Transcript Innate immune recognition

Innate Immunity & Complement
• Pin Ling (凌 斌), Ph.D.
ext 5632; [email protected]
• References:
1. Male D., J. Brostoff, D. B Roth, and I.
Roitt Immunology (7th ed., 2006),
Chapters 4 & 6
Outline
1. The Concepts of the Innate Immune
System
2. The Operations of the Innate Immune
System
3. The Complement system
4. Summary & Question
Overview of immune responses
Innate immune concept in old times
1. A healthy individual encounters trillion of microorganisms
daily but seldom gets sick.
=> Most microorganisms are destroyed by innate immunity
within minutes to hours
2. Innate immunity provides the first defense against
infections via following:
- Physical Barriers (e.g. Skin & Mucus)
- Phagocytes => Phagocytosis
- Soluble molecules (antimicrobial peptides)
3. When innate immunity fails to eliminate invasive pathogens,
adaptive immunity starts the 2nd wave immune attack.
Epithelial barriers prevent the
entry of microbes
Innate vs. Adaptive Immune Recognition
Adaptive immune recognition:
1. Antigen (Ag) receptors on T & B lymphocytes.
2. These Ag receptors generated by somatic gene
recombination.
3. They recognize diverse Ags from microbes or non-self.
Innate immune recognition:
1. How do host cells recognize invading pathogens
at the first place?
Scientists have no answer to this until the end of
the 20th century.
“Renaissance” of innate immunity
Pattern Recognition Theory (1989)
Janeway’s
in
Cold
Spring Harb SympMajor
Quant Biol Findings
54:1-13
adaptive immunity:
1. All microbes have conserved molecular
patterns, referred to PAMPs
1.(Pathogen-Associated
CD4 & CD8 as co-receptors
Molecular with
TCR to not
interact
with
MHCs.
Patterns)
present
in the
host
Actual detection of infection:
(e.g.,&dsRNA,
LPS,lymphocytes,
peptidoglycan)
=> Antigen receptors (TCR
BCR on
2. Costimulatory
signaling in T-cell
the adaptive immune
system)
2. Host APCs have so-called PRRs
activation.
=> PRRs (the innate immune
system)
(Pattern-Recognition
Receptors) for
recognizing PAMPs
Charles A. Janeway Jr., M.D.
(1943-2003), Yale Univ.
3. Th1 vs Th2 differentiation
3. PRR
activation
drives
immune
(with
his wife
K. innate
Bottomly).
responses and then regulates adaptive
immunity
Current concepts in innate immunity-I
1. Innate immunity is evolutionally the more conserved host
defense system: (1) Provides the first line of defenses
against infections, and (2) “Activates” and “Programs”
adaptive immune responses.
2. The innate immune system mainly recognizes common
structures shared by classes of microbes, called PathogenAssociated Molecular Patterns (PAMPs) such as LPS,
Peptidoglycan, Microbial DNA & RNA.
3. Receptors that recognize PAMPs are called PatternRecognition Receptors (PRRs) on innate immune cells.
4. PRRs are encoded in germline DNA => limited Diversity
Current concepts in innate immunity-II
5. Four groups of PRRs exist in host cells (immune & nonimmune cells), including: (1) TLRs, (2) RIG-like receptors
(RLRs), (3) NOD-like receptors (NLRs), and (4) C-type lectin
receptors (CLRs)
6. These PRRs distribute on cell surface, in cytosol, or in
endosomes, to sense distinct PAMPs from invading pathogens.
7. Upon sensing pathogens, PRRs trigger innate immune
responses to (1) Eliminate pathogens, and (2) Promote DC
maturation to activate & shape adaptive immune responses
8. PRRs may also recognize components from injured or dead
host cells => Danger-Associated Molecular Patterns
(DAMPs) => Autoimmune diseases
Toll-like Receptors
Toll-like Receptors
Outline
1. The Concepts of the Innate Immune
System
2. The Operations of the Innate Immune
System
3. The Complement system
4. Summary & Question
Key Topics
The Operations of Innate Immunity
(1) Macrophage & Phagocytosis
(2) Inflammation (Cytokines & Chemokines)
(3) Leukocyte trafficking
Phagocytosis by innate immunity
Recognition of bacteria by
Macrophage
Direct binding
Opsonization
Inflammation-I
1.
Inflammation- A physiological process whereby tissues
respond to infectious & non-infectious insults (also
called sterile inflammation, including toxic, traumatic, or
autoimmune insults).
2.
Four key signs:
(1) Redness (2)Swelling (3) Heat (4)Pain
3.
This process includes several phases:
(1) Initial phase-Changes in local blood flow &
accumulation of inflammatory cells (neutrophiles,
macrophages, DCs, & lymphocytes) & plasma molecules
(2) Middle phase-Resolution of initial insults
(3) Final phase-Termination of inflammation & tissue
repair
Inflammation-II
4. Inflammatory Cytokines & Chemokines from activated
macrophages regulate the recruitment of other leukocytes,
e.g., TNF-a, IL-1 & IL-6.
5. Interferons and NK cells are critical to limit viral spread
6. Plasma enzyme systems modulate inflammation and tissue
remodeling. Four major plasma enzyme systems are
following: (1) Clotting system, (2) Plasmin system, (3) Kinin
system, & (4) Complement system.
Macrophages release cytokines
and induce vasodilation
The phases of various
leukocytes to the infection site
Inflammatory cytokines secreted
by macrophages
(IL-8)
Multiple roles
of TNF-a
Leukocytes transmigrate to infection
sites
Adhesion molecules & chemokines
control leukocyte migration
Migration of Lymphocytes II
- Recruitment of Lymphocytes to the
infection site
The plasmin system regulate
tissue homeostasis
Kinin system
The adaptive immune
system triggers the
complement system
during inflammation
Outline
1. The Concepts of the Innate Immune
System
2. The Operations of the Innate Immune
System
3. The Complement system
4. Summary & Question
Key concepts in the complement
system-I
1. Complement is central to develop inflammatory responses.
2. Multiple complement pathways have evolved to label
pathogens for elimination.
The classical pathway links to the adaptive immune
system.
The alternative and lectin pathways provide innate
immunity.
3. The membrane attack pathway results in the formation of a
transmembrane pore.
4. Complement deficiencies lead to infectious diseases,
e.g., C3 deficiency => bacterial infections
Role of Complement in Inflammation
Complement Activation Pathways-I
Complement Activation Pathways-II
Positive
feedback loop
MAC: Membrane
Attack Complex
Activators of the Complement
Pathways
Key concepts in the complement
system-II
1. Complement serve major functions as follows:
(1) Chemotaxis, (2) Opsonization & cell activation, (3) Lysis
of target cells, and (4) Priming of the adaptive immune
response
2. Many cells express “Complement Receptors” to detect
complement products during immune responses.
3. C5a is chemotactic for macrophages, and C3a & C5a
activate mast cells.
4. The MAC pathway damage some bacteria and enveloped
viruses.
5. Immune complexes w/C3b are efficient in priming B cells.
The Membrane Attack Pathway
1. MAC attack plays a key role in host defense against
Gram-negative bacteria Neisseria.
2. Patients with C6 deficiency are susceptible to
Nessierial meningitis.
Complement Receptors
C3a & C5a (Anaphylatoxins) act
on mast cell activation
Opsonization & Phagocytosis by C3b
Activation of
adaptive immunity
by Complement
Measuring classical & alternative
pathways
Complement Deficiencies
SUMMARY
1. The innate immune system is not a passive defense
system but use PRRs to recognize Pathogen-Associated
Molecular Patterns (PAMPs).
2. Leukocytes migration to inflammation sites depend on
cytokines, chemokines, and adhesion molecules.
3. The complement activation pathways have evolved to
label pathogens for elimination.
4. Complement serve major functions as follows:
(1) Chemotaxis, (2) Opsonization & cell activation,
(3) Lysis of target cells, and (4) Priming of the
adaptive immune response.
Question
Why do pathogens not just mutate their
PAMPs to avoid the innate immune
recognition?
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