Transcript Lecture 3 Innate immunity continued

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Lecture 3
Innate immunity and leukocyte migration
•Relationship between plant immunity and vertebrate immunity
NODs
RNA interference by small interfering RNAs
•Quick reviewcomplement and its subversion
phagocytosis
•Leukocyte migration/extravasation
•Lymphocyte recirculation
•Distinction between spleen and lymph nodes
Next lecture: antibodies (Reading Parham, Chapters 2 and 7)
Numerous innate sensors of bacterial peptidoglycan
Mammalian NOD1 and NOD2
(intracytoplasmic sensors)
Lysozyme
(in serum and secretions)
clips here
Seen by Tlr2
(cell surface receptor)
NOD signaling activates NFkB transcription factor
Peptidoglycan
NOD domain proteins are conserved between humans and
plants (they also are related to Toll like receptors [Tlrs])
In plants
R proteins
confer
resistance *
*
to
pathogens
Humans
carrying
NOD2
mutations
develop
Crohn's
disease
(Inflammatory
bowel
disease)
How can a long lived organism like a tree survive without
adaptive immunity?
RNA interference as a widespread immune mechanism
Discovered in plants
dsRNA leads to dsRNA
degradation in infected cell,
but also sequence-specific
resistance by nearby cells
21-25bp dsRNAs
Lecellier, Charles-Henri & Voinnet, Olivier (2004)
RNA silencing: no mercy for viruses?.
Immunological Reviews
The short dsRNAs serve as templates to direct destruction of other mRNAs
Lecellier et al. 2004
Transmission of siRNAs from cell to cell in plants
Lecellier et al. 2004
Lecellier et al. 2004
Concepts
•
•
•
The multilayered nature of immunity is a general
phenomenon.
RNAi is a novel type of host defense.
(While RNAi is not believed to be a major defense
mechanism in mammals, it is operational, and can be
harnessed, for example in gene therapy.)
The NOD pathway shows that even the loss of a single
aspect of innate immunity can have disastrous
consequences for the host. (Conserved genes are
conserved for a reason, they provide fitness).
Animations
Complement
Phagocytosis
Virus subversion
Herpes simplex
Strategy 1. Hiding in
immunologically priviledged
sites.
Fig 9.4
Strategy 2. Suppress antibody and complement
mediated defense mechanisms.
Viral envelope proteins
gC and gD are important
for infection
gE and also
gC subvert
the host
response by
suppressing
antibody and
complement
mediated
lysis
From Judson et al J. Virol 2003
Figure 2-8 part 1 of 2
Figure 2-8 part 2 of 2
Figure 2-45 part 1 of 3
Figure 2-45 part 2 of 3
Figure 2-45 part 3 of 3
Figure 2-9
Animations
Leukocyte rolling
Leukocyte extravasation
Lymphocyte homing
Chemotaxis
Langerhans'
cell is a skin
dendritic cell
They migrate to
the draining
lymph node
and present
antigen to T
cells .
A microbeactivated
dendritic cell
migrating to the
draining lymph
node through the
lymphatics
Principal
lymphoid
organs
Figure 1.8
Tissue-LN connection
flow
Eventually flows to thoracic duct, then back to blood
Lymph nodes drain the connective tissues of the body
Figure 1.10
The segregation of different cell types within lymph nodes is
controlled by chemokines and adhesion molecules.
Lymphocyte
circulation
Figure 1.9
Figure 1.11
The spleen drains
the blood
Lymphoid cells
tend to
congregate in
discreet regions
Spleen II
Morphology of the spleen
Figure 1.12
GALT-gutassociated
lymphoid
tissue
Figure 2-13
Salmonella winkling their way in through M cells
Mucosal Immune System
T lymphocyte
recirculation
Bone marrow to blood
development
Blood to thymus (Differentiation and Selection
Occurs)
Thymus to lymph nodes and spleen
Lymph nodes to efferent lymphatics
To thoracic duct emptying into the left subclavian
vein
Blood to site of inflammation-extravasation
Tissues to afferent lymphatics
To draining lymph nodes
Movie
Lymphocyte trafficking
Summary of Concepts discussed
1) Leukocyte movement is rapid and directed.
•
Tissue damage, microbial motifs stimulate cell migration through
selectin upregulation, chemokine expression, and cell adhesion.
2) Lymphoid tissue is organized.
•
Chemokines expressed by fixed and motile cells in lymph node and
spleen are important in organizing lymphoid architecture.
3) Different secondary lymphoid organs sample distinct compartments
•
Lymph nodes
•
Peyer's patches
•
Spleen
4) Complement cascade is complicated
5) Even plants share some immune mechanisms with us
(NODs, RNAi)
Next time: antibodies (Reading Parham, Chapters 2 and 7)
Figure 2-10