Inflammation
Immunity
Environmental exposure
Main goal of the Immune system:
To protect the individual against disease
Bacteria
Viruses
Fungi
Parasites
Immunity
Environmental exposure
Main goal of the Immune system:
To protect the individual against disease
Main parameter of Immunity:
Immune recognition - Self vs. Foreign
Self (own): Foreign:
Immune system ignores it
Immune response is not developed
VS Immune system recognizes it
Immune response is developed
Immunoregulation
Effective
Auto-tolerance Tolerance Immune
response
Inflammation
“rubor et tumor cum calore et dolore”
(redness and swelling with heat and pain)
-Cornelius Celsus in De Medicina, 1st century A.D.
Inflammation
Inflammation is an adaptive response to noxious
conditions (infection and tissue injury) - an attempt to
restore homeostasis
Inflammation
Inflammation can be Inflammation can be induced
induced by immune by immune recognition that is
recognition of infection hypersensitivity, Disease
or tissue damage autoinflammatory or
autoimmune
Inflammation associated diseases
Inflammation
• Acute inflammation: influx of white blood cells and fluid from blood
to fight infection and aid tissue repair
• Chronic inflammation: inducer of inflammation is not removed.
Leads to tissue damage and loss of tissue function (joint destruction,
lung fibrosis, etc.)
Infection or tissue demage
Recognition of pathogens
The initial response to infection: Innate Immunity
1) Factors 2) Fluid, 3) Cytokines 4) Phagocytes
released by antimicrobial and eliminate
macrophages proteins and chemokines pathogens
and DC cause clotting released in and cell
nearby elements the site attract debries
capillaries to move from more
become more the blood to phagocytes
permeable the site
The initial response to infection: Innate Immunity
The initial response to infection:
Innate Immunity
• Recognition of infection by hard-wired recognition
molecules or recognition of tissue damage and cell death,
“danger”
• Rapid mobilization of leukocytes to the site of infection and
influx of plasma into the tissue site. (=inflammation)
• Recruited innate immune cells kill microbes/virally infected
cells (also can promote tissue repair but when dysregulated
can exacerbate tissue injury)
• Also, innate recognition promotes the adaptive immune
response, which is slower but more powerful
Leukocyte recruitment
Leukocyte recruitment
15
Leukocyte adhesion
Leukocyte recruitment
https://www.youtube.com/watch?v=fcAAnj4czzo
Luekocyte recruitment:
Neutrophils vs. Monocytes
• Acute inflammation is initially characterized as rich in neutrophils; later it is
more monocytes and lymphocytes. This is controlled by which chemokines are
expressed by the endothelial cells and by T cells.
• Neutrophils are dedicated to killing microbes and are short-lived. They often
damage host tissue as a byproduct.
• Monocytes are multi-potential, depending on cytokine signals:
+IFN-γ: a vigorous killing phenotype similar to neutrophils
+IL-4: “alternatively activated macrophages”; tissue repair, barrier immunity
+IL-10: a wound-healing type phenotype (to clean up after infection is cleared)
+GM-CSF: a dendritic cell phenotype and propagate adaptive immune
responses
Inflammatory Mediators
• Macrophages or DCs stimulated via innate immune receptors
make pro-inflammatory cytokines, especially TNF, IL-1, and IL-6
• TNF and IL-1 signal to endothelial cells to make them:
▫ Leaky to fluid (influx of plasma; containing antibodies,
complement components, etc.)
▫ Sticky for leukocytes, leading to influx of first neutrophils,
later monocytes, lymphocytes
• IL-6 promotes adaptive immune responses and has systemic
effects (“acute phase response” of liver, including CRP)
Inducers and mediators of inflammation vary depending
on the pathology
Key inducers and mediators in intestinal inflammation
Key inducers and mediators in airway inflammation
Key inducers and mediators in psoriasis
Immune balance
Effectors Regulators
Immune balance
Effectors
? Regulators
Inflammation
Therapeutics:
Current and prospective strategies
Effectors
? Regulators
Non-steroid drugs
Steroids,
immunosuppresants
Therapeutics:
Current and prospective strategies
Effectors
? Regulators
Non-steroid drugs
Steroids,
immunosuppresants
Monoclonal antibodies - Immunotherpy
Therapeutics:
Current and prospective strategies
Effectors
? Regulators
Non-steroid drugs
Steroids,
immunosuppresants
Cellular therapy -
Immunotherapy
Monoclonal antibodies - Immunotherpy
30
Complement
Role of Complement
Implication in both: innate and adaptive
immune responses
Role of Complement
Complement components
• More than 25 proteins
• Serum proteins and cell membrane bound proteins
Complement components
• Pro-enzymes
• Small and big fragments
• Small fragments (a): anaphylatoxins
• Big fragments (b): convertases, MAC formation, opsonins
35
Complement components
Lego
Pathways of complement
activation
CLASSICAL LECTIN ALTERNATIVE
PATHWAY PATHWAY PATHWAY
antibody antibody
dependent independent
Activation of C3 and
generation of C5 convertase
activation
of C5
LYTIC ATTACK
PATHWAY
Summary of Complement activation
Classical
Lectin-Binding Alternative
Pathway
Pathway Pathway
C1q MBP C3
[C4b2b] [C3bBbP]
C3 Convertase
C3a C3b C3b, C3bi
(opsonlzation)
anaphylatoxins
C5a
C5b
C5b-C 9
(membrane attack complex)
Cell Injury
Components of the Classical
Pathway
C3 C4
C1 complex
Classical Pathway
Generation of C3-convertase
Classical Pathway
Generation of C3-convertase
C4b2a is C3 convertase
C4b
Classical Pathway
Generation of C5-convertase
C4b2a3b is C5 convertase;
it leads into the Membrane
Attack Pathway
C3b
C4b
Summary of Complement activation
Classical
Lectin-Binding Alternative
Pathway
Pathway Pathway
C1q MBP C3
[C4b2b] [C3bBbP]
C3 Convertase
C3a C3b C3b, C3bi
(opsonlzation)
anaphylatoxins
C5a
C5b
C5b-C 9
(membrane attack complex)
Cell Injury
Components of mannose-binding
lectin pathway
MBL MASP1
Mannose-binding lectin pathway
C4b2a is C3 convertase; it
will lead to the generation of
C5 convertase
MASP1
MBL
Summary of Complement activation
Classical
Lectin-Binding Alternative
Pathway
Pathway Pathway
C1q MBP C3
[C4b2b] [C3bBbP]
C3 Convertase
C3a C3b C3b, C3bi
(opsonlzation)
anaphylatoxins
C5a
C5b
C5b-C 9
(membrane attack complex)
Cell Injury
Components of the
alternative pathway
C3
47
https://www.youtube.com/watch?v=qga3Wn76d9w
Spontaneous C3 activation
Generation of C3 convertase
C3 i b
C3b
C3iBb complex has a very short half life
C3-activation
the amplification loop
If spontaneously-generated
C3b is not degraded
C3b b C3 b
C3-activation
the amplification loop
C3 b b C3b
C3b
C3-activation
the amplification loop
C3 b b C3b C3b
C3b
C3-activation
the amplification loop
C3b C3b C3b
C3b
C3-activation
the amplification loop
C3b C3b
C3b
Control of spontaneous
C3 activation via DAF
DAF prevents
C3b
the binding of
CR1
factor B to C3b
Autologous cell membrane
Control of spontaneous
C3 activation via DAF
DAF dislodges
b C3b
C3b-bound
CR1
factor Bb
Autologous cell membrane
Control of spontaneous
C3 activation via CR1
C3b C3b
iC3b
CR1
CR1
Autologous cell membrane
C3b stabilization and
C5 activation
C3b finds an activator
(protector) membrane
This is stable C5 convertase
of the alternative pathway
b
C3b C3 b
C3b regulation on self and
activator surfaces
C3b
C5-convertase of the two
pathways
C5-convertase of the C5-convertase of the
Classical and lectin Alternative Pathway
Pathways
C3b C3b C3b
C4b
Lytic pathway
Generation of C5 convertase
leads to the activation of the
Lytic pathway
Components of the lytic pathway
C7
C6
C
9
Lytic pathway
C5-activation
C3b
C4b
Lytic pathway
assembly of the lytic complex
C6
C7 b
Lytic pathway:
insertion of lytic complex into cell membrane
C6
C7 b
CC C C
C9 9 9 9C
9C C C9
9 9 9
65
MAC formation
C1qrs breakdown
C1Inh
C1-inhibitor deficiency:
angioedema
Biological effects of C5a
Opsonization and phagocytosis
Role of Complement
