Download 5 dent inflammation and mucosal immunity

THE ACUTE INFLAMMATION
AND
ACUTE-PHASE RESPONSE
Innate immune mechanisms establish a state of
inflammation at sites of infection
Acute inflammation
A rapid response to an injurious agent that
serves to deliver leukocytes, plasma
proteins and fluids to the site of injury
Triggers of acute inflammation
• Infections (bacterial, viral, fungal, parasitic) & microbial toxins
• Tissue necrosis: ischemia, trauma, physical or chemical injury
(e.g., thermal injury; irradiation; some environmental chemicals)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (hypersensitivity or autoimmune reactions)
Major components of inflammation
– Vascular changes
• Vasodilation
• Vascular permeability
• Increased adhesion of white
blood cells
– Cellular events
• Recruitment and activation of
neutrophils (polymorphonuclear
leukocytes) and monocytes
Classical signs of acute inflammation
•
•
•
•
•
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function (functio laesa)
Macrophages respond to pathogens by using
different receptors to stimulate phagocytosis
and cytokine secretion
Effector functions of macrophages
Macrophages respond to infection by secreting
inflammatory cytokines
Systemic actions of cytokines in inflammation
Neutrophils are directed to sites of infection through
interactions between adhesion molecules
Neutrophil chemotaxis
acPGP: N-acetyl Proline-Glycine-Proline – neutrophil chemoattractant
MMP: matrix metalloproteinase
Migration of neutrophil and monocytes to site of infection I
Selectins, Chemokines, Integrins
Neutrophil granulocytes
• 68% of circulating leukocytes, 99% of circulating
granulocytes
• Phagocytic cells
• Are not present in healthy tissues
• Migration  elimination of pathogens (enzymes,
reactive oxygen intermediates)
• Main participants of acute inflammatory
processes
Neutrophils are stored in the bone marrow and
move in large numbers to sites of infection,
where they act and then die.
PUS
Pus is a whitish-yellow, yellow, or yellow-brown exudate produced
by vertebrates during inflammatory pyogenic bacterial infections.
Pus consists of creamy, protein-rich fluid, known as liquor puris,
and dead cells.
Acute injury of myocardium
Fever production in response to TNF, IL-1, and IL-6
proinflammatory cytokines
hypothalamic control of
body temperature
increased ‚set-point’ value
fever
ACUTE-PHASE REACTION
IL-6
Liver
Chemical mediators
 Vasodilation
– Prostaglandins (PG), nitric oxide (NO)
 Increased vascular permeability
– vasoactive amines (histamine, serotonin), C3a and C5a
(complement system), bradykinin, leukotrienes (LT), PAF
 Chemotactic leukocyte activation
– C3a, C5a, LTB4, chemokines (e.g. IL-8)
 Fever
• IL-1, IL-6, TNFα, PGE2
 Pain
• Prostaglandins, bradykinin
 Tissue damage
• Neutrophil and Macrophage products
– lysosomal enzymes
– Reactive oxygen species (ROS)
– NO
NSAIDs and Paracetamol:
inhibiting COX-1 and COX-2
 preventing the synthesis
of prostaglandins
Resolution of acute inflammation
Septic shock
Triggering factors :
• systemic infection (bacteraemia)
• microbial cell wall products and/or
toxins released from the pathogens into
blood circulation.
Result:
Systemic activation of
neutrophils and macrophages

High level of cytokine (TNF-alpha) production:
„cytokine storm”

Excessive inflammatory response
Septic shock
The key molecule of the process: TNF-alpha
TNF-alpha and other inflammatory cytokines
capillar permeability
blood pressure
high fever
multiorgan failure
DIC
disseminated
intravascular
coagulation
Therapy: anti-TNF-alpha antibody
DIC
Disseminated Intravascular Coagulation
• pathologic activation of
thrombotic process
• distress of thrombotic
process, bleeding
Features of chronic inflammation
• Prolonged host response to persistent stimulus
• Caused by microbes that resist elimination, immune
responses against self and environmental antigens, and
some toxic substances (e.g., silica)
• Characterized by persistent inflammation, tissue injury,
attempted repair by scarring
• Cellular infiltrate consisting of activated macrophages,
lymphocytes, and plasma cells, often with prominent
fibrosis
• Mediated by cytokines produced by macrophages and
lymphocytes (notably T lymphocytes), with a tendency to
an amplified and prolonged inflammatory response owing
to bidirectional interactions between these cells
MUCOSAL
IMMUNOLOGY
THE VAST MAJORITY OF INFECTOUS AGENTS INVADE
HUMAN BODY VIA MUCOSAL ROUTES
Mucosal infections are one of the biggest health
problems worldwide
S. pneumonia, H. influenzae,
influenza, RSV
Cholera vibrio, rotaviruses
B. pertussis
The global murden
of disease, WHO
THE MUCOSAL IMMUNE SYSTEM
Components
man or microbial cells
and humoral factors
Mucosa-associated lymphoid tissues (MALT)
2. Gas
exchange
3.
Food
absor
ption
1.
Reproduc
tion
The mucosal immune system takes place in the
physiologically important sites of the body
MICROBIOTA HELPS IN MAINTAINING THE GUT HOMEOSTASIS
BALANCE OF THE
IMMUNOLOGICALLY
ANTAGONISTIC CELL
TYPES IS DICTATED BY
Beneficial
MICRO-ENVIRONMENTAL
bacteria
Food
CONDITIONS
components,
nutrients
RECRUITING INFLAMMATORY CELLS
PRODUCTION OF INFLAMMATORY
CHAMOKINES
INTIMATE INTERACTIONS BETWEEN MUCOSAL EPITHELIUM AND LYMPHOID
TISSUE IN THE GALT
A
B
Discrete and more organized lymphoid organs
Abbas, Lichtman, and Pillai. Cellular and Mucosal Immunology, 7th edition. 2012
SPECIALIZED LUMINAL ANTIGEN UPTAKE IN THE MUCOSAL SURFACES
OF THE INTESTINAL AND RESPIRATORY TRACT
A Transcytosis of B FcRnintact microbes by mediated
microfold (M) cells transcytosis C
Apoptosis
mediated
transfer
D
E
Direct
sampling from
the lumen
Passive
diffusion of
humoal
antigens
Epithel
ium
Mcell
CD103+
Dendritic
cell
M cell
Lamina
propria
Mononuclear
phagocytes
expressing
FcRn
Mononu
clear
phagocy
tes
DC
THE DENDRITIC CELL-MEDIATED ANTIGEN SPECIFIC MUCOSAL
IMMUNE RESPONSE IN HEALTH
Commensal and
food derived
protein antigens
Msejt
CD103+
resident
DC
Migration
DCs and
macroph
age
BALANCED
IMMUNITY
Effector
Draining
and
lymph node
Naive CD4+regulatory
T cells
DC
Tropism! IL-6, IL-1
Circul
ation
Activat
es
effecto
rT
cells
locally
Th17 cells – IL-17
IL-12
Th1 cells – IFNγ
IL-
Regulatory T
THE MICROENVIRONEMNT OF PEYER’S PATCH INDUCES T-CELL DEPENDENT IgA
CLASS SWITHING IN B CELLS
1. DC activates naive
CD4+ T cell specific
for luminal antigen
1.
2. B cell is activated
by the same antigen
and present peptides
fo the activated CD4+
T cell
3. CD40-CD40L
interactions, the
presence of TGFß, NO
and retinoic-acid
induces IgA class
switching in B cell
4. B cell differentiates
into memory B or
sIgA secreting
plasma cell
SECRETORY IgA IS TRANSPORTED TO THE LUMEN VIA THE EPITHELIUM
The intestinal immune sytem
Virus neutralization by sIgA in the
respiratory immune sytem
Homing Properties of Intestinal Lymphocy
Lexical data :
Only retinoic-acid
CCR9 must be
known.
Appendix- Non obligatory
Immune priming and tolerance are different outcomes of
intestinal exposure to antigen
Oral/mucosal tolerance, as a form of
peripheral tolerance
BIDIRECTIONAL COMMUNICATION BETWEEN DIET, MICROBIOTA AND THE
Interdependence of Diet,
IMMUNE SYSTEM
Immune, and Microbiota
Interactions