Inflammation pdf - أ.م.د.وئام سعد عبد الحمزة

Course: Immunology

Lecturer: Dr. Weam Saad

Lecture: Inflammation

Factors affecting Innate Immunity:

1. Species; e.g. Human not affected by plants pathogens.
2. Race; genetic play role in this factor e.g. all members of particular race

are resistance to certain infections like people of African race are
resistant to malaria.

3. Individual Factors include:

 Age: increased age causes increase ability to get infections. Also,

new born are more susceptible to infections due to immature
immune system.

 Hormones: e.g. Stress causes release of steroid hormones causing

easy to get infections. Also hyperthyroidism can cause immune-
suppression.

 Nutrition: vitamins play role in good immunity, also some viruses

do not multiply in people with malnutrition.

4. Geographic location, this factor affects on normal flora composition and

exposure to the epidemic disease.

Inflammation

It is the innate response of living tissues to any injury or damage in the

site of infection. It is a reaction and an ordered process mediated by the
inflammatory mediators produced by injured tissues and immune cells. This
process consists of four major events:

1.  Increased blood supply to the region.
2.  Increased capillary permeability in the affected area (vasodilation).
3.  Increase the degree of temperature (fever).
4.  Migration of W.B.Cs from the blood vessels into the tissues.

Neutrophils are the first cells reach inflammatory sites followed by

macrophages and lymphocytes in order to generate an immune response.
Inflammatory mediators include; complement system protiens, fibrin, clotting
plasmin, kinin system, prostaglandin, serotonin, histamine, etc. the function of
these mediators is very important to initiate the immune response.

The Importance of inflammation

1. Limitation of the infection and make it localized.
2. Control the infection by stop spreading of infectious organisms to

the surrounding healthy tissues by forming the fibrin clot around.

3. Activation of the immune system to generate the proper immune

response against the pathogen.

Types of inflammations

1. Acute inflammation

The most common type of inflammations characterized by swallow,

pain, redness and heat at the site of inflammation due to Odema (or edema),
increase blood supply and toxic effects of inflammatory products on nerves
in the site of inflammation the most important sign of acute inflammation is
exudate formation.

Exudate defined as the odema inflammatory liquid forms during acute

inflammations contain high levels of protein, many inflammatory cells, low
glucose, pus and sometimes fibrin clot. The importance of exudates is:

A. Killing causative pathogen.
B. Dilution of toxins in the site of inflammation.
C. Media for immune response (Abs reaction with Ag).
D. Localization of infection and stop spreading.

Pus: it is the solid components of inflammatory exudates contain living and
dead neutrophils and the debris of dead cells of necrotic tissues.

Steps of Acute inflammation

1. After infection, increase permeability of blood vessels in the infected

site.

2. Formation of exudate which contain proteins (e.g. Albumin,

Immunoglobulins, plasmin and fibrin).

3. Aggregation of RBCs due to congestion.
4. Migration of PMNs (polymorph nucleus cells) to the site of

inflammation), followed by monocytes by the effect of chemotaxis.

5. Vesicular changes in the site of inflammation.
6. Repair damage: [re-absorption of liquids, regeneration of damaged cells

of infected tissues by repair blood vessels and fibroblast cells. This
process is called regerntion and that is the end of inflammation.

Factors affect the repair are:

1) Neutrition (vit D and C).
2) Medications and drugs e.g. antibiotics increase repair while cortisone

drugs decrease due to prevent new blood vessels formation.

Types of acute inflammations:

Acute inflammations can be classified according to the type of exudates

formed as following:

1) Serous inflammation (the exudate is serum e.g.: Tuberculosis).
2) Mucoid or catarrhal inflammation (the exudate is mucous e.g. flue or

influenza).

3) Fibrinous inflammation (the exudate is fibrin. e.g.: Diphtheria, caused by

Corynebacteria diptheriae).

4) Purulent or suppulative inflammation (the exudate is pus and called abscess.
5) Combined Inflammation when there is more than one type of inflammation

like muco-purulent or sero-fibrinous usually occur during mixed infections.

Chronic inflammation

Occurs when the pathogenic infection last for long time without treatment

or with low immune response or when the pathogen is intracellular parasite
lives inside cells and escape immune system defense mechanisms and has no
Immunogenic antigens, also when the acute inflammation left without
treatment will become chronic inflammation.

Signs of chronic inflammation:

1)  Long standing inflammation.
2)  Low exudate.
3)  Histological  changes  in  tissue  (most  important  sign)  e.g.:  Hyperplasia,

hypertrophy.

Metaplasia and suppress the physiological function, hence adding

immunosuperssor drugs (like cortisone) to the therapy in order to avoid these
histological changes for example chronic inflammation in middle ear (chronic
otitis media) lead to hearing loss due to ear drum damage.

Granulomatous inflammation.

Long standing inflammation transformed from chronic inflammation, occurs

due  to  internal  fungal  infections  and  some  intracellular  bacterial  infections
e.g.:  Tuberculosis,  laprosy,  brucellosis,  syphilis,  when  the  pathogenic
microorganism  hide  and  escape  from  host  immune  system  mechanisms  and
hide  inside cells.

Granuloma: it is the site of this type of inflammation and composed of nodule
containing a giant cell (merge of macrophage cell) in the center surrounded by
epithelial cells and some lymphocytes with fibrin deposited around these cells.

The Complement System

This system includes over than 20 proenzymes (glycoproteins)

components inactive state found in the blood. When the complement
components are activated, serial, rapid cascad events occur. Historically,
the term complement (C) was used to a heat-labile serum component able
to lyse bacteria and its activity is destroyed (or inactivated) by heating
serum at 56 C ᵒ

for 30 min.

1. Synthesis and metabolism of complement components.

Complement  glycoproteins  are  synthesized  by  liver  cells
(hepatocytes)  and  macrophages  and  many  other  cells  (e.g.  gut
epithelial  cells).  All  normal  individuals  have  complement
components in their blood. The synthetic rates for the complement
glycoproteins  increase  when  complement  is  activated  and
consumed.

2. Activation of the complement system.

This system can be activated by:

a) Antigen-antibody complexes containing IgG or IgM activate

complement by the classical pathway that starts with C1
(complement 1).

b) Membranes and cell walls of microbial organisms (e.g.

Lipopolyccharides layer [LPS] of gram –ve bacteria) and many

other substances can activate complement by the alternative
pathway.

c) Proteolytic enzymes released either from microbes or from host

cells during immune defense mechanisms, can also activate the
complement system by breaking down critical components.

3. The complement cascade induction. When the complement
component is activated, it continues activating the next component by:

 either cleaves.

 or becomes bound to an activated component or complex of

complement components.

4. Function of the complement system:

The complement system has role in both specific and non-specific

immunity. The functions of the complement system are:

1) Binding and neutralizing foreign substances that activate it.
2) Induce the ingestion of complement-coated substances by

phagocytic cells (help in the opsonization process when C3b and
C4b linked with the surface of microorganisms and attach to
Complement

receptor

phagocytic

cells

then

induce

phagocytosis).

3) Activation of many cells including PMNs cells and macrophages

4) Have roles in regulation of antibody responses.
5) Clearance of immune complexes and apoptotic cells.
6) Have roles in inflammation and tissue damage.
7) Some components (C3a, C4a and C5a), have role in Anaphylaxis (a

dangerous case of type I hypersensitivity), hence they are called
anaphylotoxins.

8) Some complement components acts as chemotactic factors e.g.

C5a.

5. Complement Pathways.

(The sequence of complement components activation)

A. Classical Pathway:

1) C1activation

C1, a multi-subunit protein containing three different proteins (C1q,
C1r  and  C1s),  binds  to  the  Fc  region  of  IgG  and  IgM  antibody
molecules that have interacted with antigen (it does not bind to free
Ab) , binding requires calcium and magnesium ions. The binding of
C1q  results  in  the  activation  of  C1r  which  in  turn  activates
C1s.  The  result is the formation of an activated “C1qrs”, which is
an enzyme that cleaves C4 into two fragments C4a and C4b.

2) C4 and C2 activation (generation of C3 convertase).

The  C4b  fragment  will  stay  (usually  binds  to  the  binds  to  the
membrane of bacteria) and the C4a fragment is released.  Activated
“C1qrs”  also  cleaves  C2  into  C2a  and  C2b.   C2a  binds  to  the
membrane  in  association  with  C4b,  and  C2b  is  released.  The
resulting  C4bC2a  complex  is  a  C3  convertase  (acts  as  enzyme),
which cleaves C3 into C3a and C3b.

3) C3 activation (generation of C5 convertase):

C3b binds to the membrane in association with C4b and C2a, and
C3a  is  released  (which  acts  as  anaphylaxis  protein  and  a
chemotactic  factor).  The  resulting  C4bC2aC3b  is  a  C5
convertase.   The  generation  of  C5  convertase  is  the  end  of  the
classical  pathway.  Many  products  of  the  classical  pathway  have
biological activities that support the host defenses:

Biological Activity of classical pathway products

Component

Biological Activity

C2b

Prokinin; have role in kinin system, causes edema

C3a

Anaphylotoxin; can activate basophils and mast cells to
degranulate resulting in increased vascular permeability and
contraction of smooth muscle cells, which may lead to
anaphylaxis

C3b

Opsonin; induces phagocytosis by binding to complement
receptors. Activation of phagocytic cells

C4a

Anaphylotoxin (weaker than C3a)

C4b

Opsonin; induces phagocytosis by binding to complement
receptors

B. Lectin Pathway

The lectin pathway is very similar to the classical pathway. It starts with
the binding of mannose-binding lectin (MBL) to bacterial surfaces. Many
serial events happens resulting C4bC2aC3b formation, which is the C5
convertase. The generation of C5 convertase is the end of the lectin
pathway.

C.Alternative Pathway

Activation of this pathway starts spontaneously and C3 will be cleaved
by the help of Factor B, Factor D, properdin and Mg

ions. Cleavage of

C3will  release  C3a  (which  acts  as  anaphylaxis  protein)  and  C3b.  when
C3b is formed, Factor B will bind to it and will be cleaved by Factor D.
The resulting C3bBb complex is a C5 convertase and this is the end of the
alternative  pathway. Generation  of  C3b  is  essential  for  the  activation  of
the alternative pathway.
The component C3b can be formed due to:

a.  During normal C3 turnover in blood
b.  In the presence of  bacterial proteases
c.  During classical pathway activation (for this reason activation of the

classical pathway is always associated with activation of the
alternative pathway which generating more activated C3).

       The  alternative  pathway  of  complement  activation  is  important
especially during the early phase of an infection, when the concentrations
of  specific  antibody  are  very  low  and  classical  pathway  activation  is
limited and in the presence of large numbers of bacteria. The alternative
pathway provides the non-specific resistance against infection without the
need  to  antibodies  and  hence  provides  a  first  line  of  defense  against  a
number of infectious agents.

D. Membrane attack complex Formation:
     Lytic pathway is the end of all the complement  system pathways, C5
convertase from all pathways (classical, lectin or alternative) cleaves C5
into  C5a  and  C5b.  Then  C5b  rapidly  binds  with  C6,  C7,  C8  and  C9
molecules. Pores will be formed in the membrane and lysis occurs due to
physical  damage  to  the  membrane.  The  complex  of  C5bC6C7C8C9  is
called the membrane attack complex (MAC).
     C5a formed in the lytic pathway is the most active anaphylotoxin. It is
a chemotactic factor for neutrophils and stimulates the respiratory burst in
them  and  it  stimulates  inflammatory  cytokine  production  by
macrophages.

Complement deficiencies and diseases

Component

Disease

Mechanism

C1, C2, C4

SLE

Opsonization of immune complexes help
keep them soluble, deficiency results in
increased precipitation in tissues and
inflammation

Factors B or D

Susceptibility to
pyogenic (pus-
forming) bacterial
infections

Not enough opsonization of bacteria

Susceptibility to
bacterial infections

Lack of opsonization and inability to utilize
the membrane attack pathway

C5, C6, C7
C8, and C9

Susceptibility to
Gram-negative
infections

Inability to attack the outer membrane of
Gram-negative bacteria