Download Innate and Adaptive Immunity - Molecular and Cell Biology

Innate and Adaptive Immunity
• Innate is FIRST LINE
OF DEFENCE: no prior
exposure needed
• Comprised of:
- INTERFERONS
- COMPLEMENT
- NATURAL KILLER
CELLS (NK)
• INFLAMMATION:
initiated by CELL
DAMAGE - activates
COMPLEMENT, MAST
CELLS, etc. Symptoms
are REDNESS, HEAT,
SWELLING, PAIN.
Neutrophil / macrophage
chemotaxis into site of
inflammation increases
response, results in
recruitment of T-cells, etc.
• CHEMOKINES are often first sign that host is
infected
• Tend to act locally near cells that make them
• Participate in:
- CONTROL OF INFLAMMATION
- INDUCTION OF ANTIVIRAL STATE
- REGULATION OF ADAPTIVE IMMUNE
RESPONSE
• Invoke GLOBAL RESPONSES: act on nervous
system, etc. Cause many classical signs of virus
infection
• Inflammatory
cytokines IL-1, IL-6
and TNF act on
BRAIN and LIVER to
produce symptoms and
ACUTE-PHASE
PROTEINS - these
have innate immune
capability; eg: activate
complement,
lymphocyte
production, etc.
• SPECIFICALLY ANTIVIRAL RESPONSE:
• produced by infected cells - triggered by dsRNA, some
structural proteins, etc: induction rapid, and transient
• secreted Ifn binds cell receptors: 1 for, 1 for 
• ,  induce antiviral state: over 100 genes induced;
leads to cell death by apoptosis if prolonged
• blocks cell proliferation, inc. NK cell activity, etc.
• induces dsRNA-activated Pkr, PO4ylates eIF2
• induces RNAse L and dsRNA-act. 2’-5’ oligoA
synthetase; 2’-5’ oligoA act. RNAse L, degrades
mRNAs
Ifn-/ and - have different
cell surface receptors but share
components Of the Jak/Stat
signal transduction pathway.
Binding of either type to the
receptors causes Tyr PO4ylation
of the different receptorassociated kinases, and of the
different Stat proteins associated
with these. Ifn-/ complex has
a unique pathway activating p113;
both activate p91/p84.
These pathways then converge in
the activation of Ifn-stimulated
response elements (ISREs); they
diverge in that Ifn-  can induce
gamma-activated site (GAS) genes
Viruses can block effects of
interferon:
• COMPLEMENT - a
complex collection of
serum defence proteins
that also amplifies
immune reactions.
• 18 serum and roughly same
no. membrane proteins
which act sequentially in a
cascade - started by
ANTIGEN-C’ or Ab-C’
interaction.
• Form MEMBRANE
ATTACK COMPLEX to lyse
cells - MOs, viruses, RBCs,
nucleated cells
• Classical pathway
activated by C1
binding Ab-Ag
complex
• Alternative
pathway activated
by C3b binding Ag
directly
Natural Killer Cells
•
•
•
•
Large, granular lymphocytes, no Ag receptors
Can constitute up to 30% of circulating lymphocytes
Act early in infection, spontaneously kill infected cells
Numbers expand quickly with viral infection, decline
with adaptive response
• Lyse cells and secrete cytokines like Ifn- and Tnf-
• Bind cells via many receptors, including lectins
• Interaction with cells governed by ACTIVATION signals
(eg: new CHO ligand) and NEGATIVE signal (eg: MHC
class I protein).
Humoral and cellular response require activation and
proliferation of Th cells
Humoral response begins
when Ag cross-links
several Ab receptors
which are then
endocytosed, and is
processed by proteolysis,
complexed with MHC
class II molecules, and
presented at the cell
surface. The Th cell then
recognises this by means
of its T-cell receptor and
secretes cytokines to
activate the cell to divide
and differentiate.
Primary lymphatic system
showing ducts and nodes:
mobile dendritic cells meet
circulating lymphocytes
in nodes
Cellular components of mucosaassociated lymphoid tissue in gut.
M cells and intraepithelial lymphocytes transfer antigen from gut to
lymphoid tissue in Peyer’s patches
Cutaneous immune system:
keratinocytes, Langerhans cells and T-cells
Keratinocytes secrete Tnf-, IL-1 and IL-6 and have
phagocytic activity and have MHC-I and II and present Ag
to T and B cells if stimulated by Ifn-. Langerhans cells
are migratory dendritic cells and have MHC-I and II
B cells have 100 000-odd identical Ab monomers as
receptors. T cells have about 100 000 identical receptors.
T cells with CD4 receptors recognise peptides bound to
MHC class II proteins and are generally Th cells. Cells
with CD8 receptors recognise peptides bound to MHC-I
and generally act as cytotoxic T cells.
Members of the Ig
superfamily of receptors
Antibody: dimer of heterodimers; heavy and light chains
both have variable regions
T-cell receptor:
heterodimer of an
 and a  chain or 
and  chains, all with
N-terminal V domains.
CD4 and CD8 are both
glycosylated type I
membrane proteins, both
of which have cytoplasmic
domains which interact
with tyrosine kinases, which
means they participate in
signal transduction events.
Both have Ig-like variable
domains.
CD4 molecules are
monomers and bind MHC
class II proteins via the 1st
two domains. CD8 proteins
are heterodimers linked by
disulphide bridges. They
bind MHC class I proteins.
Both are heterodimers,
but MHC-I  chain has
3 domains and 2 only 1
while MHC-II  and 
each have 2. MHC class
I are found on nearly all
nucleated cells, but at
highest concentration on
lymphocytes (500 000
vs 100/cell on liver
cells). MHC-II are
found only on specialist
APCs. There are 3 loci
for each type (A, B, C
for I, DR, DP and DQ for II), but many alleles, meaning individual
responses will differ considerably. Ifns stimulate MHC-I
production.
Full activation of Th cells in many cases requires interaction of other
surface proteins and co-stimulators on the APC and T-cell as well as
the TCR and MHC class II proteins. Activated Th cells make IL-2
and IL-2 receptor resulting in autostimulation. CTLs (CD8+ T-cells)
require at least 3 additional reactions, including TCR/MHC-I binding,
binding of other surface proteins on the CTL with the target cell, and
binding of cytokines produced by Th1 cells nearby.
Immature T-cells can differentiate
into Th1 or Th2 classes,
distinguished by the cytokines they
produce. They have distinct
functions and respond to Ag
stimulation with a transient burst of
cytokine stimulation that
differentially influences the
activation and proliferation of other
immune cells. Th1 cells promote
maturation of CTLs and arm APCs.
IL-12 induces immature Th
cells to mature to Th1s;
IL-4 prompts -> Th2. These
promote B cell maturation. Th1
Induce IgG2a, which activates
C1 and binds macrophages;
Th2 stimulate IgG4 and IgE, which do not. Th1 & Th2 see-saw…
The first Abs expressed by a VIRGIN B-CELL are MEMBRANE
RECEPTOR IgM/IgD. Binding and cross-linking of receptors by
an antigen triggers a signal transduction cascade, which when
reinforced by Th2-produced cytokines and growth factors secreted
by macrophages, result in cell proliferation and differentiation and
increased soluble Ab production, then CLASS-SWITCHING and
differentiation to memory and plasma cells. Memory cells last for
months to years; plasma cells last only a week or so.
How antibodies can interfere in virus infection: normal cell entry is
shown at left; what can happen with antibodies at right. Ab can
(1) aggregate; (2) neutralise; (3) stabilise; (4) change virion structure;
(5) potentially enter cell and interfere within
IgA secretory antibodies play a key
role in antiviral defence at mucosal
surfaces:
Plasma cells secrete polymeric IgA
(pIgA) that binds a receptor on the
inner side of an epithelial cell. The
pIgA is endocytosed and delivered
into vesicles targetted to the outer
side of the cell (TRANSCYTOSIS).
pIgA is then released by proteolysis
of the receptor pIgR by a surface
protease.
The IgA can bind to Ag at any stage
of the process: it can take Ag into the
cell and across into the lumen; it can
block virus attachment in the lumen;
it can bind internally and block virus
maturation / release