Innate Immunity (Acute

Inflammation
• When a pathogen breaches one of the
protective epithelial barriers and gains access
to internal tissue , it encounters an army in the
form of innate immunity

Pathogen is
Immediate innate Pathogen invade recognized by soluble
immunity 0-4 hrs tissue effector molecules
and resident
If not cleared from the body, the next line of
defense is induced

Activation of cells
Soluble effector
resident in the infected
molecule and effector
tissue, recruitment of
Induced innate cells recruited to the
effector cells,
response 4hrs-4days infeted tissue
inflammation, fever
recognize the
and acute phase
pathogen and attack
response
 Inflammation
Triggers:
• Microorganisms: Bacteria, Fungi, Parasites, Viruses,
microbial products
• Tissue destruction: cut, stab, scratch
• Foreign bodies: foreign protein (allergens), pollen, asbestos,
silica
• Physical influences: cold, heat, radiation
• Endogenous causes: tumor cells, autoimmune diseases,
extravascular blood clot, precipitated crystals
• Chemicals: Acid, alkali
 Trigger events
• Activated resident macrophage, Dendritic cells:
– secrete inflammatory cytokines: IL-1, IL-6, TNF-alpha → localized and systemic
(acute phase response) effects
– Membrane perturbation leads to breakdown of phospholipids→ arachidonic
acid → generates mediators of inflammation (thromboxanes, prostaglandins,
leukotrienes and PAF
– Chemokines (IL-8)
• Mast cells (activated by complement C5a, C3a)
– secrete inflammatory cytokines: IL-1, IL-6, TNF-alpha → localized and systemic
(acute phase response)
– histamine
– Membrane perturbation leads to breakdown of phospholipids→ arachidonic
acid → generates mediators of inflammation (thromboxanes, prostaglandins,
leukotrienes and PAF
• Complement
– Binding to PAMP is activated and produce anaphylatoxins C5a, C3a
• Kinin system (activated by tissue injury)
– Activation of Hageman factor
 Inflammatory process
• What are the localized and systemic effects of
mediators secreted in the inflammatory process?
• How are leukocytes recruited to the sites of
infection/inflammation during an innate immune
response?
• How are the offending agents destroyed and
removed?
• How is the inflammation terminated?
Pro-inflammatory cytokines
Acute inflammatory response
 Journey from the vessel to tissue: Rolling and
extravasation of leukocytes
In the lumen:
• Margination
• Rolling
• Adhesion
Across the lumen: Migration/extravasation
across the endothelium
Migration in the tissue towards a chemotactic
stimulus
Due to release of mediators local
and systemic effects of
inflammation like the following are
seen:
1. Vasodilation and leakage of
proteins and fluid
2. Sprouting of adhesive molecules
on endothelial lining making
them sticky
3. Recruitment of cells and proteins
to the site of inflammation
4. Attraction/migration of
inflammatory cells and proteins
to the site of injury, (important
list of mediators that are
chemotaxins)
5. Mast cell degranulation (release
of more inflammatory mediators)
6. Fever and acute phase reactants
 Adhesion to endothelium and diapedesis
• Normal endothelium is not sticky: does not bind leukocytes
• Inflammatory mediators (IL-1, TNF-alpha) induce the expression
of adhesion molecules on endothelial surface, establish a
chemically lighted “runway”
• Stasis of blood flow leads to margination of leukocytes
• Adhere transiently, detach and bind again through adhesion
molecules (selectin) (molecular “Velcro”). : Rolling
• Activation of high affinity integrins: leukocytes stop rolling →
arrest and spread out on endothelium
• Migrate through the endothelium : diapedesis/ transmigration
• Migrate in the tissues in response to chemokines and
chemotactic → accumulate in the extravascular site
 Endothelial Leukocyte Function
molecule molecule
P-selectin Sialyl-Lewis X Rolling
Addressins
E-selectin Sialyl-Lewis X Rolling
Addressins
Glycam-1/CD34 L-selectin Rolling
(Addressins)
ICAM-1 LFA-1,Mac-1 Arrest,
(Immunoglobulin CD11/CD18
superfamily) (α1β2 integrin)
VCAM-1 VLA-4 (α4β1 Arrest
(immunoglobulin integrin)
superfamily)
PECAM-1/CD31 Transmigration/

Adhesion platelet endothelial

celleular adhesion
molecule
Diapedesis

molecules
 Chemotactic factors produced in response to
infection and inflammatory responses:
1.Complement components (C3a, C5a)
2.Bacterial products (e.g., formyl-methionyl-leucyl-
phenylalanine [f-met-leu-phe]),
3.Chemokines (IL-8),
4.Leukotriene B4
• are powerful chemoattractants for neutrophils,
macrophages, and lymphocytes.
• ” to guide these cells to the site of an infection and
also activate them.
 What can go wrong?
1. Deficiency in production of cytokines,
chemokines ( Redundancy ???)
2. Defects in production of leukocytes
3. Defects in the adhesion molecules/ligands
Triggers release of mediators
Localized and systemic effects
Acute Phase
Response
 Acute Phase Response
• Acute-Phase Response
• Triggered by infection, tissue injury, prostaglandin
E2, interferons associated with viral infection Acute-Phase Proteins: markers of
• Promotes changes that support host defenses systemic inflammation
and include fever, anorexia, sleepiness, metabolic • Amyloids A and P
changes, and production of proteins. • C-reactive protein
• Acute-phase cytokines (IL-1, IL-6, TNF-α) are also • Fibrinogen (ESR)
endogenous pyrogens because they promote • Hepcidin
fever production. • Complement C2, C3, C4, C5, C9
• C-reactive protein binds to the polysaccharides of • α1-Antitrypsin
numerous bacteria and fungi and activates the • α1-Glycoprotein
complement pathway, facilitating removal of these
organisms from the body by enhancing
• Antithrombin III
phagocytosis. • C1 esterase inhibitor
• Hepcidin inhibits iron uptake by the gut and • Ceruloplasmin
macrophages, and this reduces availability to • Haptoglobin
microbes. • Orosomucoid
• The acute-phase proteins reinforce the innate • Plasminogen
defenses against infection, but their excessive • Transferrin
production during sepsis (induced by microbial • Lipopolysaccharide-binding
products like endotoxin) can cause serious protein
problems, such as shock. • Mannose-binding protein
Cytokine
storms and
sepsis
Sepsis
and
cytokine
storm
Congenital Diseases of Defective Phagocytic Cell Function Characterized by
recurrent Bacterial Infections
Disease
Leukocyte adhesion deficiency (LAD)
Chediak-Higashi syndrome
Neutrophils specific granule
deficiency
Chronic granulomatous disease
Myeloperoxidase deficiency
Defect
LAD-1 (defective β-2 integrin
expression or function (CD11/CD18)
LAD-2 (defective fucosylation, selectin
binding
Defective lysosomal granules, poor
chemotaxis
Absent neutrophil granules
Deficient NADPH oxidase with absent
H2O2 production
Deficient HOCl production
 Acute and Chronic inflammation
Action Mediators
Acute Inflammation
Histamine, bradykinin, C3a, C5a,
Increased vascular permeability
leukotrienes, PAF, substance P
Histamine, prostaglandins, PAF, nitric oxide
Vasodilation
(NO)
Pain Bradykinin, prostaglandins
Leukocyte adhesion Leukotriene B4, IL-1, TNF-α, C5a
C5a, C3a, IL-8, chemokines, PAF, leukotriene
Leukocyte chemotaxis
B4
Acute-phase response IL-1, IL-6, TNF-α
Proteases, free radicals, NO, neutrophil
Tissue damage
granule contents
Fever IL-1, TNF, prostaglandins
Chronic Inflammation
Activation of T cells and macrophages, and T cells (TNF, IL-17, IFN-γ), macrophages (IL-1,
acute-phase processes TNF-α, IL-23, IL-12), cytokines
Cytokine† Source Trigger Action Target
Acute-phase responses,
promotes inflammation, Endothelial cells,
fever, symptoms of sepsis, neutrophils, macrophages,
TNF-α Macrophages, T cells PAMP, inflammation cachexia, vascular hypothalamus, liver,
permeability, altered muscle, mast cells, other
muscle tone, apoptosis cells
(some cells)

Acute-phase responses,
promotes inflammation, Endothelial cells,
IL-1 (α, β Macrophages, keratinocytes,
PAMP, inflammation fever, supports symptoms hypothalamus, liver, and
cleaved) endothelial and some epithelial cells
of sepsis, synthesis of other cells
acute-phase proteins

Acute-phase responses,
Macrophages, endothelial cells, T reinforces acute-phase Macrophages, endothelial
IL-6 PAMP, inflammation
cells responses, stimulation of T cells, T cells
and B cells

Inhibit virus replication,

Type 1 IFNs (α, Most cells, plasmacytoid dendritic Viral infection (especially Virus-infected cells, NK
activate NK cells, enhance
β) cells RNA viruses) cells, T cells
immune response

Chemotaxis, targeting of Leukocytes, lymphocytes,

Macrophages, dendritic cells, many PAMP, inflammation, C5a,
Chemokines cells to endothelial cells, and other
other cells TNF-α
infection/inflammation cells

Promotes TH1 immune

IL-12 Dendritic cells, macrophages PAMP NK cells, T cells
response, activates NK cell

IL-23 Dendritic cells, macrophages PAMP Promotes TH17 response T cells

IL-18 (cleaved) Macrophages/inflammasome PAMP, inflammation Promotes IFN-γ production NK cells, T cells

Activates antimicrobial
IL-18, IL-12 (TH1 activity, production of Macrophages, dendritic
Type II IFN (γ) NK cells, T cells
responses) inducible nitric oxide cells, B cells, etc.
synthetase, other