Chapter 14:
Innate Immune System
Overview of
Immune
Defenses
• First-line defenses:
– Intact, healthy skin and
mucous membranes
– Normal microbiota
Overview of
Immune
Defenses
• Sensory systems:
– Pattern recognition
receptors
• Toll-like receptors
• NOD-like receptors
• RIG-like receptors
– Complement system
• Alternative pathway
• Classic pathway
• Lectin pathway
Overview of
Immune
Defenses
• Innate effector actions:
– Inflammatory response
– Interferon response
– Opsonization
– Membrane attack complex
First-line
defenses:
SKIN
High turnover
Immune surveillance:
dendritic cells, macrophages
Salt
Normal skin biota
SALT
First-line
defenses:
MUCOUS
MEMBRANES
High turnover
Immune surveillance:
dendritic cells, macrophages
Secretions
Normal biota
MALT
Mucosal epithelium:
intestinal mucosa
Mucosal surfaces:
respiratory mucosa
Antimicrobial • Produced by animals:
– Lysozyme
substances
– Peroxidase enzymes
– Lactoferrin
– Transferrin
– Defensins
• Produced by your
microbiota:
– Fatty acids
– Colicins
– Lactic acid
Cells of the
Immune
System
• Granulocytes:
–
–
–
–
Neutrophils
Eosinophils
Basophils
Mast cells
• Mononuclear phagocytes:
– Monocytes
– Macrophages
– Dendritic cells
• Lymphocytes:
– T cells
– B cells
– NK cells
Neutrophils
• Phagocytic
• Granules:
– Lysozyme, Phospholipase A2,
myeloperoxidase, elastase,
acid hydrolases, lactoferrin . . .
• Most numerous leukocyte in
circulation
• Migration to tissue = major
component of inflammatory
response
• Short life span
• NETs
• Phagocytic
• Lysosomes:
Macrophages
– Lysozyme, peroxidase. . .
• Mature, tissue form of
monocyte
• Increased migration and
maturation of monocytes to
tissue in inflammatory
response
• Long life span
• TLRs: on cell surface & in
lysosomes
• Cytokines:
• Activation → enhanced
killing power
Dendritic Cells
• Phagocytic sentinel cells
• Antigen presenting cells
• Most = monocyte/
macrophage cell line
• Long life span
• Important bridge between
innate & adaptive
immunity
Natural Killer Cells
• Non-specific lymphocytes
– Do not require antigenic
stimulation
Cell Communication:
SURFACE RECEPTORS
Cell Communication:
CYTOKINES
•
•
•
•
•
Chemokines
Colony stimulating factors
Interferons
Interleukins
Tumor necrosis factor (TNF)
Interferons α and β
Cell Communication: ADHESION
MOLECULES
• Integrins: large family, widely expressed, involved
in interaction with ECM
• Selectins: small family, differentially expressed by
leukocytes & endothelial cells, involved in
leukocyte extravasation
• Cadherins: large family, widely expressed,
involved in adhesion between cells
• ICAMs & VCAMs: part of immunoglobulin
superfamily; many roles in immune
response/inflammation
Pattern Recognition Receptors
• Recognition of PATHOGEN-ASSOCIATED
MOLECULAR PATTERNS / MICROBE-ASSOCIATED
MOLECULAR PATTERNS (PAMPs / MAMPs):
–
–
–
–
–
Peptidoglycan
Lipopolysaccharide
Techoic acid
Flagellin subunits
Viral RNA
• Recognition of DANGER-ASSOCIATED
MOLECULAR PATTERNS (DAMPs):
– Molecules that indicate cellular damage
Pattern Recognition Receptors
• Toll-like receptors (TLRs):
– Membrane-bound receptors
– Macrophages, dendritic cells, cells lining sterile
sites (i.e., mesothelial cells)
– Detection of PAMPs → signal to nucleus →
upregulation of gene expression → response
Pattern Recognition Receptors
• NOD-like receptors (NLRs):
– Located in the cytoplasm – most (all?) cells
– Detect PAMPs or DAMPs
Pattern Recognition Receptors
• RIG-like receptors (RLRs):
– Located in the cytoplasm – most (all?) cells
– Recognize viral RNA
– Allow cells to detect a viral invader
– Recognition of viral RNA by RLR → synthesis and
secretion of interferons → expression of inactive
viral proteins → activation of IVPs by dsRNA →
apoptosis of infected cells
The Complement System
• Consists of interacting proteins produced in
the liver and found in blood and tissues
• These proteins promote
– Opsonization
– Inflammation
– Cell lysis
The Complement System
• Central feature = splitting of C3 → C3a & C3b
• Enzyme that splits C3 = C3 convertase
• C3 also spontaneously degenerates to form C3a &
C3b at a constant rate
• Alternative pathway: C3b binds to foreign cell
surface receptors → formation of C3 convertase
• Lectin pathway: pattern recognition receptors =
mannose binding lectins (MBLs): bind to
mannose molecules on microbial surface →
formation of C3 convertase
• Classical pathway: antibody binds antigen =
antigen-antibody complex → formation of C3
convertase (adaptive immune response)
Phagocytosis
•
•
•
•
Chemotaxis
Recognition and attachment
Engulfment
Phagosome maturation and formation of
phagolysosome
• Destruction and digestion
• Exocytosis
Phagocytosis
The inflammatory response
• Acute inflammation – example of activation:
– TLR on sentinel MØ recognizes PAMP → MØ
produces TNF → induces liver to synthesize acute
phase proteins → activation of phagocytes,
activation of complement
– Tissue damage: “Danger Model” of immune
system – ex. = activation of coagulation cascade in
response to blood vessel damage
The Acute Inflammatory Response
•
•
•
•
•
Calor = heat: increased blood flow to site
Rumor = redness: increased blood flow
Tumor = swelling: fluid and cells accumulate
Dolor = pain: pressure + chemical mediators
Functio laesa: many possible causes
The acute inflammatory response
Recruitment of leukocytes from the
blood to a site of acute inflammation:
Chronic inflammation
• Acute response is unsuccessful in resolving the
problem
• Can last years, often associated with significant
tissue damage
• May be due to chronic infection, repetitive injury,
chronic implantation of foreign material or selfperpetuating because of damage induced by the
immune system itself in the absence of ongoing
infection/other external cause
Fever
• Protective mechanism = resetting of the
thermostat
– Make the body less hospitable to pathogens
– Slowed microbial growth = time to raise a defense
– Increases rate of enzymatic reactions → enhanced
inflammation, phagocytosis, lymphocyte proliferation,
hematopoiesis, production/release of cytokines and
antibodies
• Pyrogens:
– Endogenous: interferons
– Exogenous: LPS
Fever
Fever ≠ acute inflammation!
Fever = a systemic change in the body
temperature
Heat associated with acute inflammation =
localized increase in temperature