Transcript LACZIK_Pharmacology - 3.practice

INTERACTION BETWEEN
MICROORGANISMS AND THE
IMMUNE SYSTEM INFLAMMATION
Antigenic properties of pathogenic and
non-pathogenic organisms
Symbiotic, non-pathogenic microbes
– mucosal membrane, skin
Bacteria, Fungi, Protozoa
Gut – colonalization after birth
1012 bakteria/g intestinal content
1000 species
100-times more bacterial genes then eukaryotic
„peaceful” commensalisms
vitamins (i.e. K1 vitamin)
real ecosystem, survival of the fittest
competition with pathogenic organism (wide
spectral antibiotic treatment can do harm!)
the few who brake in through the gut
epithelium induce local immune response
Important role in:
-development of mucosal and systemic
immunity
-normal development of peripheral
lymphoid organs
-Maintenance of basic level of immunity
Patogens
Bacteria,
Fungi,
Protozoa,
Viruses
Helmints
COMPLEX ANTIGENS
Strong immunogens
„You are, what you eat!”
Gut normal flora play an important role in:
- Development of mucosal and systemic immunity
- Normal development of peripheral lymphoid organs
- Maintenance of basic level of immunity
THE GOOD, THE BAD &
THE UGLY
Some facts about gut flora:
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More than 500 microbial species live in a healthy adult gut, adding two pounds to its weight
There are 1012 bacteria/g in the gut
There are 100-times more bacterial genes than eukaryotic genes
They produce a significant portion of vitamin K1
The challenge is to get an immune response that:
1. Eliminates pathogens
2. Limits commensal location and growth
3. Does not respond to harmless antigens in the food
4. Does not over-respond to harmful antigens in the food
Immunesurveillance saves lives
Under optimal conditions bacteria divide every
15-20 minutes. Physical conditions in the human
body are amenable for bacterial growth
MUCOSAL SURFACES AND THE SKIN ARE THE MOST COMMON
ENTRY SITES FOR PATHOGENS
Leading causes of death worldwide. About 15 million (>25%)
of 57 million annual deaths worldwide are the direct result of
infectious disease. Figures published by the World Health
Organization (see http://www.who.int/whr/en and ref.7).
Vaccine components
Attenuated
pathogen
Killed
pathogen
Microbial
extract /
product
Bacterial
Diseases
Typhoid fever
(PO)
BCG (M. bovis)
Typhoid fever
Cholera
B. pertussis (DPT)
Plague (Y. pestis)
Anthrax
B. pertussis (DTPa)
Diphtheria (Tox.)
Tetanus (Tox.)
*Meningococcal
*Pneumococcal
*H. influenzae b
Viral
Diseases
Measles
Mumps
Rubella
Polio (Sabin - PO)
Yellow fever
Polio (Salk)
Hep. A
Influenza
Rabies
Japanese encephalitis
Hepatitis B
(HbSAg)
ACUTE INFLAMMATION
AND ACUTE-PHASE
RESPONSE
Acute inflammation
A rapid response to an injurious agent that serves to deliver
mediators of host defense to the site of injury, namelyleukocytes and plasma proteins.
Triggers of acute inflammation:
 Infections (Bacterial, Viral, Parasitic and Microbial toxins)
 Trauma (Blunt or penetrating)
 Physical and Chemical agents (Thermal injury, irradiation, environmental
chemicals)
 Tissue Necrosis
 Foreign bodies (Splinters, Dirt, Sutures)
 Immune reaction (Hypersensitivity or autoimmune reaction)
MAJOR COMPONENTS OF INFLAMMATION
(1) Increased vascular diameter  Increased flood flow.
(2) Structural changes in the microvasculature  increased permeability.
That permits plasma proteins and leukocytes to leave the circulation and
enter the tissue.
(3) Migration of the leukocytes from the micro-circulation, their
accumulation in the focus of injury and their activation to eliminate the
offending agent.
Chemotactic gradient
The classic symptoms of inflammation:
Redness (rubor)
Swelling (tumor)
Heat (calor)
Pain (dolor)
Loss of function (functio laesa)
Pus is a whitish-yellow, yellow, or yellow-brown exudate
produced by vertebrates during inflammatory pyogenic
bacterial infections. Pus consists of a thin, protein-rich fluid,
known as liquor puris, and dead cells.
MIGRATION OF NEUTROPHILS
BLOOD
TO INFLAMMED
TISSUE
Neutrophil granulocytes
are the main cell types
involved in inflammatory
processes.
Endothelial Adhesion Molecules during Inflammation
Neutrophil Transendothelial Migration (Diapedesis)
Migration of Neutrophils
Extravasation
Order of innate cells appearance in the inflamed site
Initiation of inflammation
Pathogens activate macrophages to release cytokines and are
then phagocytized and digested in phagolysosomes
Later…
The binding of bacteria to these innate
receptors causes activation of the
phagocyte. This results in the synthesis
and release of cytokines and the
induction of lipid mediators of
inflammation.
Receptors and cell-surface molecules of macrophages
LPS receptor (CD14) + TLR4
Scavenger receptor
Mannose receptor
MHCI
TLR – pattern
recognition
FcRI (CD64)
Ag + IgG
complex
FcRII (CD32)
FcRIII (CD16)
Peroxidáz
Savas hidroláz
LFA1 (CD11a/CD18)
MHCII
CR1 (CD35)
CR3 (CD11b/CD18)
CHEMICAL MEDIATORS
• Vasodilation
– Prostaglandins, Nitric Oxide
• Increased Vascular Permeability
– Vasoactive amines (histamine, serotonin), C3a and
C5a, Bradykinin, Leukotrienes, PAF,
• Chemotaxic Leukocyte Activation
– C5a, LTB4, Chemokines
CHEMICAL MEDIATORS OF
INFLAMMATION
The Basics
• Fever
– IL-1, IL-6, TNF, Prostaglandins
• Pain
– Prostaglandins, Bradykinin
• Tissue Damage
– Neutrophil and Macrophage products
– Lysosomal enzymes
– Oxygen metabolites
– NO
Consequences of macrophage activation
Synthesis of cytokines
ACUTE-PHASE
RESPONSE PROTEINS
During an APR their concentration
increases up to x1000
THE ACUTE PHASE RESPONSE
IL- 6
C-reactive protein
Mannose binding
lectin/protein
Opsonization
Complement activation
Pentraxin family
MBL/MBP
Opsonization
Complement activation
Collectin family
Liver
SP-A and SP-D
Opsonization in the lung
Collectin family
Serum Amyloid Protein (SAP)
Opsonization
Enhance chemotaxis
Complement activation
Enhance leukocyteendothel adhesion
Pentraxin family
Fibrinogen
Blood clot formation
Converts thrombin  fibrin
IL-6 induces the production of acute phase protiens
Resolution of Acute Inflammation
Septic shock
Triggering factors:
Systemic infection
Microbial cell wall products and/or
Toxins released from the site of infection
Host factors:
Neutrophils and macrophages mobilize to the site of
infection

„cytokine storm” release huge amounts of cytokines (TNF)

Imbalance in the maintain of homeostatic
cytokine production, coagulation, and vascular
integrity
The result………
shock, disseminated intravascular coagulation
(DIC), multiple organ failure (MOF), and mortality
Toxic Shock Syndrome caused by SAg
Polyclonal extensive activation of T cells
Over-production of INF-γ
Activates Macrophages
Over-production of IL-1, IL-6 and TNF-α
Cytokine
‘storm’
The key molecule
is TNF-α
Capillary permeability
Blood pressure
Therapy includes:
Fluids, organ support
Anti-TNF-α antibody (in the very beginning)
Antibiotics
Corticosteroids
NE
FFP in DIC
Fever, Rash
Multi-organ failure
Disseminated
intravascular
Coagulation (DIC)
Coma, Death
Similar findings found in Septic Shock caused by bacteremia/viremia
NSAIDs (salicylates)
ASA
Mesalazine /
Mesalamine
Other NSAIDs
Flurbiprofen
Ibuprofen
Naproxen
Diclofenac