Responses
1. Innate responses (humoral and cellular)
Acute-phase response: Early response to infection
Specific for sialic acid
Lipoteichoic acid
contaminant
‘Endocrine’ effects
Acute-phase response: Early response to infection
Too much of a good thing:
Systemic Inflammation (Harmful)
(Toxic Shock or Endotoxic Shock)
A primary cause of death by infection
Acute-phase response: Early response to infection
Many bacteria produce proteases to establish infection:
These are countered by Serpin and a2-macroglobulin
Serpin: plasma protease inhibitors (~10% of plasma proteins)
Acute-phase response: Early response to infection
a2-macroglobulin- Protease inhibitor in the plasma
Acute-phase response: Early response to infection
C-reactive protein
Mannose binding lectin
2. Immunity to intracellular pathogens
Innate Immunity to Virus Infection:
IFN-a/b (Type 1 IFN) produced in response to viral dsRNA
Reduced protein synthesis, production of RNAse to degrade viral RNA
NK cells
1. Kill infected or transformed targets
2. Produced IFN-g (activates macrophages)
These functions act as a ‘stop-gap’ attempt
to control infection while the specific immune
response develops.
DO NOT
MEMORIZE
intracellular
intracellular
extracellular
How does the immune system decide to mount a Th1 or Th2 response?
Production of IL-12 early in
the response promotes
Th0 cells to preferentially
differentiate into Th1 cells
Hypothesis: A Th2 response is generated in the absence of IL-12
Early inflammatory
response by
Dendritic cells and Macrophage (PAMPs)
IL-2 + IFN-g
IL-12
CMI
Th1
IL-10 inhibits
IFN-g production
Th2
IL-4
inhibits
IL-12 production
3. Immunity to extracellular pathogens and toxins
Antibody Function
3.1. Block binding of pathogen or toxin to host cells
3.2. Opsonize for phagocytosis (antigen clearance
mediated by Fc receptors on phagocytic cells)
3.3. Activate complement for MAC formation, and
generation of C3b and C5a
3.4. Activator of Antibody Dependent Cellular
Cytotoxicity (ADCC)
3.5. Degranulate mast cells and eosinophils.
Mast Cells and Eosinophils are Important
In Immunity to Worms (very large pathogens)
Mast Cells: Production and release of
Histamine (vasodilation and smooth
muscle contraction) causes flushing
action to expel the pathogen and
increase eosinophil access to the
pathogen.
Eosinophils Production of granules that contain
Major basic protein and eosinophil cationic
protein (and other materials) that are directly toxic
to parasites
4. Immunological Memory
Functionally:
Faster more robust response that generally protects against
damage from infection
4.1 Memory B-cells: Lymphatic circulation and perhaps bone marrow.
No surface markers to clearly define memory B-cells.
Long-lived and respond rapidly to infection with high affinity ‘switched’ Ig.
(Evidence for existence of memory B-cells)
4.2 Memory T-cells: CD45RA to CD45RO expression. Migration in
lymphatic circulation, blood, and peripheral tissues including mucosal tissue
Memory CD8+ T-cells survive on IL-15. (Evidence for CD8+ memory T-cells is
ability to kill targets rapidly and without co-stimulation).
E
Naïve
Effector
Memory
M
5. Introduction to Evasion of the Host Response
Pathogens attempt to resist destruction by many
mechanisms including:
5.1 Suppressing/Shifting the Immune Response
5.2 Antigenic Variation
5.3 ‘Hiding’ from the Immune Response
5.1 Suppressing/Shifting the Immune Response
Encoding immunosuppressive proteins in the pathogen’s genome
that shift responses from Th1 to Th2, or receptors for cytokines to
block their activity: viruses express genes for IL-10
Polyclonal activation of lymphocytes by bacterial mitogens (e.g.
LPS). Causes partial activation and proliferation of many clones.
Without secondary signals resulting in death or poor responses
(B-cells make low affinity IgM and don’t switch)
Production of bacterial or viral ‘superantigens’ that promote
polyclonal T-cell activation; exhaustion of T-cells and cell death;
production of inflammatory cytokines by T-cells.
Instead of order, the immune system becomes disordered
Superantigens induce activation of many T lymphocytes
Superantigens include some
bacterial toxins. They induce
cytokine production by a large
percentage of T-cells (10-20%)
that results in an exacerbated
inflammatory response.
(Toxic Shock Syndrome)
TNF and IL-6 are 2 such T-cell
derived cytokines
5.2 Antigenic Variation
Different ‘strains’ or individuals of a species express
antigenically distinct forms of surface molecules: e.g. bacterial
serotypes
During replication, mutations in genes that encode surface
proteins result in new forms of the surface proteins
‘antigenic shift’ or ‘antigen drift’:
e. g. viruses such as influenza and HIV
Some pathogens carry multiple genes that encode
antigenically distinct forms of surface proteins in their genome:
e.g. some parasites
5.3 ‘Hiding’ from the Immune System
Down regulating MHC expression in infected cells
e.g. many viruses
Becoming dormant in immunologically privileged sites
e.g. viruses such as herpes simplex virus
Defenses
Against Infection
Many different types of pathogens of various
sizes and lifestyles requires a multi-layered
system to protect both the extracellular and
intracellular environments of the complex human
host for a relatively long time.