Key Concepts for Module 2
Innate Immunity
Required Reading: Parham Textbook Chapters 2 and 3
• Complement
• Macrophages
• Pathogen recognition receptors
• Inflammatory Mediators
• Neutrophils
• Acute Phase Proteins CRP ad MBL
• Responses to Virus
COMPLEMENT
System of soluble
proteins in blood, lymph
and extracellular fluids
C1 – C9
Factors D, B, H, I
Activation Step 1
“Fixation” of C3
(binding to bacterium)
Mechanism for C3 activation
Inactive
Cleavage by
proteases
3 complement pathways
Alternative pathway of
complement activation
Soluble alternative C3
Spontaneous exposure and hydrolysis of convertase = iC3Bb
C3 without cleavage
Enhanced near pathogen surface
iC3 functions like C3b
• Most C3 will become hydrolyzed, or attach to serum proteins – a few become cell-bound
• Cell-bound C3 can bind B and form C3bBb more surface bound C3b made….
Membrane bound
alternative C3
convertase = C3bBb
Rapid exponential increase in surface C3b
Regulation of complement
Prevent too rapid depletion of C3
Prevent destruction of host cells
DAF - Decay accelerating
factor
MCP - Membrane co-factor
protein
Role of complement in phagocytosis
Functions beyond opsonization - Membrane attack complex
First step in forming membrane attack complex (MAC)
C5a (with C3a)
will act on blood vessels
C5 convertase =
C3b2Bb
Final steps in membrane attack complex (MAC)
Local inflammation from
complement cleavage products
C3a and C5a are
Anaphylatoxins
Cause smooth muscle contraction,
histamine release from mast cells, and
enhanced vascular permeability
Macrophages
The first effector cells encountered
by pathogen.
Long lived
• Complement receptors
(CR1 – C3b; CR3, CR4 – iC3b)
CR3 and CR4 also bind microbial
surface (LPS), lipophosphoglycan,
hemagglutinin
• Lectins
(carbohydrate binding receptors)
• Scavenger receptors - negative
charges
Macrophage differentiation in response to
cytokines secreted by T cells
Macrophage Receptors –
Facilitate Phagocytosis and Initiate Signaling
Germline-encoded Pattern Recognition Receptors
(PRRs)
TLRs Toll-like receptors
NLRs Nod-like receptors
RLRs RIG-I-Like Receptors
PRR activation rapidly targets
invading pathogens and
infected host cells for
elimination through immune
cell recruitment,
phagocytosis, and autophagy.
PRRs also induce
transcriptional and
posttranslational programs
leading to the production of
inflammatory mediators TIR = Toll / Il-1 Receptor (TIR) domain
Toll like Insects Mammals
receptors –
Common
evolutionary
source
Induces anti-bacterial immune Induces inflammatory
response gene mediators
TLR Ligands
Recognition of PAMPs from different classes
of microbial pathogens
Viruses, bacteria, fungi, and protozoa display several different PAMPs, some of which are
shared between different classes of pathogens. Major PAMPs are nucleic acids, including
DNA, dsRNA, ssRNA, and 5′-triphosphate RNA, as well as surface glycoproteins (GP),
lipoproteins (LP), and membrane components (peptidoglycans [PG], lipoteichoic acid
[LTA], LPS, and GPI anchors). These PAMPs are recognized by different families of
PRRs.
TLRs – both membrane and vesicular
LPS
Double stranded
Viral DNA
Lipopeptides
TLR signaling with MyD88
MyD88 = myeloid differentiation primary response (MyD) 88
NOD receptors
Nucleotide-binding oligomerization domain
Cytoplasmic
Recognize breakdown products of common
constituents of both Gram-positive and
Gram-negative bacteria
Act as dimers and interact with adapter
via Pyrin Domain (PYD)
INFLAMMASOME – Nod-like Receptors (NLRs)
Regulation of IL-1b and IL-18 production
ASC
Inactive
In addition to secreting IL-1β and IL-18, caspase-1 contributes to host defense through an
inflammatory cell death program known as pyroptosis that occurs in myeloid cells infected with
bacterial pathogens such as Salmonella typhimurium, Francisella tularensis, and Bacillus
anthracis
Pro-inflammatory
cytokines
Inflammation = Swelling,
Reddening, Pain
Figure 8-15
Results from Dilation, Reduced
blood flow, Increased permeability
Neutrophils
Also known as
polymorphonuclear leukocytes
(PMNs)
Highly phagocytic
PMN Trafficking
Figure 8-19 part 1 of 2
Inflammatory mediators cause changes in the adhesion molecules
of the vascular endothelium. P-selectin, E-selectin
Induction of complementary adhesion molecules on neutrophils.
CXCL8 induces conformational changes in LFA-1, turning a weak
interaction with endothelium into strong ones
PMN Trafficking
Figure 8-19 part 2 of 2
S-Lex
E-selectin
PMN Killing Mechanisms
Lysozyme
Defensins Raise pH
Proteases
Etc
Macrophage produced TNFa, IL1 and IL6
have a spectrum of biological activity
Systemic effect of the cytokines is fever
Actions of acute response proteins
produced by liver
Acute phase proteins
Produced by liver in
response to the cytokines Figure 8-23
released.
C reactive protein binds the
phosphorylcholine of LPS
Allows C1q to be activated
without specific antibody
Mannose-binding lectin
activated C4 and C2
The importance of MBL
illustrated by deficiency of
MBL and susceptibility to
infection.
Mannose binding lectin (MBL)
MASP =
MBL
Associated
Serine
Protease
Carbohydrate
binding
domains
Action of MBL
C4b2a C3bBb
MBL resembles C1 which
Is recruited by Ab or CRP
C1 and the Classical Pathway without Ab
C1r and C1s are proteases
C1 can be targeted to membranes by IgM (and IgG)
C-reactive protein (CRP) and the Classical Pathway
Three pathways – Related proteins
Figure 8-24
Response to Virus
Interferon Response
Infected cells produce type I interferons: IFNb and IFNa.
Triggered by viral RNA
Interferon response
upregulates genes to
interfere with viral
genome replication:
Oligoadenylate
synthetase
endonuclease activated
to degrade viral RNA
PI kinase
phosphorylates elF-2 to
prevents viral protein
synthesis and virion
production
Detection of viral RNA leads to expression of IFN
RIG-I like receptors (RLR) - cytoplasmic sensors of
pathogen-associated molecular patterns (PAMPs)
within viral RNA
Details of viral DNA response
Type I Interferon response
Natural Killer (NK) cells
5-25% blood lymphocytes
Secrete:
• IFN - stimulate killing
• IL-12 - cytokines
IFN also activates
macrophages
NK cells
NK receptors
Recognize cell surface molecules altered in response to
infection, malignancy, trauma
Killing by NK cells
Depends on balance of
activating vs. inhibitory
signals
MIC = major histocompatibility complex (MHC) class I chain-related
Expressed during cell stress and are up-regulated in tumor cells and during
viral infections
Interaction between macrophages and NK cells