2. Inflammation
Is a protective response of the body’s to
injury
Consist of complex biological process by
body responds to pathogens and irritants
Eliminate the initial cause of cell injury
destroying and neutralizing the harmful
agents
Remove the damaged tissue
Generate new tissue
5. Inflammation
The basis of the five cardinal signs
Increased blood flow due to vascular dilatation gives
redness and heat.
Increased vascular permeability gives oedema
causing tissue swelling.
Certain chemical mediators stimulate sensory nerve
endings giving pain. Nerves also stimulated by
stretching from oedema.
Pain and swelling result in loss of function.
12. Summary: role of Inflammation in
innate immunity
Initiation of phagocytosis – killing of pathogen
Limiting the spread of infection
Stimulate adaptive immune response
Initiate tissue repair
16. The phases of inflammatory response at the
injured site
1. Changes in vascular caliber (Vasodilatation) and
increased blood flow
2. Increased vascular permeability
3. Fluid and leukocyte exudation
4. Phagocytosis and killing
17. First event in an acute inflammatory response to injury is
vasodilatation (i.e. dilatation of blood vessels) of arterioles
around the injured area.
Due to dilatation of arterioles, more blood flows to the
injured site.
Due to increased blood flow, the injured area becomes red
and warm.
Redness and heat are the first two signs of inflammation in
the injured area.Due to increased blood flow, the injured
area becomes red and warm.
1. Changes in Vascular Caliber (Vasodilatation)
and Increased Blood Flow:
18. Inflammation and vascular changes
Vasodilatation
Increased capillary
permeability
Normal blood vessel Dilated blood vessel
Normal blood vessel
Leaky blood vessel
19. The small blood vessel wall is made of thin endothelium
(called vascular endothelium).
Normally the vascular endothelium permits free exchange of
water and small molecules between blood and tissue
spaces; but limits the passage of plasma proteins (whose
molecular sizes are large) from the blood into tissue spaces.
But after tissue injury, the permeability of blood vessels in the
injured area increases.
Consequently, the plasma proteins (including the antibody
molecules), leukocytes, and more fluid from the blood exude
into tissue spaces
2. Increased Vascular Permeability:
21. Apart from fluid and plasma proteins, the leukocytes,
especially neutrophils and monocytes come out of the blood
vessels and accumulate in vast numbers in the injured area
(The sequence of events with respect to the movement of
leukocytes from blood vessels into tissue spaces is
described later).
In most of the acute inflammations, neutrophils predominate
in the first 6 to 24 hours, being replaced by monocytes in 24
to 48 hours.
3. Leucocytic Exudation and
Chemotaxis:
24. The leukocytes engulf (phagocytose) the microbes and kill
them. Phagocytosis and intracellular killing of ingested
microbe (such as bacteria) can be described in three
interrelated steps.
i. Recognition and attachment of leukocyte to bacteria
ii. Engulfment (phagocytosis) of bacteria
Killing or degradation of bacteria
Recognition and Attachment of Leukocytes to Bacteria:
The leukocytes recognize the microorganisms through serum factors called
opsonins. There are two major opsonins.
1. IgG (subtypes IgGl and IgG3) and
2. C3b (opsonic fragment of C3), which is generated by activation of complement
system by direct or alternative pathway.
4. Phagocytosis and Intracellular
Killing:
25. Inflammation and innate immunity
Mast cells – similar to basophils in blood;
mast cells are present in tissues and release histamines in response to wound / infection /irritant
Histamin
e
Pathogen
removal
Adaptive immune
response
+ + +
37. What is a Phagocyte?
A cell that engulfs and digests material such as cell
debris and microbes, including invading organisms.
Surface of cell contains pattern recognition
receptors to recognize material to be ingested.
38. The Process of Phagocytosis
~A series of complex steps allowing
phagocytes to engulf and destroy
invading microorganisms.
~Most pathogens have evolved an ability
to evade one or more of the steps
(resistance).
44. Step 1
Chemotaxis- Phagocytic cells are recruited to
site of infection or tissue damage by chemical
stimuli (chemoattractants).
45. Step 2
Recognition & Attachment- Receptors located on
outside of phagocyte recognize and bind (directly
or indirectly).
~Direct binding-receptors recognize and bind to
patterns of compounds found on invaders
~Indirect binding-particle is opsonized, coating
particle with antibody substance for easier
ingestion
46. Step 3
Engulfment-Phagocytic cell engulfs invader, forming a
membrane-bound vacuole called a phagosome.
~Cytoskeleton of phagocyte rearranges to form armlike
extensions (pseudopods) that surround material being
engulfed.
47. Step 4
Fusion of the phagosome with the lysosome -
within the phagocyte, the phagosome moves
along the cytoskeleton to where it can fuse with
lysosomes.
~ Lysosomes-membrane bound bodies filled with
various digestive enzymes like lysozyme and
proteases.
~ Fusion creates a phagolysosome.
~ In neutrophils, membrane-bound bodies are
granules.
48. Step 5
Destruction & Digestion-Oxygen consumption increases,
sugars metabolized (aerobic respiration), highly toxic
oxygen products produced (superoxide, hydrogen
peroxide, singlet oxygen, hydroxyl radicals).
~As available O2 in phagolysosome is consumed metabolic
pathway switches to fermentation, producing lactic acid
and lowering pH.
~Enzymes degrade peptidoglycan of the bacterial cell walls,
and other parts of the cell.
49. Step 6
Exocytosis-membrane-bound vesicle
containing digested material fuses with the
plasma membrane. Material is expelled to
the external environment.
50. What do neutrophils do?
Phagocytosis
Contact, Recognition, Internalisation.
Opsonins: e.g. Fc and C3b receptors
Cytoskeletal changes (as with chemotaxis);
‘zipper’ effect.
51.
52. THE PHAGOCYTES
Margination
Endothelium-phagocyte interactions; adhesion molecules.
Histamine & thrombin activate P-selectin on endothelium
(minutes)
IL-1, TNF activate E selectin on endothelium (hours)
ICAM-1 (Intercellular Adhesion Molecule 1) and VCAM-1(vascular cell
adhesion molecule) also upregulated on endothelium
Lymphocyte function-associated antigen 1 (LFA-1), VLA-4 (very late
activation antigen) activation on neutrophils
53. How do neutrophils escape from vessels?
Relaxation of inter-endothelial cell junctions
Digestion of vascular basement membrane
Movement
57. How do neutrophils move?
Diapedesis and Emigration; Chemotaxis.
Chemotaxis implies detection of concentration
gradients
Receptor-ligand binding
Phospholipase C activation
Local release of free intracellular Ca+
Rearrangement of cytoskeleton
Production of pseudopod
58. What do neutrophils do?
Microbial killing
Phagosomes fuse with lysosomes to produce secondary
lysosomes.
Mechanisms:
O2 dependent
NADPH oxidase activated; produces superoxide ion. This
converts to hydrogen peroxide.
H2O2-Myeloperoxidase-halide system: produces HOCl.
(i.e. bleach!)
Myeloperoxidase independent:
Uses superoxide and hydroxyl radicals. Less efficient.
59. O2 independent killing mechanisms
Lysozyme & hydrolases
Lactoferrin
Bactericidal Permeability Increasing Protein (BPI)
Cationic proteins (‘Defensins’)
Major Basic Protein (MBP; Eosinophils)
60. SYSTEMIC EFFECTS OF ACUTE
INFLAMMATION
Fever
‘Endogenous pyrogens’ produced: IL1 and TNFa
IL1 - prostaglandins in hypothalamus
hence aspirin etc. reduce fever
Leukocytosis
IL1 and TNFa produce an accelerated release from marrow
Macrophages, T lymphocytes produce colony-stimulating
factors
Bacterial infections - neutrophils, viral - lymphocytes
Clinically useful
61. PROBLEMS CAUSED BY ACUTE INFLAMMATION
Local
Swelling: Blockage of tubes, e.g. bile duct, intestine
Exudate: Compression e.g. cardiac tamponade
Loss of fluid e.g. burns
Pain & loss of function - especially if prolonged
62. PROBLEMS CAUSED BY ACUTE
INFLAMMATION
Systemic
Acute phase response
Spread of micro-organisms and toxins
SHOCK
64. Immunogens and antigens
• Immunogen / antigen: a substance that elicits
an immune response [i.e. a humoral (antibody
response) or cell-mediated immune response]
Immune response generator
Though the two terms are used interchangeably – there are differences between
the two
Antigen: any substance that binds to an antibody (or a T-cell
receptor) – But some antigens cannot elicit an immune
response.
All immunogens are antigens but not all antigens are
immunogens
65. Epitope
• Epitope: the portion of an antigen that is recognized
and bound by an antibody (Ab) or a T-cell receptor
(TCR)
• Epitope = antigenic determinant
66. Epitopes
•Epitope: the portion of an antigen that is recognized and bound by an Ab or a T Cell receptor
One protein may have multiple antigenic determinant
68. Immunogenicity
• Immunogencity: is the ability to induce a humoral
(antibody) and/or cell-mediated immune response.
• Weak immunogens
• Strong immunogens
69. What determines immunogenicity ?
• Foreignness: essential for immunogenicity (self-responsive
immune cells are eliminated during lymphocyte development)
• Size: Bigger>Smaller
• Chemical composition: Proteins > nucleic acids /
polysaccharides / lipids
• Structure: Primary /secondary /tertiary structures play a role
• Physical form: Particulate> Soluble
70. Host factors affecting immunogencity
• Difference across species (interspecies)
• Differences within a species (intraspecies)
- Responders / non-responders to vaccine
- differences in disease severity in epidemics
Genetics
Age
71. Isoantigens
• Isoantigens: Antigens present in some but not all
members of a species
• Blood group antigens – basis of blood grouping
• MHC (major histocompatibility complex)- cell surface
glycoproteins
72. Autoantigens
• Autoantigens are substances capable of immunizing
the host from which they are obtained.
• Self antigens are ordinarily non-antigenic
• Modifications of self-antigens are capable of eliciting
an immune response
73. Haptens
• Haptens are small molecules which are non-
immunogenic, thus could never induce an
immune response by themselves.
76. What is an antibody?
• Produced by Plasma cell (B-lymphocytes producing Ab)
• Essential part of adaptive immunity
• Specifically bind a unique antigenic epitope (also called an
antigenic determinant)
• Possesses antigen binding sites
• Members of the class of proteins called immunoglobulins
77. What does an antibody look like ?
• 2 identical heavy chains
• 2 identical light chains
• Each heavy chain – has a
constant and a variable
region
• Each light chain has a
constant and a variable
region
H H
L L
Constant
region
Variable
region
79. Antibody: Fab
Fab region
• Variable region of the
antibody
• Tip of the antibody
• Binds the antigen
• Specificity of antigen
binding determined by
VH and VL
80. Antibody: Fc
Fc region
• Constant region
• Base of the antibody
• Can bind cell receptors
and complement
proteins
81. • Antibodies occur in 2 forms
– Soluble Ag: secreted in blood and tissue
– Membrane-bound Ag: found on surface of B-cell, also
known as a B-cell receptor (BCR)
Antibodies exist in two forms
82. Case: A 3-year-old boy is brought to the
emergency department
• CC: a productive cough, fever (temp 102.1 C),
and headache.
• PEx: healthy boy with rales present on
auscultation of the left lower chest.
• CxR:intra-alveolar infiltrate in the left lower lobe.
• Hx: mother reports multiple episodes (approx. 5
per year) of recurrent bacterial infections
including otitis media, sinusitis, pneumonia, and
purulent skin lesions. These infections usually
responded to antibiotic treatment.
