2.
The immune system recognizes the presence of pathogens by
several proteins that bind to molecules secreted by the
pathogen or carried on their surface.
The cells responsible for these immune responses include:
a)
c)
e)
g)
B-Cells
Macrophages
Basophils
Endothelial cells
b)
d)
f)
h)
T-Cells
Neutrophils
Eosinophils
Mast cells
These cells have distinct roles in the immune system and
communicate with other immune cells by cytokines, which
control proliferation, differentiation and function of cells of
the immune system.
3.
4.
The development of an effective immune response involves
lymphoid cells, inflammatory cells, and hematopoietic cells.
The complex interactions among these cells are mediated by a
group of proteins collectively designated cytokines to denote
their role in cell-to-cell communication.
Cytokines / immunocytokines (Greek , cyto =‘cell’ & kinos
=‘movement’) are low molecular weight regulatory proteins or
glycoproteins secreted by white blood cells and various other
cells in the body in response to a number of stimuli.
5.
Cytokines bind to specific receptors on
the membrane of target cells, triggering
signal-transduction
pathways
that
ultimately alter gene expression in the
target cells.
The cytokines and their fully assembled
receptors exhibit very high affinity for
each other and deliver intracellular
signals.
The cytokines and their receptors exhibit
very high affinity for each other, with
dissociation constants ranging from
10 –10 to 10 –12 M.
Because their affinities are so high,
cytokines can mediate biological effects
at picomolar concentrations.
6.
A particular cytokine may
bind to receptors on the
membrane of the same cell
that secreted it, exerting
autocrine action.
It may bind to receptors on a
target cell in close proximity
to the producer cell, exerting
paracrine action.
In a few cases, it may bind to
target cells in distant parts of
the body, exerting endocrine
action
7.
Cytokines exhibit
the attributes of:
Pleiotropy,
Redundancy,
Synergy,
Antagonism,
cascade
induction,
which
permit
them to regulate
cellular activity
in a coordinated,
interactive way.
8. •Two or more cytokines that mediate similar functions are said to be redundant.
•Cytokine synergism occurs when the combined effect of two cytokines on cellular
activity.
• antagonism that is, the effects of one cytokine inhibit or offset the effects of another
cytokine.
9.
Interleukins - that act as mediators between leukocytes. The
vast majority of these are produced by T-helper cells.
Lymphokines - produced by lymphocytes.
Monokines - produced exclusively by monocytes.
Interferons - involved in antiviral responses.
Colony Stimulating Factors - support the growth of cells blood
cell .
Chemokines - mediate chemoattraction (chemotaxis) between
cells.
10.
Cytokines have been classified on the basis of their biological
responses into pro or anti-inflammatory cytokines, depending
on their effects on immunocytes .
Major cytokines include:
Lymphokines
Interleukins (IL)
Monokines
Interferons (IFN)
colony stimulating factors (CSF)
Tumor Necrosis Factors-Alpha and Beta (TNF)
11. # Type-1 & Type-2
Type-1 cytokines are cytokines produced by Th1 T-helper cells.
Include IL-2 (IL2), IFN-gamma (IFN-G), IL-12 (IL12) & TNFbeta (TNF-b).
Type-2 cytokines are those produced by Th2 T-helper cells.
Include IL-4 (IL4), IL-5 (IL5), IL-6 (IL6), IL-10(IL10), and IL-13
(IL13).
# Mediators of natural immunity:
TNF-α, IL-1, IL-10, IL-12, type I interferons (IFN-α and IFN-β),
IFN-γ, and chemokines.
# Mediators of adaptive immunity:
IL-2, IL-4, IL-5, TGF-β, IL-10 and IFN-γ.
12. # Classified into family groups according to the types of
secondary and tertiary structure.
IL-6 (IL6), IL-11 (IL11), CNTF (C-NTF), LIF, OSM (OncostatinM), EPO (Erythropoietin), G-CSF (GCSF), GH (Growth
Hormone), PRL (Prolactin), IL-10 (IL10), IFN-alpha (IFN-A),
IFN-beta (IFN-B) form long chain 4 helix bundles.
IL-2 (IL2), IL-4 (IL4), IL-7 (IL7), IL-9 (IL9), IL-13 (IL13), IL-3
(IL3), IL-5 (IL5), GM-CSF (GMCSF), M-CSF (MCSF), SCF, IFNgamma (IFNG) form short chain 4 helix bundles.
Beta foil structures are formed by IL1-alpha (IL1A), IL1-beta
(IL1B), aFGF (FGF-acidic), bFGF (FGF-basic), INT-2 (INT2), KGF
(FGF7).
EGF, TGF-alpha (TGF-A), Betacellulin (BTC), SCDGF,
Amphiregulin, HB-EGF, form EGF-like antiparallel beta-sheets.
13.
Lymphokines are a subset of cytokines that are produced by a
type of immune cell known as a lymphocyte.
They are protein mediators typically produced by T cells to direct
the immune system response by signalling between its cells.
Lymphokines have many roles, including the attraction of other
immune cells, including macrophages and other lymphocytes, to
an infected site and their subsequent activation to prepare them
to mount an immune response.
Circulating lymphocytes can detect a very small concentration of
lymphokine and then move up the concentration gradient
towards where the immune response is required.
Lymphokines aid B cells to produce antibodies.
15. Actions of lymphokines include:
Activates B cells, inhibits macrophage function : IL-10.
Activation of neutrophils, eosinophils, and monocyte
/macrophages :GM-CSF .
Bone resorption : osteoclast activating factor
Bone marrow – growth and differentiation of immune cells :IL-3
B cell growth and differentiation :IL-4.
B cell differentiation, activates some microphages (pmn) :IL-5
Co-stimulator of T cells, induces growth in B cells :IL-6
Inflammation, fever, catabolism and cachexia, activation of
some microphages :TNF
Hematopoiesis stimulators :IL-3, IL-7, GM-CSF
Macrophage-activating activity (MAF) :INF-γ
Stimulates proliferation of activated T and B cells : IL-2
Inhibits T cell growth, activates macrophages :TGFβ
16.
A monokine is a type of cytokine produced primarily
by monocytes and macrophages.
Examples include interleukin 1 and tumor necrosis factoralpha.
Other monokines include alpha and beta interferon,
and colony stimulating factors.
17.
a variety of naturally occuring polypeptides that are
the family of cytokines which affect functions of specific cell
types and are found in small quantities.
They
are
secreted
regulatory
proteins
produced
by lymphocytes, monocytes and various other cell types and
are released by cells in response to antigenic and nonantigenic stimuli. Consist of IL1 to IL37.
IL-1 activates Antigen Presenting Cells and CD4+ lymphocytes;
affects the differentiation of the B-Cells and T-Cells and other
immunocompetent cells and takes part in the regulation of
production of other cytokines and GM-CSF (GranulocyteMacrophage Colony-Stimulating Factor).
IL-2 stimulates the proliferation and activation of B-Cells and
T-Cells. IL-4 plays a role in the differentiation of TH2, in
allergic responses, and in the switching of antibody types.
18.
IL-3 is a potent activator of hemopoietic cells. It stimulates NKCells and acts as a synergist with IL-4 during the induction of
CD4+ lymphocyte activation process.
IL-5 stimulates the production and maturation of eosinophils
during inflammation.
IL-7 is known as the growth factor of the immature B-Cells and
T-Cells. It induces apoptosis of tumor cells and causes
differentiation of cells from a subgroup of acute myeloblastic
leukemia.
IL-8 acts as a chemotactic factor that attracts neutrophils,
basophils and T-Cells to sites of inflammation.
IL-9 stimulates the excretion of IL-2, IL-4, IL-6, IL-11, and takes
part in a stimulation of cytotoxicity of T-killers and NK-Cells,
inducing apoptosis.
IL-10 acts to repress secretion of pro-inflammatory cytokines.
19.
IL-11 is a pro-inflammative factor, which regulates the
functions of B-Cells and T-Cells. It also takes part in the
induction of various killer cells activities and acts as an autocrine
factor for the proliferation of megacaryocytes.
IL-12 is a critical linker between the innate immunity and
adaptive immunity, capable of TH1 (T Helper Type-1)
differentiation and IFN-Gamma release by T-Cells and NK cells.
IL-13 is very sensitive to monocytes and B-Cells. IL-13 does not
act on T-Cells but inhibits the proliferation of leukemic pro-BCells.
IL-14 is a BCGF (B-Cell Growth Factor) and the hyper
production of this interleukin enables the progression of NHL-B
(B-cell Type Non Hodgkin's lymphoma).
IL-15 is analogous to IL-2 and increases the anti-tumor activities
of T-killers and NK-Cells, and the production of cytokines CD4+
lymphocytes.
20.
IL-17 is principally produced by CD4+ T-Cells, which induces
granulopoiesis via GMCSF. It takes part in the regulation of
many cytokines and can reinforce the antibody dependant
tumor cell destruction.
IL-18 acts as a synergist with IL-12, especially in the induction
of IFN-Gamma production and inhibition of angiogenesis.
IL-19 is produced mainly by monocytes and is similar to IL-10
in its function. It is stimulated by GM-CSF and regulates the
functions of macrophages, and also suppresses the activities of
TH1 and TH2.
IL-21 executes an important role in the regulation of
hematopoiesis and immune response. It promotes a high
production of T-Cells, fast growth and maturation of NK-Cells
and B-Cells population.
IL-22 is produced by activated T-Cells in acute inflammation. It
is similar to IL-10 in function, but does not prohibit the
production of pro-inflammatory cytokines through monocytes.
21.
Interferons play an important role in the first line of
defense against viral infections.
They are part of the non specific immune system and are
induced at an early stage in viral infection before the
specific immune system has had time to respond.
Interferons are made by cells in response to an
appropriate stimulus, and are released into the
surrounding medium; they then bind to receptors on
target cells and induce transcription of approximately
20-30 genes in the target cells, and this results in an
anti-viral state in the target cells.
22.
Based on the type of receptor through which they signal, human
interferons have been classified into three major types.
1. Interferon type I:
All type I IFNs bind to a specific cell surface receptor
complex known as the IFN α receptor (IFNAR) that consists
of IFNAR1 and IFNAR2 chains. The type I interferons
present in humans are IFN-α, IFN-β and IFN-ω.
2. Interferon type II:
Binds to IFNGR that consists of IFNGR1 and IFNGR2 chains.
In humans this is IFN-γ.
3. Interferon type III:
Signal through a receptor complex consisting of IL10R2 (also
called CRF2-4) and IFNLR1 (also called CRF2-12).
23.
24.
Chemokines are a family of small cytokines, or Signaling
proteins secreted by cells.
Their name is derived from their ability to induce directed
chemotaxis in nearby responsive cells; they are chemotactic
cytokines.
Proteins are classified as chemokines according to shared
structural characteristics such as small size (they are all
approximately 8-10 kilodaltons in size), and the presence of
four cysteine residues in conserved locations that are key to
forming their 3-dimensional shape.
25.
Chemokines have been classified into four main subfamilies :
1.
2.
3.
4.
CXC Chemokines (contain CXL1 to CXL17)
CC Chemokines (contain CCL1 to CCL28)
CX3C Chemokines (contain CX3CL1)
XC Chemokines (contain XCL1 & XCL2)
All of these proteins exert their biological effects by
interacting with G protein-linked transmembrane
receptors called chemokine receptors, that are selectively
found on the surfaces of their target cells.
26.
Colony-stimulating factors (CSFs) are secreted glycoproteins that
bind to receptor proteins on the surfaces of hemopoietic stem
cells, thereby activating intracellular signaling pathways that can
cause the cells to proliferate and differentiate into a specific kind
of blood cell.
The colony-stimulating factors are soluble, in contrast to other,
membrane-bound
substances
of
the
hematopoietic
microenvironment.
They transduce by paracrine, endocrine, or autocrine signaling.
Colony-stimulating factors include:
◦ CSF1 - Macrophage colony-stimulating factor(MCSF)
◦ CSF2 - Granulocyte macrophage colony stimulating
factors(GMCSF).
◦ CSF3 - Granulocyte colony-stimulating factors(GCSF)
27.
Tumor necrosis factors (or the TNF family) refer to a group
of cytokines that can cause cell death (apoptosis).
Nineteen cytokines have been identified as part of the TNF family
on the basis of sequence, functional, and structural
similarities. They include:
Tumor necrosis factor (TNF), formerly known as TNFα or TNF
alpha, is the best-known member of this class. TNF is
a monocyte-derived cytotoxin that has been implicated in tumor
regression, septic shock, and cachexia.
Lymphotoxin-alpha, formerly known as Tumor necrosis factorbeta (TNF-β), is a cytokine that is inhibited by interleukin 10.
Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta),
two related cytokines produced by lymphocytes that are
cytotoxic for a wide range of tumor cells in vitro and in vivo.
28.
T cell antigen gp39 (CD40L), a cytokine that seems to be
important in B-cell development and activation.
CD27L, a cytokine that plays a role in T-cell activation. It
induces the proliferation of co-stimulated T cells and enhances
the generation of cytolytic T cells.
CD30L, a cytokine that induces proliferation of T cells.
FASL, a cytokine involved in cell death.
4-1BBL, an inducible T cell surface molecule that contributes to
T-cell stimulation.
OX40L, a cytokine that co-stimulates T cell proliferation and
cytokine production.
TNF-related apoptosis inducing ligand (TRAIL), a cytokine that
induces apoptosis.
29.
30.
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse
structurally, but almost all belong to one of five families of
receptor proteins:
◦ Immunoglobulin super family receptors
◦ Class I cytokine receptor family (also known as the
hematopoietin receptor family)
◦ Class II cytokine receptor family (also known as the
interferon receptor family)
◦ TNF receptor family.
◦ Chemokine receptor family.
