1. 1
Faculty of Medicine and General Science
Sana'a University
CLINICAL IMMUNOLOGY
DR: Mohammed Bamashmoos(MD)
Associate Prof. of Internal medicine and
endocrinology (Sana'a University )
2. 2
Definition ; its defined as defines mechanism of the body against invading
pathogen . the immune system is composed of two major subdivision , the innate
(nonspecific ) and the adaptive (specific ) immune system
Immune system
Innate adaptive
Anatomical immunological cellular
humeral
Humeral
cellular
Types ;
1)-Innate immunity ;
Function ;
a-its first line of defense against invading pathogen
b-its non-specific
c-its natural
d-it provide activation of cytokines and complement system
e-it cause killing of invading pathogen by phagocytosis
f-it provide link between innate and adaptive immune system via antigen
presenting cells
components ;
1-anatomical barrier
2-immunological
Anatomical barrier ;
a-mechanical factors ;
Epithelial surface ; skin and mucus membrane , movement of cilia and
peristaltic movement of intestine , flushing action of tears and saliva ,
tapering effect of mucus that line respiratory and GIT
b-chemical factors . ; Fatty acids in sweat inhibit the growth of bacteria.
Lysozyme and phospholipase found in tears, saliva and nasal secretions
can breakdown the cell wall of bacteria and destabilize bacterial
membranes. The low pH of sweat and gastric secretions prevents growth
(low molecular weight proteins) found in the lung
Defensins
of bacteria.
and gastrointestinal tract have antimicrobial activity. Surfactants in the
3. 3
lung act as opsonins (substances that promote phagocytosis of particles
by phagocytic cells)
c-biological factors ;
The normal flora of the skin and in the gastrointestinal tract can prevent
the colonization of pathogenic bacteria by secreting toxic substances or by
competing with pathogenic bacteria for nutrients or attachment to cell
surfaces.
Table 1- summarize physic-chemical barriers to infection
Table 1. Physico-chemical barriers to infections
System/Organ Active
component
Effector Mechanism
Skin Squamous
cells; Sweat
Desquamation; flushing, organic
acids
GI tract Columnar
cells
Peristalsis, low pH, bile acid,
flushing, thiocyanate
Lung Tracheal
cilia
Mucocialiary elevator,
surfactant
Nasopharynx
and eye
Mucus,
saliva, tears
Flushing, lysozyme
Circulation and
lymphoid
organs
Phagocytic
cells
NK cells and
K-cell
LAK
Phagocytosis and intracellular
killing
Direct and antibody dependent
cytolysis
IL2-activated cytolysis
Serum Lactoferrin
and
Transferrin
Iron binding
Interferons Antiviral proteins
TNF-alpha antiviral, phagocyte activation
Lysozyme Peptidoglycan hydrolysis
Fibronectin Opsonization and phagocytosis
Complement Opsonization, enhanced
phagocytosis, inflammation
4. 4
Immunological
-Humeral
A-inflammatory mediators ;
Inflammation; is one of the first responses of the immune system to infection or
irritation. Inflammation is stimulated by chemical factors released by injured
cells and serves to establish a physical barrier against the spread of infection,
and to promote healing of any damaged tissue following the clearance of
pathogens.
The process of acute inflammation is initiated by cells already present in all
tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells,
and mastocytes..
Types and function ;
Chemical factors produced during inflammation (histamine, bradykinin,
serotonin, leukotriene’s, and prostaglandins) sensitize pain receptors, cause
vasodilatation of the blood vessels at the scene, and attract phagocytes,
especially neutrophils. Neutrophils then trigger other parts of the immune
system by releasing factors that summon other leukocytes and lymphocytes.
Cytokines produced by macrophages and other cells of the innate immune
system mediate the inflammatory response.
The inflammatory response is characterized by the following symptoms:
redness
hotness
swelling
pain
possible dysfunction of the organs or tissues involved.
1-Histamine
Synthesis and metabolism
Histamine is derived from the decarboxylation of the amino acid histidine, a
reaction catalyzed by the enzymeL-histidine decarboxylase.
Once formed, histamine is either stored or rapidly inactivated by its primary
degradative enzymes, histamine-N-methyltransferase or diamine oxidase. In the
central nervous system, histamine released into the synapses is primarily broken
down by histamine-N-methyltransferase, while in other tissues both enzymes
may play a role.
5. 5
Storage and release
Most histamine in the body is generated in granules in mast cells and in white
blood cells called basophils and eosinophil’s. Mast cells are especially numerous
at sites of potential injury — the nose, mouth, and feet, internal body surfaces,
and blood vessels. Non-mast cell histamine is found in several tissues, including
the brain, where it functions as a neurotransmitter. Another important site of
histamine storage and release is the enterochromaffin like (ECL) cell of the
stomach.
Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies.
Reduction of IgE overproduction may lower the likelihood of allergens
Mechanism of action
Histamine exerts its effects by binding to G protein-coupled histamine receptors,
designated H1 through H4.
Type s Location Function
Histamine
H1
receptor
CNS: Produced in the
tuberomamillary
nucleus, projecting to the
dorsal raphe, locus
coeruleus, and either to
and/or through the
hippocampal formation,
amygdala, basal ganglia,
thalamus, superior
colliculus, and
cerebellum
PNS: Smooth muscle and
endothelium
CNS: sleep-wake cycle, body
temperature, endocrine
homeostasis, appetite, mood,
learning, and memory
PNS: Causes
bronchoconstriction, ,
vasodilation and separation
of endothelial cells
(responsible for hives), and
pain and itching due to insect
stings; the primary receptors
involved in allergic rhinitis
symptoms and motion
sickness
Histamine
H2
receptor
Located on parietal cells and
vascular smooth muscle cells
Primarily involved in vasodilation.
Also stimulate gastric acid secretion
Histamine
Found on central nervous
system and to a lesser extent
Decreased neurotransmitter
release: histamine, acetylcholine,
norepinephrine, serotonin
6. 6
H3
receptor
peripheral nervous system
tissue
Histamine
H4
receptor
Found primarily in the
basophils and in the bone
marrow. It is also found on
thymus, small intestine, spleen,
and colon.
2- Bradykinin
Plays a role in chemotaxis.
Synthesis
high-molecular-weight kininogen (HMWK or HK), is catalyzed by the enzyme
kallikrein to form bradykinin .
Metabolism
In humans, bradykinin is broken down by three kininases: angiotensin-
converting enzyme (ACE), aminopeptidase P (APP), and carboxypeptidase N
(CPN),.
Effect
- it cause drop in blood pressure due to
1- It is a potent endothelium-dependent vasodilator,
2- increases vascular permeability
3- Bradykinin also causes natriuresis, contributing to the drop in blood pressure.
-It causes contraction of non-vascular smooth muscle in the bronchus and gut, --
-its involved in the mechanism of pain.
- Bradykinin is also thought to be the cause of the dry cough in some patients on
angiotensin-converting enzyme (ACE) inhibitor drugs. It is thought that
bradykinin is converted to inactive metabolites by ACE, therefore inhibition of
this enzyme leads to increased levels of bradykinin, which causes a dry cough via
bronchoconstriction. This refractory cough is a common cause for stopping ACE
inhibitor therapy, in which case angiotensin II receptor antagonists (ARBs) are
the next line of treatment.
7. 7
3-Leukotrienes ;
Synthesis
Eicosanoid synthesis. (Leukotrienes at right.)
The lipoxygenase pathway is active in leukocytes and other immunocompetent
cells, including mast cells, eosinophils, neutrophils, monocytes, and basophils.
When such cells are activated, arachidonic acid is liberated from cell membrane
phospholipids by phospholipase A2, and donated by the 5-lipoxygenase-
activating protein (FLAP) to 5-lipoxygenase.
5-Lipoxygenase (5-LO) uses FLAP to convert arachidonic acid into 5-
hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to
5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-
HETE to convert it into leukotriene A4 (LTA4), an unstable epoxide.
In cells equipped with LTA4 hydrolase, such as neutrophils and monocytes, LTA4
is converted to the dihydroxy acid leukotriene LTB4, which is a powerful
chemoattractant for neutrophils
In cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is
conjugated with the tripeptideglutathione to form the first of the cysteinyl-
leukotrienes, LTC4. Outside the cell, LTC4 can be converted by ubiquitous
enzymes to form successively LTD4 and LTE4, which retain biological activity.
Function
Leukotrienes are involved in asthmatic and allergic reactions and act to sustain
inflammatory reactions.
Leukotrienes are very important agents in the inflammatory response. Some
such as LTB4 have a chemotactic effect on migrating neutrophils, and as such
help to bring the necessary cells to the tissue.
8. 8
Leukotrienes also have a powerful effect in bronchoconstriction and increase
vascular permeability
4-Prostaglandin
Biosynthesis;
The cyclooxygenase pathway or the lipoxygenase pathway to form either
prostaglandin and Prostaglandins are found in most tissues and organs. They are
produced by almost all nucleated cells. They are autocrine and paracrine lipid
mediators that act upon platelets, endothelium, uterine and mast cells. They are
synthesized in the cell from the essential fatty acids (EFAs).
An intermediate arachidonic acid is created from diacylglycerol via
phospholipase-A2, then brought to either thromboxane or leukotriene
respectively. The cyclooxygenase pathway produces thromboxane, prostacyclin
and prostaglandin D, E and F.
Biosynthesis of eicosanoids
Function
There are currently ten known prostaglandin receptors on various cell types.
Prostaglandins ligate a sub-family of cell surface seven-trans membrane
receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-
9. 9
4, FP, IP1-2, and TP, corresponding to the receptor that ligates the corresponding
prostaglandin (e.g., DP1-2 receptors bind to PGD2).
The diversity of receptors means that prostaglandins act on an array of cells and
have a wide variety of effects such as:
cause constriction or dilation in vascular smooth muscle cells
cause aggregation or disaggregation of platelets
sensitize spinal neurons to pain
induce labor
decrease intraocular pressure
regulate inflammation
regulate calcium movement
regulate hormones
control cell growth
acts on thermoregulatory center of hypothalamus to produce fever
acts on mesangial cells in the glomerulus of the kidney to increase
glomerular filtration rate
acts on parietal cells in the stomach wall to inhibit acid secretion
Types
The following is a comparison of different types of prostaglandin, prostacyclin I2
(PGI2), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α).
Type
Receptor
type
Function
PGI2 IP Gs
vasodilation
inhibit platelet aggregation
bronchodilation
PGE2
EP1 Gq
bronchoconstriction
GI tractsmooth muscle contraction
EP2 Gs
bronchodilation
GI tractsmooth muscle relaxation
vasodilation
EP3 Gi
↓ gastric acid secretion
↑ gastricmucus secretion
uterus contraction (when pregnant)
GI tractsmooth muscle contraction
lipolysis inhibition
↑ autonomicneurotransmitters
↑ platelet response to their agonists and ↑
atherothrombosis in vivo
Unspecified hyperalgesia
10. 10
pyrogenic
PGF2α FP Gq
uterus contraction
bronchoconstriction
Clinical uses
Synthetic prostaglandins are used:
To induce childbirth (parturition) or abortion (PGE2 or PGF2, with or
without mifepristone, a progesterone antagonist);
To prevent closure of patent ductus arteriosus in newborns with
particular cyanotic heart defects (PGE1)
To prevent and treat peptic ulcers (PGE)
As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb
In pulmonary hypertension
In treatment of glaucoma (as in bimatoprost ophthalmic solution, a
synthetic prostamide analog with ocular hypotensive activity)
To treat erectile dysfunction or in penile rehabilitation following surgery
(PGE1 as alprostadil)
B-Complement system ;
Its plasma protein that are synthesized by the liver and other cells , it’s the major
humeral nonspecific defense mechanism , its activated in cascade leading to final
cell lysis .
Function ;
-Anti-infective as
- opsonization by C3b and C4b ,
- chemo taxis (attracting phagocytic cells ),
- activation of leucocytes ,
- cell lysis .
-Interplay between innate and adaptive immunity
-Clearance of
- immune complex and
- apoptotic cells
Pathway of activation;
11. 11
1- Classical pathway
2- Manose binding lectin (MBL) pathway
3- Alternative pathway
3
C- Cytokines
Types and function ;
12. 12
Cytokines are a diverse group of non-antibody proteins that act as mediators
between cells. They were initially identified as products of immune cells that act
as mediators and regulators of immune processes but many cytokines are now
known to be produced by cells other than immune cells and they can have effects
on non-immune cells as well. Cytokines are currently being used clinically as
biological response modifiers for the treatment of various disorders. The term
cytokine is a general term used to describe a large group of proteins but there
are other terms that are commonly used to describe particular kinds of
cytokines.
These include:
Monokines, cytokines produced by mononuclear phagocytic cells
Lymphokines, cytokines produced by activated lymphocytes, especially
Th cells
Interleukins, cytokines that act as mediators between leukocytes
Source ; from hematopoietic and non hematopoietic cells
One cytokine often influences the synthesis of other cytokines. They can produce
cascades, or enhance or suppress production of other cytokines. In addition,
they can often influence the action of other cytokines. The effects can be:
Antagonistic
Additive
Synergistic
Cytokines bind to specific receptors on target cells with high affinity and the cells
that respond to a cytokine are either: 1) the same cell that secreted cytokine
(autocrine); 2) a nearby cell (paracrine) or 3) a distant cell reached through the
circulation (endocrine). Cellular responses to cytokines are generally slow
(hours) because they require new mRNA and protein synthesis.
CATEGORIES OF CYTOKINES
Classification and types of cytokines
Cytokines can be grouped into different categories based on their functions or
their source but it is important to remember that because they can be produced
by many different cells and act on many different cells, any attempt to categorize
them will be subject to limitations
1- Interleukins
Its cytokines that exerts its effect in the leucocytes ( it ranges from IL1- IL 24 )
2- Interferon’s
13. 13
- Type 1 interferon ( α and β )
- Type 2 interferon ( gamma )
3- Chemokine’s
Its cytokines that have chemo attractant effect ;
- MCP-1
- MCP-2
- MCP-3
- RANTES
- EOTAXIN
4- Colony stimulating factors ;
- GCSF
- NMCSF
- MCSF
5- Tumor necrosis factors
- TNF α
- TNFβ
- TGFα
Function
A. Mediators of natural immunity
Cytokines that play a major role in the innate immune system include: TNF-α, IL-
1, IL-10, IL-12, type I interferons (IFN-α and IFN-β), IFN-γ, and chemokines.
1. TNF-α
Tumor necrosis factor alpha is produced by activated macrophages is response
to microbes, especially the lipopolysaccharide (LPS) of Gram negative bacteria. It
is an important mediator of acute inflammation. It mediates the recruitment of
neutrophils and macrophages to sites of infection by stimulating endothelial cells
to produce adhesion molecules and by producing chemokines which are
chemotactic cytokines. TNF- α also acts on the hypothalamus to produce fever
and it promotes the production of acute phase proteins.
2. IL-1
Interleukin 1 is another inflammatory cytokine produced by activated
macrophages. Its effects are similar to that of TNF-α and it also helps to activate
T cells.
3. IL-10
Interleukin 10 is produced by activated macrophages and Th2 cells. It is
predominantly an inhibitory cytokine. It inhibits production of IFN-γ by Th1
cells, which shifts immune responses toward a Th2 type. It also inhibits cytokine
production by activated macrophages and the expression of class II MHC and co-
stimulatory molecules on macrophages, resulting in a dampening of immune
14. 14
responses.
4. IL-12
Interleukin 12 is produced by activated macrophages and dendritic cells. It
stimulates the production of IFN-γ and induces the differentiation of Th cells to
become Th1 cells. In addition, it enhances the cytolytic functions of Tc and NK
cells.
5. Type I interferons
Type I interferons (IFN-α and IFN-β) are produced by many cell types and they
function to inhibit viral replication in cells. They also increase expression of class
I MHC molecules on cells making them more susceptible to killing by CTLs. Type I
interferons also activate NK cells.
6. INF-γ
Interferon gamma is an important cytokine produced by primarily by Th1 cells,
although it can also be produced by Tc and NK cells to a lesser extent. It has
numerous functions in both the innate and adaptive immune systems .
Regulates macrophage and NK cell activations. Stimulates immunoglobulin
secretion by B cells. Induction of class II histocompatibility antigens. TH1 T cell
differentiation.
7. Chemokines
Chemokines are chemotactic cytokines produced by many kinds of leukocytes
and other cell types. They represent a large family of molecules that function to
recruit leukocytes to sites of infection and play a role in lymphocyte trafficking.
B. Mediators of adaptive immunity
Cytokines that play a major role in the adaptive immune system include: IL-2, IL-
4, IL-5, TGF-β, IL-10 and IFN-γ.
1. IL-2
Interleukin 2 is produced by Th cells, although it can also be produced by Tc cells
to a lesser extent. It is the major growth factor for T cells. It also promotes the
growth of B cells and can activate NK cells and monocytes . IL-2 acts on T cells in
an autocrine fashion. Activation of T cells results in expression of IL-2R and the
production of IL-2. The IL-2 binds to the IL-R and promotes cell division. When
the T cells are no longer being stimulated by antigen, the IL-2R will eventually
decay and the proliferative phase ends .
2. IL-4
Interleukin 4 is produced by macrophages and Th2 cells. It stimulates the
development of Th2 cells from naïve Th cells and it promotes the growth of
differentiated Th2 cells resulting in the production of an antibody response. It
also stimulates Ig class switching to the IgE isotype.
15. 15
3. IL-5
Interleukin 5 is produced by Th2 cells and it functions to promote the growth
and differentiation of B cells and eosinophiles. It also activates mature
eosinophiles.
4. TGF-β
Transforming growth factor beta is produced by T cells and many other cell
types. It is primarily an inhibitory cytokine. It inhibits the proliferation of T cells
and the activation of macrophages. It also acts on PMNs and endothelial cells to
block the effects of pro-inflammatory cytokines.
C. Stimulators of hematopoesis
Some cytokines stimulate the differentiation of hematopoetic cells. These include
GM-CSF which promotes the differentiation of bone marrow progenitors, M-CSF,
which promotes growth and differentiation of progenitors into monocytes and
macrophages and G-CSF, which promotes production of PMNs.
Table 2- summarize different cytokines and its function
16. 16
Table 2. Cytokines and Cytokine Receptors
Cytokine Receptor Cell Source Cell Target Biologic
Activity
IL-1
,
Type I IL-1r,
Type II IL-1r
Monocytes/macr
ophages, B cells,
fibroblasts, most
epithelial cells
including thymic
epithelium,
endothelial cells
All cells Upregulates
adhesion
molecule
expression,
neutrophil and
macrophage
emigration,
mimics shock,
fever,
upregulates
hepatic acute-
phase protein
production,
facilitates
hematopoiesis
IL-2
IL-2r
, ,
common
T cells T cells, B cells,
NK cells,
monocytes-
macrophages
Promotes T cell
activation and
proliferation, B
cell growth, NK
cell
proliferation
and activation,
enhanced
monocyte/macr
ophage cytolytic
activity
IL-3 IL-3r,
common
T cells, NK cells,
mast cells
Monocytes-
macrophages,
mast cells,
eosinophils,
bone marrow
progenitors
Stimulates
hematopoietic
progenitors
IL-4
IL-4r ,
common
T cells, mast
cells, basophils
T cells, B cells,
NK cells,
monocytes-
macrophages,
neutrophils,
eosinophils,
endothelial
cells, fibroblasts
Stimulates TH2
helper T cell
differentiation
and
proliferation.
Stimulates B cell
Ig class switch
to IgG1 and IgE
anti-
inflammatory
17. 17
action on T cells,
monocytes
IL-5
IL-5r ,
common
T cells, mast
cells, eosinophils
Eosinophils,
basophils,
murine B cells
Regulates
eosinophil
migration and
activation
IL-6 IL-6r, gp130 Monocytes-
macrophages, B
cells, fibroblasts,
most epithelium
including thymic
epithelium,
endothelial cells
T cells, B cells,
epithelial cells,
hepatocytes,
monocytes-
macrophages
Induces acute-
phase protein
production, T
and B cell
differentiation
and growth,
myeloma cell
growth, and
osteoclast
growth and
activation
IL-7
IL-7r ,
common
Bone marrow,
thymic epithelial
cells
T cells, B cells,
bone marrow
cells
Differentiates B,
T, and NK cell
precursors,
activates T and
NK cells
IL-8 CXCR1,
CXCR2
Monocytes-
macrophages, T
cells,
neutrophils,
fibroblasts,
endothelial cells,
epithelial cells
Neutrophils, T
cells,
monocytes-
macrophages,
endothelial
cells, basophils
Induces
neutrophil,
monocyte, and T
cell migration,
induces
neutrophil
adherence to
endothelial cells
and histamine
release from
basophils, and
stimulates
angiogenesis.
Suppresses
proliferation of
hepatic
precursors
IL-9
IL-9r ,
common
T cells Bone marrow
progenitors, B
cells, T cells,
mast cells
Induces mast
cell
proliferation
and function,
synergizes with
IL-4 in IgG and
IgE production
18. 18
and T cell
growth,
activation, and
differentiation
IL-10 IL-10r Monocytes-
macrophages, T
cells, B cells,
keratinocytes,
mast cells
Monocytes-
macrophages, T
cells, B cells, NK
cells, mast cells
Inhibits
macrophage
proinflammator
y cytokine
production,
downregulates
cytokine class II
antigen and B7-
1 and B7-2
expression,
inhibits
differentiation
of TH1 helper T
cells, inhibits
NK cell function,
stimulates mast
cell
proliferation
and function, B
cell activation,
and
differentiation
IL-11 IL-11, gp130 Bone marrow
stromal cells
Megakaryocytes
, B cells,
hepatocytes
Induces
megakaryocyte
colony
formation and
maturation,
enhances
antibody
responses,
stimulates
acute-phase
protein
production
IL-12 (35-kD
and 40-kD
subunits)
IL-12r Activated
macrophages,
dendritic cells,
neutrophils
T cells, NK cells Induces TH1 T
helper cell
formation and
lymphokine-
activated killer
cell formation.
Increases CD8+
CTL cytolytic
19. 19
activity; IL-
17, IFN-
.
IL-13 IL-13/IL-4 T cells (TH2) Monocytes-
macrophages, B
cells,
endothelial
cells,
keratinocytes
Upregulates
VCAM-1 and C-C
chemokine
expression on
endothelial cells
and B cell
activation and
differentiation,
and inhibits
macrophage
proinflammator
y cytokine
production
IL-14 Unknown T cells Normal and
malignant B
cells
Induces B cell
proliferation
IL-15
IL-15r ,
common
, IL2r
Monocytes-
macrophages,
epithelial cells,
fibroblasts
T cells, NK cells Promotes T cell
activation and
proliferation,
angiogenesis,
and NK cells
IL-16 CD4 Mast cells,
eosinophils,
CD8+ T cells,
respiratory
epithelium
CD4+ T cells,
monocytesmacr
ophages,
eosinophils
Promotes
chemoattraction
of CD4+ T cells,
monocytes, and
eosinophils.
Inhibits HIV
replication.
Inhibits T cell
activation
through CD3/T
cell receptor
IL-17 IL17r CD4+ T cells Fibroblasts,
endothelium,
epithelium
Enhances
cytokine
secretion
IL-18 IL-18r (IL-
1R-related
protein)
Keratinocytes,
macrophages
T cells, B cells,
NK cells
Upregulates
IFN-
production,
20. 20
enhances NK
cell cytotoxicity
IL-21
IL-
chain/IL-
21R
CD4 T cells NK cells Downregulates
NK cell–
activating
molecules,
NKG2D/DAP10
IL-23 IL-
12Rb1/IL23
R
Macrophages,
other cell types
T cells Opposite effects
of IL-12 (
IL-17, IFN-
)
IFN-
Type I
interferon
receptor
All cells All cells Promotes
antiviral
activity.
Stimulates T
cell,
macrophage,
and NK cell
activity. Direct
antitumor
effects.
Upregulates
MHC class I
antigen
expression.
Used
therapeutically
in viral and
autoimmune
conditions
IFN-
Type I
interferon
receptor
All cells All cells Antiviral
activity.
Stimulates T
cell,
macrophage,
and NK cell
activity. Direct
antitumor
effects.
Upregulates
MHC class I
antigen
expression.
Used
therapeutically
21. 21
in viral and
autoimmune
conditions
IFN-
Type II
interferon
receptor
T cells, NK cells All cells Regulates
macrophage and
NK cell
activations.
Stimulates
immunoglobulin
secretion by B
cells. Induction
of class II
histocompatibili
ty antigens. TH1
T cell
differentiation.
TNF-
TNFrI,
TNFrII
Monocytes-
macrophages,
mast cells,
basophils,
eosinophils, NK
cells, B cells, T
cells,
keratinocytes,
fibroblasts,
thymic epithelial
cells
All cells except
erythrocytes
Fever, anorexia,
shock, capillary
leak syndrome,
enhanced
leukocyte
cytotoxicity,
enhanced NK
cell function,
acute phase
protein
synthesis,
proinflammator
y cytokine
induction.
TNF-
TNFrI,
TNFrII
T cells, B cells All cells except
erythrocytes
Cell cytotoxicity,
lymph node and
spleen
development.
LT- LT R
T cells All cells except
erythrocytes
Cell cytotoxicity,
normal lymph
node
development
G-CSF G-CSFr;
gp130
Monocytes-
macrophages,
fibroblasts,
endothelial cells,
thymic epithelial
cells, stromal
cells
Myeloid cells,
endothelial cells
Regulates
myelopoiesis.
Enhances
survival and
function of
neutrophils.
Clinical use in
reversing
22. 22
neutropenia
after cytotoxic
chemotherapy.
GM-CSF GM-CSFr,
common
T cells,
monocytesmacro
phages,
fibroblasts,
endothelial cells,
thymic epithelial
cells
Monocytes-
macrophages,
neutrophils,
eosinophils,
fibroblasts,
endothelial cells
Regulates
myelopoiesis.
Enhances
macrophage
bactericidal and
tumoricidal
activity.
Mediator of
dendritic cell
maturation and
function.
Upregulates NK
cell function.
Clinical use in
reversing
neutropenia
after cytotoxic
chemotherapy.
M-CSF M-CSFr (c-
fmsprotoonc
ogene
Fibroblasts,
endothelial cells,
monocytesmacro
phages, T cells, B
cells, epithelial
cells including
thymic
epithelium
Monocytes-
macrophages
Regulates
monocyte-
macrophage
production and
function.
LIF LIFr; gp130 Activated T cells,
bone marrow
stromal cells,
thymic
epithelium
Megakaryocytes
, monocytes,
hepatocytes,
possibly
lymphocyte
subpopulations
Induces hepatic
acute-phase
protein
production.
Stimulates
macrophage
differentiation.
Promotes
growth of
myeloma cells
and
hematopoietic
progenitors.
Stimulates
thrombopoiesis.
OSM OSMr; LIFr;
gp130
Activated
monocytesmacro
phages and T
cells, bone
Neurons,
hepatocytes,
monocytes-
macrophages,
Induces hepatic
acute-phase
protein
production.
23. 23
marrow stromal
cells, some
breast carcinoma
cell lines,
myeloma cells
adipocytes,
alveolar
epithelial cells,
embryonic stem
cells,
melanocytes,
endothelial
cells,
fibroblasts,
myeloma cells
Stimulates
macrophage
differentiation.
Promotes
growth of
myeloma cells
and
hematopoietic
progenitors.
Stimulates
thrombopoiesis.
Stimulates
growth of
Kaposi’s
sarcoma cells.
SCF SCFr (c-
kitprotoonc
ogene)
Bone marrow
stromal cells and
fibroblasts
Embryonic stem
cells, myeloid
and lymphoid
precursors,
mast cells.
Stimulates
hematopoietic
progenitor cell
growth, mast
cell growth,
promotes
embryonic stem
cell migration.
TGF- (3
isoforms)
Type I, II, III
TGF-
receptor
Most cell types Most cell types Downregulates
T cell,
macrophage,
and granulocyte
responses.
Stimulates
synthesis of
matrix proteins.
Stimulates
angiogenesis.
Lymphotacti
n/SCM-1
Unknown NK cells, mast
cells, double
negative
thymocytes,
activated CD8+ T
cells
T cells, NK cells Chemoattractan
t for
lymphocytes.
Only known
chemokine of C
class.
MCP-1 CCR2 Fibroblasts,
smoothmuscle
cells, activated
PBMCs
Monocytes-
macrophages,
NK cells,
memory T cells,
basophils
Chemoattractan
t for monocytes,
activated
memory T cells,
and NK cells.
Induces granule
release from
CD8+ T cells and
NK cells. Potent
24. 24
histamine-
releasing factor
for basophils.
Suppresses
proliferation of
hematopoietic
precursors.
Regulates
monocyte
protease
production.
MCP-2 CCR1, CCR2 Fibroblasts,
activated PBMCs
Monocytes-
macrophages, T
cells,
eosinophils,
basophils, NK
cells
Chemoattractan
t for monocytes,
memory and
naïve T cells,
eosinophils, ?NK
cells. Activates
basophils and
eosinophils.
Regulates
monocyte
protease
production.
MCP-3 CCR1, CCR2 Fibroblasts,
activated PBMCs
Monocytes-
macrophages, T
cells,
eosinophils,
basophils, NK
cells, dendritic
cells
Chemoattractan
t for monocytes,
memory and
naïve T cells,
dendritic cells,
eosinophils, ?NK
cells. Activates
basophils and
eosinophils.
Regulates
monocyte
protease
production.
MCP-4 CCR2, CCR3 Lung, colon,
small intestinal
epithelial cells,
activated
endothelial cells
Monocytes-
macrophages, T
cells,
eosinophils,
basophils
Chemoattractan
t for monocytes,
T cells,
eosinophils, and
basophils
Eotaxin CCR3 Pulmonary
epithelial cells,
heart
Eosinophils,
basophils
Potent
chemoattractant
for eosinophils
and basophils.
Induces allergic
airways disease.
Acts in concert
25. 25
with IL-5 to
activate
eosinophils.
Antibodies to
eotaxin inhibit
airway
inflammation.
TARC CCR4 Thymus,
dendritic cells,
activated T cells
T cells, NK cells Chemoattractan
t for T and NK
cells.
MDC CCR4 Monocytes-
macrophages,
dendritic cells,
thymus
Activated T cells Chemoattractan
t for activated T
cells. Inhibits
infection with T
cell tropic HIV.
MIP-1
CCR1, CCR5 Monocytes-
macrophages, T
cells
Monocytes-
macrophages, T
cells, dendritic
cells, NK cells,
eosinophils,
basophils
Chemoattractan
t for monocytes,
T cells, dendritic
cells, NK cells,
and weak
chemoattractant
for eosinophils
and basophils.
Activates NK
cell function.
Suppresses
proliferation of
hematopoietic
precursors.
Necessary for
myocarditis
associated with
Coxsackie virus
infection.
Inhibits
infection with
monocytotropic
HIV.
MIP-1
CCR5 Monocytes-
macrophages, T
cells
Monocytesmacr
ophages, T cells,
NK cells,
dendritic cells
Chemoattractan
t for monocytes,
T cells, and NK
cells. Activates
NK cell function.
Inhibits
infection with
monocytotropic
HIV.
26. 26
RANTES CCR1, CCR2,
CCR5
Monocytes-
macrophages, T
cells, fibroblasts,
eosinophils
Monocytes-
macrophages, T
cells, NK cells,
dendritic cells,
eosinophils,
basophils
Chemoattractan
tfor
monocytesmacr
ophages, CD4+,
CD45Ro+T cells,
CD8+ T cells, NK
cells,
eosinophils, and
basophils.
Induces
histamine
release from
basophils.
Inhibits
infections with
monocytotropic
HIV.
LARC/MIP-
3
/Exodus-1
CCR6 Dendritic cells,
fetal liver cells,
activated T cells
T cells, B cells Chemoattractan
t for
lymphocytes.
ELC/MIP-
3
CCR7 Thymus, lymph
node, appendix
Activated T cells
and B cells
Chemoattractan
t for B and T
cells. Receptor
upregulated on
EBV-infected B
cells and HSV-
infected T cells.
I-309/TCA-3 CCR8 Activated T cells Monocytes-
macrophages, T
cells
Chemoattractan
t for monocytes.
Prevents
glucocorticoid-
induced
apoptosis in
some T cell
lines.
SLC/TCA-
4/Exodus-2
Unknown Thymic epithelial
cells, lymph
node, appendix
and spleen
T cells Chemoattractan
t for T
lymphocytes.
Inhibits
hematopoiesis.
DC-
CK1/PARC
Unknown Dendritic cells in
secondary
lymphoid tissues
Naïve T cells May have a role
in induction of
immune
responses.
TECK Unknown Dendritic cells,
thymus, liver,
T cells,
monocytesmacr
Thymic
dendritic cell–
27. 27
small intestine ophages,
dendritic cells
derived
cytokine,
possibly
involved in T
cell
development
GRO-
/MGSA
CXCR2 Activated
granulocytes,
monocyte-
macrophages,
and epithelial
cells.
Neutrophils,
epithelial cells,
?endothelial
cells
Neutrophil
chemoattractant
and activator.
Mitogenic for
some melanoma
cell lines.
Suppresses
proliferation of
hematopoietic
precursors.
Angiogenic
activity.
GRO-
/MIP-2
CXCR2 Activated
granulocytes and
monocyte-
macrophages
Neutrophils and
?endothelial
cells.
Neutrophil
chemoattractant
and activator.
Angiogenic
activity.
NAP-2 CXCR2 Platelets Neutrophils,
basophils
Derived from
platelet basic
protein.
Neutrophil
chemoattractant
and activator.
IP-10 CXCR3 Monocytes-
macrophages, T
cells, fibroblasts,
endothelial cells,
epithelial cells
Activated T
cells,
tumorinfiltratin
g lymphocytes,
?endothelial
cells, ?NK cells
IFN- -
inducible
protein that is a
chemoattractant
for T cells.
Suppresses
proliferation of
hematopoietic
precursors.
MIG CXCR3 Monocytes-
macrophages, T
cells, fibroblasts
Activated T
cells,
tumorinfiltratin
g lymphocytes
IFN- -
inducible
protein that is a
chemoattractant
for T cells.
Suppresses
proliferation of
hematopoietic
28. 28
precursors.
SDF-1 CXCR4 Fibroblasts T cells, dendritic
cells, ?basophils,
?endothelial
cells
Low-potency,
high-efficacy T
cell
chemoattractant
. Required for B-
lymphocyte
development.
Prevents
infection of
CD4+, CXCR4+
cells by T cell
tropic HIV.
Fractalkine CX3CR1 Activated
endothelial cells
NK cells, T cells,
monocytes-
macrophages
Cell-surface
chemokine/muc
in hybrid
molecule that
functions as a
chemoattractant
, leukocyte
activator, and
cell adhesion
molecule.
PF-4 Unknown Platelets,
megakaryocytes
Fibroblasts,
endothelial cells
Chemoattractan
t for fibroblasts.
Suppresses
proliferation of
hematopoietic
precursors.
Inhibits
endothelial cell
proliferation
and
angiogenesis.
Abbreviations: IL, interleukin; NK, natural killer; TH1 and TH2
2- cells of innate immunity
Monocytes-Macrophages
Monocytes arise from precursor cells within bone marrow and circulate with a
half-life ranging from 1 to 3 days. Monocytes leave the peripheral circulation by
marginating in capillaries and migrating into a vast extravascular pool. Tissue
macrophages arise from monocytes that have migrated out of the circulation and
by in situ proliferation of macrophage precursors in tissue. Common locations
29. 29
where tissue macrophages (and certain of their specialized forms) are found are
lymph node, spleen, bone marrow, perivascular connective tissue, serous cavities
such as the peritoneum, pleura, skin connective tissue, lung (alveolar
macrophages), liver (Kupffer cells), bone (osteoclasts), central nervous system
(microglia cells), and synovium .
In general, monocytes-macrophages are on the first line of defense associated
with innate immunity and ingest and destroy microorganisms through the
release of toxic products such as hydrogen peroxide (H2O2) and nitric oxide (NO).
Inflammatory mediators produced by macrophages attract additional effector
cells such as neutrophils to the site of infection. Macrophage mediators include
prostaglandins; leukotrienes; platelet activating factor; cytokines such as
interleukin (IL)-1, tumor necrosis factor (TNF)- IL-6, and IL-12; and chemokines
Dendritic Cells
Human dendritic cells (DCs) are heterogonous and contain several subsets,
including myeloid DCs and plasmacytoid DCs. Myeloid DCs can differentiate into
either macrophages-monocytes or tissue-specific DCs. In contrast to myeloid
DCs, plasmacytoid DCs are inefficient antigen-presenting cells but are potent
producers of type I interferon (IFN) (e.g., IFN-α) in response to viral infections.
The maturation of DCs is regulated through cell-to-cell contact and soluble
factors, and DCs attract immune effectors through secretion of chemokines.
Function ;
-acts mainly as antigen presenting cells
-secrete many cytokines and chemokines
-have phagocytic function
-play important rule in immune system regulation
Figure 2-- summarize the function of DCs
30. 30
Neutrophils, Eosinophils, and Basophils
Granulocytes are derived from stem cells in bone marrow. Each type of
granulocyte (neutrophil, eosinophil, or basophil) is derived from a different
subclass of progenitor cell that is stimulated to proliferate by colony-stimulating
factors During terminal maturation of granulocytes, class-specific nuclear
morphology and cytoplasmic granules appear that allow for histologic
identification of granulocyte type.
Neutrophils express Fc receptors for IgG (CD16) and receptors for activated
complement components (C3b or CD35). Upon interaction of neutrophils with
opsonized bacteria or immune complexes, azurophilic granules (containing
myeloperoxidase, lysozyme, elastase, and other enzymes) and specific granules
(containing lactoferrin, lysozyme, collagenase, and other enzymes) are released,
and microbicidal superoxide radicals (O2–) are generated at the neutrophil
surface. The generation of superoxide leads to inflammation by direct injury to
tissue and by alteration of macromolecules such as collagen and DNA.
Eosinophils express Fc receptors for IgG (CD32) and are potent cytotoxic effector
cells for various parasitic organisms. In Nippostrongylusbrasiliensishelminth
infection, eosinophils are important cytotoxic effector cells for removal of these
31. 31
parasites. Key to regulation of eosinophil cytotoxicity to N. brasiliensis worms are
antigen-specific T helper cells that produce IL-4, thus providing an example of
regulation of innate immune responses by adaptive immunity antigen-specific T
cells. Intracytoplasmic contents of eosinophils, such as major basic protein,
eosinophil cationic protein, and eosinophil-derived neurotoxin, are capable of
directly damaging tissues and may be responsible in part for the organ system
dysfunction in the hypereosinophilic syndromes.Since the eosinophil granule
contains anti-inflammatory types of enzymes (histaminase, arylsulfatase,
phospholipase D), eosinophils may homeostaticallydownregulate or terminate
ongoing inflammatory responses.
Natural killer cells ;
Large granular lymphocytes (LGLs) or NK cells account for ~5–15% of
peripheral blood lymphocytes. NK cells are nonadherent, nonphagocytic cells
with large azurophilic cytoplasmic granules. NK cells express surface receptors
for the Fc portion of IgG (CD16) .
Function ; have two important function , kills viral infected cells and tumor cells
by two ways ; antibody-dependent cellular cytotoxicity (ADCC) and NK cell
activity. ADCC is the binding of an opsonized (antibody-coated) target cell to an
Fc receptor–bearing effector cell via the Fc region of antibody, resulting in lysis
of the target by the effector cell.
NK cell cytotoxicity ( death pathway ) , there is down regulation of surface
receptor of virally infected cells and tumor cells so the NK cells will identify them
as non self and react against them .
INITIOTION OF INFLAMMATORY RESPONSE
Steps ;
1-cell recruitment ;it the movement of the cells toward the site of inflammation ,
its due to the release of chemo attractant substance .
Types and source ;
-from bacterial cell wall
-leukotriene B4 from mast cell
-chemo attractant cytokine from macrophage
-C5a from activation of complement
These substance cause migration of phagocytic cells by three mechanism
a-up regulation of neutrophil adhesion molecules (L-selection, integrin .
leucocyte functional antigen -1 ) which increase stickiness of cells
32. 32
b-increased expression of adhesion molecules in vascular cells (E-selection ,
intracellular adhesion molecules ) tethering and rolling of neutrophil along the
endothelium then stopping of movement and diapedesis
c-chemo taxis ; the movement of the cell in the tissue to the site of inflammation
2-phagocytosis and intracellular killing ; the cells ingest the organism by
formation of pseudopodia , they form vesicle in cytoplasm of cells called
phagosome which fuse with cytoplasmic lysosome to form phagolysosome
Intracellular killing occur by two mechanism ;
- Oxygen dependent response (respiratory burst ) , its due to the
production of reactive oxygen metabolites as hydrogen peroxide
via reduction of oxygen by cytochrome dependent NADPH oxidase
- Oxygen independent , due to release of neutrophil cytoplasmic
granules
Adaptive immune system
function ;
33. 33
the recognition of specific “non-self” antigens in the presence of “self”,
during the process of antigen presentation.
the generation of responses that are tailored to maximally eliminate
specific pathogens or pathogen infected cells.
the development of immunological memory, in which each pathogen is
“remembered” by a signature antibody. These memory cells can be called
upon to quickly eliminate a pathogen should subsequent infections occur.
types
1) cellular
2) humeral
Cellular ;
T- lymphocyte ; T cells or T lymphocytes belong to a group of white
blood cells known as lymphocytes, and play a central role in cell-mediated
immunity. They can be distinguished from other lymphocytes, such as B
cells and natural killer cells (NK cells), by the presence of a T cell receptor
(TCR) on the cell surface. They are called T cells because they mature in
the thymus. There are several subsets of T cells, each with a distinct
function
Development in the thymus ; All T cells originate from hematopoietic
stem cells in the bone marrow. Hematopoietic progenitors derived from
hematopoietic stem cells populate the thymus and expand by cell division
to generate a large population of immature thymocytes. The earliest
thymocytes express neither CD4 nor CD8, and are therefore classed as
double-negative (CD4-CD8-) cells. As they progress through their
development they become double-positive thymocytes (CD4+CD8+), and
finally mature to single-positive (CD4+CD8- or CD4-CD8+) thymocytes that
are then released from the thymus to peripheral tissues.
About 98% of thymocytes die during the development processes in the
thymus by failing either positive selection or negative selection, whereas
the other 2% survive and leave the thymus to become mature
immunocompetent T cells.
Types and function ;
1) helper T –cells (TH cells) assist other white blood cells in
immunologic processes, including maturation of B cells into plasma cells
and memory B cells, and activation of cytotoxic T cells and macrophages.
These cells are also known as CD4+ T cells because they express the CD4
protein on their surface. Helper T cells become activated when they are
presented with peptide antigens by MHC class II molecules, which are
34. 34
expressed on the surface of antigen presenting cells (APCs). Once
activated, they divide rapidly and secrete small proteins called cytokines
that regulate or assist in the active immune response. These cells can
differentiate into one of several subtypes, including TH1, TH2, TH3, TH17,
or TFH, which secrete different cytokines to facilitate a different type of
immune response. Signaling from the APC directs T cells into particular
subtypes.
Four kinds have been identified:
Th1
• These participate in both cell-mediated immunity and
antibody-mediated immunity. They are essential for
controlling such intracellular pathogens as viruses and
certain bacteria, e.g., Listeria and Mycobacterium
tuberculosis (the bacillus that causes tb). They provide
cytokine-mediated "help" to cytotoxic T lymphocytes —
perhaps the body's most potent weapon against
intracellular pathogens.
Th2
• These provide help for B cells and are essential for the
production of IgE antibodies and assist in the production of
some subclasses of IgG as well. Antibodies are needed to
control extracellular pathogens (which — unlike
intracellular parasites — are exposed to antibodies in blood
and other body fluids).
Tfh
• These also provide help to B cells enabling them to develop
into antibody-secreting plasma cells. This occurs in nests of
lymphoid cells — called follicles — in the lymph nodes. The
most abundant helper T cells there are B-cell helpers called
follicular helper T (Tfh) cells.
Th17
• These protect surfaces (e.g., skin, lining of the intestine)
against extracellular bacteria.
Mechanism of activation ;
the helper T – cells recognize antigen presented by antigen presenting cells in
conjunction with MHC molecules class 11 as they have surface receptor for both
antigen and MHC11 ,
Th0
according to type of Ag
types of cytokines
Th1 Th 2
35. 35
It secrete IL2 , IL3 . IFN gamma it secrete IL4 , IL5, IL6
It stimulate primiry the cell mediated , it stimulate hummural immunity
Immunity as cytotoxic T-cells ,NKCs as antibodies production
2) cytotoxic T –cell
types ;- short lived ( it cause lyses of viral infected cell and tumor cells
- long lived ( memory T- cell ) which of two types ;
. Effector memory , it reside in non lymphoid organ and respond
rapidly to repeated pathogenic infection
-central memory , it homes in LN , they replenish long and short
lived T-cells as needed
36. 36
Function ; Cytotoxic T cells (TC
cells, or CTLs) destroy virally infected cells
and tumor cells, and are also implicated in transplant rejection. These
cells are also known as CD8
+
T cells since they express the CD8
glycoprotein at their surface. These cells recognize their targets by
binding to antigen associated with MHC class I, which is present on the
surface of all nucleated cells. Through IL-10, adenosine and other
molecules secreted by regulatory T cells, the CD8
+
cells can be inactivated
to an anergic state, which prevent autoimmune diseases such as
experimental autoimmune encephalomyelitis
Memory T cells are a subset of antigen-specific T cells that persist long-term after
an infection has resolved. They quickly expand to large numbers of effector T
cells upon re-exposure to their cognate antigen, thus providing the immune
system with "memory" against past infections. Memory T cells comprise two
subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM
cells). Memory cells may be either CD4
+
or CD8
+
. Memory T cells typically
express the cell surface protein
Mechanism of activation ; the cytotoxic T- cells recognize antigen by antigen
presenting cells in conjunction with MHC molecules class 1
Regulatory
Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial
for the maintenance of immunological tolerance. Their major role is to shut down
37. 37
T cell-mediated immunity toward the end of an immune reaction and to suppress
auto-reactive T cells that escaped the process of negative selection in the thymus.
also they secrete the most important cytokines ( IL10, TGF beta )
2- Humeral immunity ; Antibodies ;
B cells belong to a group of white blood cells known as lymphocytes, making
them a vital part of the immune system -- specifically the humeral immunity
branch of the adaptive immune system. B cells can be distinguished from other
lymphocytes, such as T cells and natural killer cells (NK cells), by the presence of
a protein on the B cell's outer surface known as a B cell receptor (BCR). This
specialized receptor protein allows a B cell to bind to a specific antigen.
The principal functions of B cells are to make antibodies against antigens, to
perform the role of antigen-presenting cells (APCs), and to develop into memory
B cells after activation by antigen interaction. Recently, a new, suppressive
function of B cells has been discovered.[1]
The abbreviation "B", in B cell, comes from the bursa of Fabricius in birds, where
they mature. In mammals, immature B cells are formed in the bone marrow,
which is used as a backronym for the cells' name.
Figure show the mechanism of activation of B –cells
Function of antibodies ;
6- Elimination of infective organism by ;
- Binding to prevent adhesion and invasion of organism
38. 38
- Opsonization
- Lysis in combination with the complement
7- Antitoxin activity e.g tetanus
8- Sensitization of the cells for antibodies dependent cytotoxicity
9- Immunoregulation by
- Acting as antigen receptor to B- cells
- Presenting antigen to helper T- cells
Types ;
1- IgM ;
- Its large molecules
- Its mainly present intravascular
- Its major antibodies for primary immune response
- It does not cross the placenta
2- IgG ;
- Mainly in the serum
- Its antibodies foe secondary response and has high Ag affinity
- It’s the only antibodies that can cross the placenta
- Its most antibodies for resistance to infection
3- IgA;
- Its present in the serum
- Its antibodies of secretion . it present in the GIT, GUT , RT
4- IgD ;
- Very low serum level ,
- Its function as antigen receptor in the surface of Beta cells , and
may have immunoregulatory rules
5- IgE ;
- Very low amount in the serum as its bound to membrane in mast
cells and basophil
- It has ant parasitic function
Interaction between innate and adaptive immune system
1- Antigen processing and presentation ; types
39. 39
a- Exogenous antigen ; is phagocytized by APCs ( DCs, and macrophage ) and
processed by reticuloendothelial system and exposed in the surface of
cells in conjunction with MHC molecules class 2
b- Endogenous antigen ; is phagocytized by all parenchymal cells and
processed by reticuloendothelial system and exposed in the surface of
cells in conjunction with MHC molecules class 1
2- Antigen recognition ;
Those antigen who are presented in conjunction with MHC molecules class 2 is
recognized by Helper T-cells , while antigen who are presented in conjunction
with MHC molecules class 1 is recognized by cytotoxic T-cells
-
40. 40
2- Autoimmune diseases
Mechanism of control of immune system ;
1-mechanism of control of innate immunity
Humeral ; - suppression of cytokines signaling by family of intracellular
protein
-Adenosine and adenosine phosphate , they decrease the production of
stimulatory cytokines and increase inhibitory cytokines
-control of complement system . inhibition of C1 by C1 estrase ,
inhibition of C3 cleavage by C3 convertase inhibitor , DAF
Cellular ;- the cytokines IL10 and TGFbeta , they inhibit both innate and
adaptive immunity . IL10 directly inhibit macrophage function and indirectly
inhibit NKCS and TH-1
-Tyro 3 family of receptor , they belong to family of tyrosine kinase , they
are responsible for homeostasis regulation of immune system by inhibiting the
magnitude of macrophage and dendritic cells activation after stimulation
-control of phagocytic cells by apoptosis , and DCS
2-mechanism of control of adaptive immunity
By immunological tolerance ;
- Definition ; it’s the ability of the immune system to react against
non-self-antigen and to ignore self-antigen
- Types
1- Central tolerance ; this takes place in the thymus where the
auto reactive T-cells are destroyed in the thymus by
macrophage and DCs
2- Peripheral tolerance ; the auto reactive T-cells that escape
central deletion undergo peripheral tolerance by one of
following mechanisms
- Anergy ; its functional inactivation of T- cells , its due to secretion
of small amount of costimulatory molecules which is enough to
keep cells alive but not enough for function
- Suppression by regulatory T-cells
- Clonal deletion (apoptosis )
- Antigen sequestration
3-risk factors of autoimmune diseases ;
41. 41
a- Rules of genes ;
—
MHC molecules gene ; mechanism ;
—
variation in the ability of different allelic variation of MHC to present auto
antigen peptide to auto reactive T-cells or specific MHC gene product may
be them self the source of peptide
—
Phosphatase gene expressed by verity of hematopoietic cells that dawn
regulate Ag . receptor mediated stimulation . loss of function of this gene
are associated with autoimmune diseases
—
Inherited homogenous deficiency of early protein of classic pathway of
complement
—
Abnormality in the gene encoding in regulation of apoptosis
—
B- sex and environmental factors
—
Autoimmune diseases is common in female , which is explained by .
—
- large inflammatory response in female
—
- decreased production of immunosuppressive cytokines
—
- imbalanced X-chromosome activation
—
Mechanism of autoimmune diseases ;
- Exogenous ;
1- Molecular mimicry ( cross reactivity )
2- Super antigen stimulation ; super antigen is antigen that is
capable of stimulation of adaptive immune system without
need to be presented by APCs , e,g ;staphylococcal
enterotoxin
- Endogenous
1- Altered antigen presentation
- Loss of immunological privilege; some antigen are hidden in
certain immunologically privileged sites as brain and eyes and
testes , so its not recognized by immune system as self , damage to
this sites will results in release of these antigen so immune system
will recognize them as non self and react against them , for
example , multiple sclerosis , external opthalmoplagia , and orchitis
- Alteration of self antigen ; this is due to damage of self antigen by
drugs or toxin so the immune system will recognize them as non
self and react against them ; for example , autoimmune drug
induced hemolytic anaemia
2- increased T- cell help ; due to
- Cytokines overproduction
- Incretion production of costimulatory molecules
3- Increased B- cell function . due to
- Cytokines overproduction
- Incretion production of costimulatory molecules
42. 42
4-cytokinmes imbalance
- Over expression as in ( IBD , Arthritis , vasculitis )
- Under expression as in ( SLE , IBD)
5-apoptotioc defect ; apoptosis plays important rule in
regulation of normal immune response to antigen ;
Function of apoptosis ;
- Eliminate microbe infected cells
- Eliminate cells with damaged DNA
- Eliminate activated immune cells that are no longer needed
Types of diseases due to apoptotic defect ;
- Autoimmune diseases ; as SLE , lymphoproliferative diseases
- Cancer diseases
6-defect in the regulatory cells
Mechanism of tissue damage ;
1- Autoantibodies mediated damage acts by ;
- Blocking and inactivating . example ;
Ant acetylcholine receptor antibodies ( MG)
Antiphosphlipid B glycoprotein complex (antiphospholipidsyndrome )
Anti insulin receptor ( insulin resistance )
Anti intrinsic factors ( pernicious anaemia )
- Stimulation ,example
TSH receptor antibodies ( graves diseases )
ANCA ( Wagner's granulomatosis
- Complement activation , example
Good pasture syndrome
- Immune complex formation , example
GN
Anti double strand DNA
- Opsonization , example
Plat.111b|11a ,autoimmune thrombocytopenia
Rh Ag , I Ag , autoimmune hemolytic anaemia
- Antibodies dependent cellular cytotoxicity
Ant thyroid peroxidase antibodies ( hashimotos thyroiditis )
Ant thyroglobulin Abs
2- cellular mediated
- Cytokine production , examples ( RA , type I DM , MS )
- Cellular cytotoxicity as type 1 DM
43. 43
Types of autoimmune diseases ;
1- Organ specific ;
- CNS , ( MS, GBS , MG, stiff man syndrome )
- CVD as ARF , MI
- Chest as good pasture syndrome
- Endocrine ; as type 1 DM , Addison syndrome , Gravis diseases ,
Hashimotos thyroiditis , autoimmune polygladular failure
syndrome , immune mediated infertility
- Blood , example , autoimmune thrombocytopenia , hemolytic
anaemia
- GIT . example , IBD, AIH , Primary biliary cirrhosis , pernicious
anaemia
- Renal , GPS , GN
2- organ non specific ( systemic )
SLE , RA, Scleroderma , polymyocytis , vacuities , Sjogrean syndrome , APL
syndrome
Diagnosis of autoimmune diseases ;
There are three criteria for diagnosis
1- The presence of autoantibodies ;
Table 3- summarize different types of autoantibodies
Table 3. Recombinant or Purified Autoantigens Recognized by Autoantibodies
Associated with Human Autoimmune Disorders
Autoantigen Autoimmune
Diseases
Autoantigen Autoimmune
Diseases
Cell- or Organ-Specific Autoimmunity
Acetylcholine
receptor
Myasthenia gravis Insulin
receptor
Type B insulin
resistance,
acanthosis, systemic
lupus erythematosus
(SLE)
Actin Chronic active
hepatitis, primary
biliary cirrhosis
Intrinsic
factor type 1
Pernicious anemia
Adenine nucleotide
translator (ANT)
Dilated
cardiomyopathy,
myocarditis
Leukocyte
function-
associated
antigen (LFA-
Treatment-resistant
Lyme arthritis
46. 46
nucleoside-stimulated
ATPase
polymerase I–
III (RNP)
SLE
Fibrillarin Scleroderma Signal
recognition
protein
(SRP54)
Polymyositis
Fibronectin SLE, RA, morphea Topoisomeras
e-1 (Scl-70)
Scleroderma,
Raynaud syndrome
Glucose-6-phosphate
isomerase
RA Tublin Chronic liver disease,
visceral leishmaniasis
2-Glycoprotein I
(B2-GPI)
Primary
antiphospholipid
syndrome
Golgin (95, 97, 160,
180)
Sjögren’s
syndrome, SLE,
RA
Vimentin Systemic
autoimmune disease
Heat shock protein Various immune-
related disorders
Hemidesmosomal
protein 180
Bullous
pemphigoid,
herpes
gestationis,
cicatricialpemphi
goid
Plasma Protein and
Cytokine
Autoimmunity
C1 inhibitor Autoimmune C1
deficiency
Glycoprotein
IIb/IIIg and
Ib/IX
Autoimmune
thrombocytopenia
purpura
C1q SLE, membrane
proliferative
glomerulonephriti
s (MPGN)
IgA Immunodeficiency
associated with SLE,
pernicious anemia,
thyroiditis, Sjögren’s
syndrome and
chronic active
hepatitis
Cytokines (IL-1 ,
IL-1 , IL-6, IL-10,
LIF)
RA, systemic
sclerosis, normal
subjects
Factor II, factor V,
factor VII, factor VIII,
factor IX, factor X,
Prolonged
coagulation time
Oxidized LDL
(OxLDL)
Atherosclerosis
47. 47
factor XI, thrombin
vWF
Cancer and
Paraneoplastic
Autoimmunity
Amphiphysin Neuropathy, small
cell lung cancer
p62 (IGF-II
mRNA-
binding
protein)
Hepatocellular
carcinoma (China)
Cyclin B1 Hepatocellular
carcinoma
Recoverin Cancer-associated
retinopathy
DNA topoisomerase II Liver cancer Ri protein Paraneoplasticopsocl
onus myoclonus
ataxia
Desmoplakin Paraneoplastic
pemphigus
Gephyrin Paraneoplastic
stiff-person
syndrome
IV
spectrin
Lower motor neuron
syndrome
Hu proteins Paraneoplastic
encephalomyelitis
Synaptotagmi
n
Lambert-Eaton
myasthenic syndrome
Neuronal nicotinic
acetylcholine receptor
Subacute
autonomic
neuropathy,
cancer
Voltage-gated
calcium
channels
Lambert-Eaton
myasthenic syndrome
p53 Cancer, SLE Yo protein Paraneoplastic
cerebellar
degeneration
Source: From A Lernmark et al: J Clin Invest 108:1091, 2001; with permission.
2- Histological evidence of infiltration of tissue by immune
cells
3- If these autoantibodies can cross the placenta it can
induce autoimmune diseases to the fetus
Treatment of autoimmune diseases ;
1- Corticosteroids
2- Immunosuppressive drugs
3- Biological therapy ;
Immunotherapy Many therapies for autoimmune and inflammatory diseases
involve the use of nonspecific immune-modulating or immunosuppressive agents
such as glucocorticoids or cytotoxic drugs. The goal of development of new
48. 48
treatments for immune-mediated diseases is to design ways to specifically
interrupt pathologic immune responses, leaving nonpathologic immune
responses intact. Novel ways to interrupt pathologic immune responses that are
under investigation include the use of anti-inflammatory cytokines or specific
cytokine inhibitors as anti-inflammatory agents, the use of monoclonal
antibodies against T or B lymphocytes as therapeutic agents, the induction of
anergy by administration of soluble CTLA-4 protein, the use of intravenous Ig for
certain infections and immune complex–mediated diseases, the use of specific
cytokines to reconstitute components of the immune system, and bone marrow
transplantation to replace the pathogenic immune system with a more normal
immune system (Chaps. 60, 316, and 189). In particular, the use of a monoclonal
antibody to B cells (rituximab, anti-CD20 MAb) is approved in the United States
for the treatment of non-Hodgkin's lymphoma (Chap. 110) and, in combination
with methotrexate, for treatment of adult patients with severe rheumatoid
arthritis resistant to TNF- inhibitors
—
Cytokines and Cytokine Inhibitors
. Use of anti-TNF- antibody therapy has resulted in clinical improvement in
patients with these diseases and has opened the way for targeting TNF- to treat
other severe forms of autoimmune and/or inflammatory disease. Blockage of
TNF- has been effective in rheumatoid arthritis, psoriasis, Crohn's disease, and
ankylosing spondylitis. Anti-TNF- MAb (infliximab) has been approved by the FDA
for treatment of patients with rheumatoid arthritis.
Other cytokine inhibitors are recombinant soluble TNF- receptor (R) fused to
human Ig and Anakinra (soluble IL-1 receptor antagonist, or IL-1 ra). The
treatment of autoinflammatory syndromes (Table 314-6) with recombinant IL-1
receptor antagonist can prevent symptoms in these syndromes, since the
overproduction of IL-1 is a hallmark of these diseases. Soluble TNF-R
(etanercept) and IL-1 ra act to inhibit the activity of pathogenic cytokines in
rheumatoid arthritis, i.e., TNF- and IL-1, respectively. Similarly, anti-IL-6, IFN-,
and IL-11 act to inhibit pathogenic proinflammatory cytokines. Anti-IL-6 inhibits
IL-6 activity, while IFN- and IL-11 decrease IL-1 and TNF- production
—
Monoclonal antibodies ; Monoclonal Antibodies to T and B Cells
Crohn's disease, and anti–IL-12/IL-23p40 antibody therapy has
been studied as a treatment.
—
The OKT3 MAb against human T cells has been used for several years as a T cell–
specific immunosuppressive agent that can substitute for horse anti-thymocyte
globulin (ATG) in the treatment of solid organ transplant rejection. OKT3
produces fewer allergic reactions than ATG but does induce human anti-mouse Ig
antibody—thus limiting its use. Anti-CD4 MAb therapy has been used in trials to
treat patients with rheumatoid arthritis. While inducing profound
immunosuppression, anti-CD4 MAb treatment also induces susceptibility to
severe infections. Treatment of patients with a MAb against the T cell molecule
CD40 ligand (CD154) is under investigation to induce tolerance to organ
transplants, with promising results reported in animal studies. Monoclonal
antibodies to the CD25 (IL-2) receptor (Basiliximab) are being used for
49. 49
treatment of graft-versus-host disease in bone marrow transplantation, and anti-
CD20 MAb (rituximab) is used to treat hematologic neoplasms, autoimmune
diseases, and kidney transplant rejection. The anti-IgE monoclonal antibody
(omalizumab) is used for blocking antigen-specific IgE that causes hay fever and
allergic rhinitis (Chap. 317); however, side effects of anti-IgE include increased
risk of anaphylaxis. Studies have shown that Th
17 cells, in addition to Th
1, are
mediators of inflammation in
Examples of cytokines ;
50. 50
Examples of cytokines inhibitors
—
—
3-IMMUNODEFFICIENCY DISEASES ;
1- Deficiency of innate immune system
a- Defect in the cells ;
- Defect in the neutrophil number ;
Congenital ;its due to defect in the maturation and release of neutrophil
from bone marrow , its rare and mild diseases , benign variant of
congenital neutropenia called cyclic neutropenia in which there is
repeated cycle of neutropenia every 3-5 weeks
Acquired
- Decreased production due to bone marrow suppression by ; drugs
, diseases as leukemia , aplastic anemia , chemical
- Increased destruction ; as in hypersplenism . autoimmune , drugs
Common organism ;
- Bacterial as staphylococcal , E-coli , Klabsiela , Proteus ,
Psedomonus , Bacteroids
- Fungal
Clinical presentation ; bacteremia , septicemia , fungemia . local infection , there
is no or mild pus formation
51. 51
Treatments ;
- Try to decrease the dose of immunosuppressive drugs
- Use of GCSF, GMCSF
- Prophylactic anti bacterial and anti fungal
-defect in the neutrophil function ; causes;
- Congenital ;
Leucocyte adhesion defect ; its autosomal recessive diseases due to defect
in the synthesis of adhesion molecules
Hyper immunoglobulin E syndrome ; its characterized by ;
- Very high level if IgE
- Impaired neutrophil locomotion
- Eczema
- Frequent staphylococcal infection and abscess
Chronic granulomatous diseases ; its autosomal recessive disorders
characterized by defective generation of free radical due to deficiency in
the cytochrome dependent NADPH oxidase leads to defective oxidative
pathway of intracellular killing
Age ; early or late child hood
Clinical picture ; chronic granulomatous suppuration in the LN , spleen . liver ,
bone , skin
Diagnosis ; use of nitro blue tetrazolim test , this test is used to asses the
oxidative pathway
Treatments ; antibiotics , use of IFNgregularly to increase monocyte ,
macrophage killing
. –acquired ;
a- Steroid therapy ; it impair vascular endothelial cell adhesion molecules
b- Influenza infection ; it impairsphagolyzosome fusion
c- DM
d- Myeloid leukemia
e- Hypophosphatemia
f- Hodgkin lymphoma
g- Liver cirrhosis
Clinical picture ;
Mucocutenous sepsis in the mouth and perianal area . chronic abscess in tissue
and LN
b-complement deficiency ;
- Deficiency of C3 and C1q
- Deficiency of lytic component pathway
- MP lectin deficiency
Its present clinically with recurrent infection with capculated bacterial
infection
2-defficiency of the adaptive immune system
a- Antibody deficiency
- Congenital ;
52. 52
1-X-linked hypogammaglobelenemia ; its X- linked diseases characterized by
defect of differentiation of pro B-cells to B-cells leads to decreased Ig , B-cells and
plasma cells while T-cells is normal
C-P ; age ( 3-6 months )
Recurrent bacterial infection
No viral infection
Rare fungal infection
Treatment by Ig replacement
2- common variable immunodeficiency
Its due to defective interaction between B-cells and T- cells lead to arrested
maturation of B- cells .
Characteristic ; - Ig deficiency specially IgG .
-normal B-cells number and normal T-cells
Age ; old child hood and adult
C-P ; - increased susceptibility to infection
-hyperplasia of LN
-autoimmune diseases
-malignancy of LN
Diagnosis ; Ig deficiency
-normal B-cells number
Treatment ; Ig
3-IgA deficiency ; its very common
C-P ; no symptom , or recurrent infection , allergy and autoimmune diseases
-Acquired ;
a- myeloma , lymphoma
b-splenectomy
c-congenital rubella
b-T-cells deficiency
1- Congenital ;
- DiGeorge anomaly
- IL 2defficiency
- Signal transduction defect
- MHC molecules class 2 deficiency
2-acquired ;
- HIV
- Measles
- Immunosuppressive drugs
- Steroid
Clinical evaluation of immune function ;
done by investigation of all four major component of immune system ;
- Humeral ( B- cells)
- Cell mediated ( T-cells , macrophage )
- Phagocytic cells
- Complement
Indication for evaluation ;
- Recurrent infection
- Chronic infection
- Infection with unusual pathogen
53. 53
- Autoimmune diseases
Laboratory evaluation
a- Initial screening tests ;
- CBC total and differential
- Serum Ig level
b- Specific ;
1-Humeral ( B-cells )
Assessment of B- cells function ; by measurement of serum immunoglobulin , and
response to immunization with protein ( tetanus protein )
Assessment of B-cells number by ;
- Membrane bound Ig
- Detecting surface receptor by monoclonal antibodies ( CD19,
CD20)
2-cell mediated ;
- Assessment of T-cells number ; by detecting surface receptor by
monoclonal antibodies as ;
CD 3for all cells
CD4 for helper T-cells
CD8 for cytotoxic T-cells
-assessment of T-cells function ; by delayed hypersensitivity skin test as
PPD
3-phagocytic function ; reduction of nitro blue tetrazolim test
4-complement
- CH50 assay ( for classic and alternative pathway )
- C3 , C4 , and other component
4- Hypersensitivity reaction
MECHANISMS OF HYPERSENSITIVITY REACTIONS
Individuals who have been previously exposed to an antigen are said to be
sensitized. Sometimes, repeat exposures to the same antigen trigger a pathologic
reaction; such reactions are described as hypersensitivity, implying an excessive
response to antigen. There are several important general features of
hypersensitivity disorders.
• Both exogenous and endogenous antigens may elicit hypersensitivity
reactions. Humans live in an environment teeming with substances capable
of eliciting immune responses. Exogenous antigens include those in dust,
pollens, foods, drugs, microbes, chemicals, and some blood products that
are used in clinical practice. The immune responses against such exogenous
antigens may take a variety of forms, ranging from annoying but trivial
discomforts, such as itching of the skin, to potentially fatal diseases, such as
bronchial asthma and anaphylaxis. Injurious immune reactions may also be
evoked by endogenous tissue antigens. Immune responses against self, or
54. 54
autologous, antigens, cause the important group of autoimmune diseases.
• The development of hypersensitivity diseases (both allergic and autoimmune
disorders) is often associated with the inheritance of particular susceptibility
genes. HLA genes and many non-HLA genes have been implicated in
different diseases; specific examples will be described in the context of the
diseases.
• A general principle that has emerged is that hypersensitivity reflects an
imbalance between the effector mechanisms of immune responses and the
control mechanisms that serve to normally limit such responses. We will
return to this concept when we consider autoimmunity.
Types of hypersensitivity reaction ;
a-Immediate (Type I) Hypersensitivity
Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring
within minutes after the combination of an antigen with antibody bound to mast
cells in individuals previously sensitized to the antigen. These reactions are often
called allergy, and the antigens that elicit them are allergens. Immediate
hypersensitivity may occur as a systemic disorder or as a local reaction. The
systemic reaction usually follows injection of an antigen into a sensitized
individual. Sometimes, within minutes the patient goes into a state of shock,
which may be fatal. Local reactions are diverse and vary depending on the portal
of entry of the allergen. They may take the form of localized cutaneous swellings
(skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis and
conjunctivitis), hay fever, bronchial asthma, or allergic gastroenteritis (food
allergy)..
Risk factors ;
1- Genetic (atopic ) , if one parent is atopic the child has 25-
40% chance of being atopic , if both parents are affected the
child has 50-75% chance of being atopic , the exact atopic
gene is not known .
2- Environmental factors ;
- Age ;exposure to allergen in the first few years
- Intercurrent infection , as RTI
- Non specific irritant ; as pollutant , cigerrete
3-immune deficiency; it causes hypersensitivity by ;
-greater allergen exposures
-decreased T-cells regulation of IgE production
Regulation of IgE production ;
55. 55
Th1 Th2
INF gamma , IL2 IL4,IL5
INFgamma , IL2 suppress the IG production by B-cells
IL4 is switch factors of B-cells to produce IgE ,
IL5 increase eosinophil production
So Th2 is the drive for atopic response while Th1 suppress it
Mechanism of allergic diseases ;
When allergen enter to the body it will bind to receptor in the B-cells it will
activates and release IgE , which will bind to receptor in the mast cells leads to its
activation and release of inflammatory mediators which is of two types ;
Preformed Mediators.
Mediators contained within mast cell granules are the first to be released, and
can be divided into three categories:
• Vasoactive amines. The most important mast cell–derived amine is
histamine. Histamine causes intense smooth muscle contraction, increased
vascular permeability, and increased mucus secretion by nasal, bronchial,
and gastric glands.
• Enzymes. These are contained in the granule matrix and include neutral
proteases (chymase, tryptase) and several acid hydrolases. The enzymes
cause tissue damage and lead to the generation of kinins and activated
components of complement (e.g., C3a) by acting on their precursor
proteins.
• Proteoglycans. These include heparin, a well-known anticoagulant, and
chondroitin sulfate. The proteoglycans serve to package and store the
amines in the granules.
Newly formed mediators (Lipid Mediators).
The major lipid mediators are synthesized by sequential reactions in the mast cell
membranes that lead to activation of phospholipase A2, an enzyme that acts on
membrane phospholipids to yield arachidonic acid. This is the parent compound
from which leukotrienes and prostaglandins are derived by the 5-lipoxygenase
and cyclooxygenase pathways
56. 56
• Leukotrienes. Leukotrienes C4 and D4 are the most potent vasoactive and
spasmogenic agents known. On a molar basis, they are several thousand
times more active than histamine in increasing vascular permeability and
causing bronchial smooth muscle contraction. Leukotriene B4 is highly
chemotactic for neutrophils, eosinophils, and monocytes.
• Prostaglandin D2. This is the most abundant mediator produced in mast
cells by the cyclooxygenase pathway. It causes intense bronchospasm as
well as increased mucus secretion.
• Platelet-activating factor (PAF). PAF is produced by some mast cell
populations. It causes platelet aggregation, release of histamine,
bronchospasm, increased vascular permeability, and vasodilation. In
addition, it is chemotactic for neutrophils and eosinophils, and at high
concentrations it activates the inflammatory cells, causing them to
degranulate. Although the production of PAF is also triggered by the
activation of phospholipase A2, it is not a product of arachidonic acid
metabolism.
Cytokines.
Mast cells are sources of many cytokines, which may play an important role at
several stages of immediate hypersensitivity reactions. The cytokines include:
TNF, IL-1, and chemokines, which promote leukocyte recruitment (typical of the
late-phase reaction); IL-4, which amplifies the TH2 response; and numerous
others. The inflammatory cells that are recruited by mast cell–derived TNF and
chemokines are additional sources of cytokines and of histamine-releasing
factors that cause further mast cell degranulation..
2-autoimmunity ( type 2 hypersensitivity )
3-Immune Complex–Mediated (Type III) Hypersensitivity
Antigen-antibody complexes produce tissue damage mainly by eliciting
inflammation at the sites of deposition. The pathologic reaction is initiated when
antigen combines with antibody within the circulation (circulating immune
complexes), and these are deposited typically in vessel walls .Sometimes the
complexes are formed at extravascular sites where antigen may have been
“planted” previously (called in situ immune complexes). The antigens that form
immune complexes may be exogenous, such as a foreign protein that is injected
or produced by an infectious microbe, or endogenous, if the individual produces
antibody against self-components (autoimmunity). Examples of immune
complex disorders and the antigens involved are listed in. Immune complex–
mediated diseases can be systemic, if immune complexes are formed in the
circulation and are deposited in many organs, or localized to particular organs,
such as the kidney (glomerulonephritis), joints (arthritis), or the small blood
vessels of the skin if the complexes are deposited or formed in these tissues.
-- Examples of Immune Complex–Mediated Diseases
57. 57
Disease Antigen Involved
Clinicopathologic
Manifestations
Systemic lupus
erythematosus
Nuclear antigens Nephritis, skin lesions,
arthritis, others
Poststreptococcal
glomerulonephritis
Streptococcal cell wall
antigen(s); may be “planted” in
glomerular basement
membrane
Nephritis
Polyarteritisnodosa Hepatitis B virus antigens in
some cases
Systemic vasculitis
Reactive arthritis Bacterial antigens (e.g.,
Yersinia)
Acute arthritis
Serum sickness Various proteins, e.g., foreign
serum protein (horse anti-
thymocyte globulin)
Arthritis, vasculitis,
nephritis
Arthus reaction
(experimental)
Various foreign proteins Cutaneous vasculitis
Mechanism of formation of immune complex diseases
Immune complex are often formed in healthy individual for examples after
eating antibodies against food antigen , normally they are cleared by
- Attach to receptor in RBC and removed by liver and spleen
- Cleared by complement
If they persist it can causese diseases
Pathogenesis ;
Ag , Abs complex
Activation of the classic pathway of complement
Release of C3a and C5a
Increased expression of adhesion molecules on surface of endothelial cells and
on the neutrophil
Adhesion of neutrophil to vascular endothelium
Activation of neutrophil by binding of Abs to FC receptor and binding of C3a to
CR on surfice of neutrophil
58. 58
Tissue damage by release of oxygen free radical
Also the inflammatory mediators cause separation of vascular endothelial cells ,
so the neutrophil and immune complex will pass to the tissue
Immune complex deposition
Sites ;
1- In the wall of vessels at sites of turbulent blood flow ( at
bifurcation of vessels )
2- At high hydrostatic pressure gradient ( glomeruli , and
synovium )
Effects ;
- Inflammation of large vessels with micro aneurism formation ( eg,
polyarteritisnodosa )
- Inflammation of small vessels , platelets activation by immune
complex , microthrombous formation leads to tissue infarction (
MI, stroke )
4-type 4 ( delayed hypersensitivity reaction )
-- Examples of T Cell–Mediated (Type IV) Hypersensitivity
Disease
Specificity of Pathogenic
T Cells
Clinicopathologic
Manifestations
Type 1 diabetes
mellitus
Antigens of pancreatic islet
β cells (insulin, glutamic
acid decarboxylase, others)
Insulitis (chronic inflammation
in islets), destruction of β cells;
diabetes
Multiple sclerosis Protein antigens in CNS
myelin (myelin basic
protein, proteolipid
protein)
Demyelination in CNS with
perivascular inflammation;
paralysis, ocular lesions
Rheumatoid
arthritis
Unknown antigen in joint
synovium (type II
collagen?); role of
antibodies?
Chronic arthritis with
inflammation, destruction of
articular cartilage and bone
Crohn disease Unknown antigen; role for
commensal bacteria
Chronic intestinal
inflammation, obstruction
59. 59
Disease
Specificity of Pathogenic
T Cells
Clinicopathologic
Manifestations
Peripheral
neuropathy;
Guillain-Barré
syndrome?
Protein antigens of
peripheral nerve myelin
Neuritis, paralysis
Contact sensitivity
(dermatitis)
Various environmental
antigens (e.g., poison ivy)
Skin inflammation with
blisters
CNS, central nervous system.
Pathogenesis ;
The cellular events in T cell–mediated hypersensitivity consist of a series of
reactions in which cytokines play important roles. The reactions can be divided
into the following stages.
Proliferation and Differentiation of CD4+ T Cells.
Naive CD4+ T cells recognize peptides displayed by dendritic cells and secrete IL-
2, which functions as an autocrine growth factor to stimulate proliferation of the
antigen-responsive T cells. The subsequent differentiation of antigen-stimulated
T cells to TH1 or TH17 cells is driven by the cytokines produced by APCs at the
time of T-cell activation . In some situations the APCs (dendritic cells and
macrophages) produce IL-12, which induces differentiation of CD4+ T cells to the
TH1 subset. IFN-γ produced by these effector cells promotes further TH1
development, thus amplifying the reaction. If the APCs produce inflammatory
cytokines such as IL-1, IL-6, and a close relative of IL-12 called IL-23, these work
in collaboration with transforming growth factor-β (TGF-β) (made by many cell
types) to stimulate differentiation of T cells to the TH17 subset. Some of the
differentiated effector cells enter the circulation and may remain in the memory
pool of T cells for long periods, sometimes years.
Responses of Differentiated Effector T Cells.
Upon repeat exposure to an antigen, previously activated T cells recognize the
antigen displayed by APCs and respond. TH1 cells secrete cytokines, mainly IFN-
γ, which are responsible for many of the manifestations of delayed-type
hypersensitivity. IFN-γ–activated macrophages are altered in several ways: their
ability to phagocytose and kill microorganisms is markedly augmented; they
express more class II MHC molecules on the surface, thus facilitating further
antigen presentation; they secrete TNF, IL-1, and chemokines, which promote
inflammation ,and they produce more IL-12, thereby amplifying the TH1
response. Thus, activated macrophages serve to eliminate the offending antigen;
if the activation is sustained, continued inflammation and tissue injury result.
TH17 cells are activated by some microbial antigens and by self-antigens in
autoimmune diseases. Activated TH17 cells secrete IL-17, IL-22, chemokines, and
several other cytokines. Collectively, these cytokines recruit neutrophils and
60. 60
monocytes to the reaction, thus promoting inflammation. TH17 cells also produce
IL-21, which amplifies the TH17 response.
The classic example of DTH is the tuberculin reaction, which is produced by the
intracutaneous injection of purified protein derivative (PPD, also called
tuberculin), a protein-containing antigen of the tubercle bacillus. In a previously
sensitized individual, reddening and induration of the site appear in 8 to 12
hours, reach a peak in 24 to 72 hours, and thereafter slowly subside.
Morphologically, delayed-type hypersensitivity is characterized by the
accumulation of mononuclear cells, mainly CD4+ T cells and macrophages,
around venules, producing perivascular “cuffing” In fully developed lesions, the
venules show marked endothelial hypertrophy, reflecting cytokine-mediated
endothelial activation.
.
Contact dermatitis is a common example of tissue injury resulting from DTH
reactions. It may be evoked by contact with urushiol, the antigenic component of
poison ivy or poison oak, and presents as a vesicular dermatitis
Reactions of CD8+ T Cells: Cell-Mediated Cytotoxicity
In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-bearing target
cells. Tissue destruction by CTLs may be an important component of many T
cell–mediated diseases, such as type 1 diabetes. CTLs directed against cell
surface histocompatibility antigens play an important role in graft rejection, to
be discussed later. They also play a role in reactions against viruses. In a virus-
infected cell, viral peptides are displayed by class I MHC molecules and the
complex is recognized by the TCR of CD8+ T lymphocytes. The killing of infected
cells leads to the elimination of the infection, and is responsible for cell damage
that accompanies the infection (e.g., in viral hepatitis). Tumor-associated
antigens are also presented on the cell surface, and CTLs are involved in tumor
rejection
The principal mechanism of T cell–mediated killing of targets involves perforins
and granzymes, preformed mediators contained in the lysosome-like granules of
CTLs. CTLs that recognize the target cells secrete a complex consisting of
perforin, granzymes, and a protein called serglycin, which enters target cells by
endocytosis. In the target cell cytoplasm, perforin facilitates the release of the
granzymes from the complex. Granzymes are proteases that cleave and activate
caspases, which induce apoptosis of the target cells .Activated CTLs also express
Fas ligand, a molecule with homology to TNF, which can bind to Fas expressed on
target cells and trigger apoptosis.
CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in
inflammatory reactions resembling DTH, especially following virus infections
and exposure to some contact sensitizing agents.
