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CYTOKINES bacterial products, to specific cell
receptors or through the recognition of
• Cytokines are small soluble proteins that
foreign antigens by host lymphocytes.
regulates the immune system,
orchestrating both innate and adaptive Effects of Cytokine
immunity to infection.
The effects of cytokines in vivo include
• These are produced by different cell regulation of growth, differentiation, and
types and have modulating effects on gene expression by many different cell types,
the hematopoietic and immune system including leukocytes.
through activation of cell-bound
• autocrine stimulation (i.e., affecting
receptor.
the same cell that secreted it)
• Cytokines cascade produces a spectrum • paracrine (i.e., affecting a target cell
of activities that lead to the rapid in close proximity) activities. ( Near
generation of innate and adaptive by cells)
immune responses. In fact, the ability or • endocrine (i.e., systemic) activities.
inability to generate certain cytokine
patterns often determines the clinical Pleiotropy
course of infection. • single cytokine that can have many
• In extreme cases, massive production different actions
and dysregulation produces a “cytokine Redundancy
storm” that leads to shock, multiorgan
failure or even death. • Different cytokines activate some of the
same pathways and genes.
CYTOKINES • many cytokines share receptor subunits
• They are Chemical messengers that • IL-6, IL-11, leukemia inhibitory factor,
regulate the immune system, oncostatin M, ciliary neurotrophic factor,
orchestrating both innate immunity and and cardiotrophin all utilize the gp130
the adaptive response to infection. They subunit as part of their receptors.
are small proteins produced by several Synergistic reaction
different types of cells that influence the
hematopoietic and immune systems • Cytokines often act in networks; if the
through activation of cell-bound effects complement and enhance each
receptors. other.
• Cytokines that are produced by the T
Cytokine Storm
cells are known as Lymphokines
• Cytokines that are produced by the • A massive overproduction and
Monocytes/Macrophages are known as dysregulation of cytokines produced by
Monokines hyperstimulation of the immune
response or hypercytokinemia.
STIMULI
• may lead to shock, multiorgan failure, or
• Cytokines are induced in response to the even death, thus contributing to
binding of stimuli, such as bacterial pathogenesis
lipopolysaccharides, flagellin, or other
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6. Interferons

Cytokines of the Innate immune response

• Cytokines involved in the innate immune

response are responsible for many of the
physical symptoms attributed to
inflammation, such as fever, swelling,
pain and cellular infiltrates into the
damaged tissues.

• The innate immune response is non-

specific but occurs within the first hours
of contact with microorganisms. The
main function of the innate immune
response is to recruit effector cells to
the area, and this is where the cytokines
Antagonism are involved.
• A cytokine that may counteract the Cytokines of the innate immune response
action of another cytokine includes:

• Chemokines

• Interferon alpha and beta

• Transforming Growth Factor beta

• Tumor necrosis factor alpha

• Interleukin-1

• Interleukin-6
MAJOR CLASSIFICATION OF CYTOKINES Chemokines
1. Interleukins (IL) • Guide immune cells to target, regulate
2. Chemokines cell movement/ migration, and promote
changes cell adhesion/ cell motility
3. Colony stimulating factors (CSF)
• Chemokines are family of cytokines that
4. Tumor necrosis factor (TNF) enhance motility and promote
5. Transforming growth factor (TGF) migration of many types of white blood
cells toward the source of chemokine
(chemotaxis).

• Chemokines are classified into four

families based on the position of N-
terminal cysteine residues:
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• CXC – contains single amino acid
between 1st and 2nd cysteines

• CC – has adjacent cysteine

Note
residues.
• CXCR4 and CCR5 serves as a receptor for
• C – lacks one of the cysteine
and HIV in CD4+ cells thus absence of
• CX3C – has 3 amino acids these receptors presents an immunity to
between the cysteines. HIV.

Chemokines plays a key role in initiation and • RANTES and SDF-1 is highly polymorphic
development of inflammatory responses in ligands that blocks virus ability to bind
numerous disease processes. and delays the progression to full-blown
AIDS.

• HIV uses the chemokine receptors

CXCR4 and CCR5 as coreceptors for
infection of CD4+ T lymphocytes and
macrophages.

CC Chemokines

Induce migration of lymphocytes and

monocytes

CCL2 (MCP-1) - Promotes Th2 immunity and

release of histamine by basophils

CCL3 (MIP-1a) - Recruits Monocyte/

Macrophages/ Neutrophils, Promotes Th1
immunity

CCL4 (MIP-1b) - Recruits monocytes and natural

killer cells

CCL5 (RANTES) - Recruits eosinophils/ T cells/

Basophils, activates natural killer cells

CXC Chemokines

• Induce migration of neutrophils

CXCL8 (IL-8) - Recruits neutrophils to infected

tissues

CXCL7 - Released from activated platelets.

Activates neutrophils, promotes angiogenesis

CXCL1/CXCL2/CXCL3 - promote angiogenesis,

activate neutrophils
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• Stimulate fibroblast • IFN-beta (Fibroblast IFN /Epithelial cell
proliferation IFN) – secreted by fibroblasts
-efficacious in treating multiple sclerosis
• Released by endothelial
• Function: They both inhibits viral
cells/ fibroblasts/
replication
monocytes

• CCL21

• Secreted by stromal cells

• Recruit dendritic cells to the

lymph nodes

• CCL18/CCL19

• Secreted by dendritic cells

• Recruit T and B cells to the

lymph nodes

• CXCL13

• Secreted by follicular dendritic TGF- B

cells
• Transforming Growth Factor was
• Recruits B cells to B cell zone identified as a factor that induces
(Binds CXCR5) in the lymph antiproliferative activity in a wide
nodes variety of cell types. Active TGF-β is
Type 1 IFN primarily a regulator of cell growth,
differentiation, apoptosis, migration,
• These IFNs are produced by dendritic and the inflammatory response. Thus, it
cells and induce production of proteins acts as a control to help downregulate
and pathways that directly interfere with the inflammatory response when no
viral replication and cell division. - longer needed.
Steven’s 4th edition
• Regulates the expression of CD8 in CD4–
• Type I IFN activates natural killer (NK) CD8– thymocytes and acts as an
cells and enhances the expression of autocrine inhibitory factor for immature
class I MHC proteins, thus increasing the thymocytes.
recognition and killing of virus-infected
cells • Blocks the production of IL-12 and
strongly inhibits the induction of IFN-
• IFN-alpha (leukocyte interferon) – gamma
secreted by leukocytes
• It is recognized as an important factor in
-has been used to treat hepatitis C and the establishment of oral tolerance to
Kaposi’s sarcoma, as well as certain bacteria normally found in the mouth
leukemias and lymphomas
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TNF-a • IL-1 acts as an endogenous pyrogen
(induces fever) in the acute-phase
• Known as cachectin, produced mainly by
response through its actions on the
the macrophages and NK cells
hypothalamus.
• It is secreted by activated monocytes
• IL-1 induces the production of vascular
and macrophage
cell-adhesion molecules as well as
• Lipopolysaccharide found in gram chemokines and IL-6.
negative bacteria – major stimulus for
• IL-1β is responsible for most of the
TNF-a production
systemic activity attributed to IL-1,
• Secretion of higher levels will lead to including fever, activation of phagocytes,
septic shock. and production of acute-phase proteins

• Tumor necrosis factor were first isolated • These chemokines and cell-adhesion
from tumor cells and were so named molecules attract and assist leukocytes
because they induced lysis in these cells. to enter the inflamed area through a
process known as diapedesis.
• TNF-α is most prominent member of the
TNF, which consists of at least 19 IL-6
different peptides.
• It is a major factor for production of
• It exists in both membrane-bound and Acute phase reactants
soluble forms and causes vasodilation • It is a single protein produced by
and increases Vaso permeability. lymphoid and non-lymphoid cell
types and is primarily triggered its
• The soluble form is derived from the secretion by IL-1.
membrane bound form by proteolytic • This pleiotropic cytokine affects
cleavage with TNF-α-converting enzyme. inflammation, acute phase
Membrane bound TNF-α can mediate all reactions, immunoglobulin
cytotoxic and inflammatory effects of synthesis, and activation of T and B
TNF through cell-to-cell contact. cells. IL-6 stimulates B cells to
• The main trigger of TNF-α production is proliferate and differentiate into
the presence of lipopolysaccharide plasma cells.
found in gram-negative bacteria. • IL-6 binds to IL-6Rα (IL-6 specific
receptor) and gp130 and is activated
• TNF has a deleterious effect, leading to by Janus kinase (JAK). The binding of
septic shock, sudden drop in blood IL-6 causes the genes for producing
pressure, disseminated intravascular CRP, complement C3 and fibrinogen
coagulation and tissue fluid infiltration. are activated.
IL-1 Cytokines of the Adaptive immune response
• IL-1α and IL-1β are proinflammatory • Cytokines involved in adaptive immune
cytokines produced by monocytes, response are mainly secreted by T-
macrophages, and dendritic cells early helper cells (Th cells) and affects T and B
on in the immune response cell function more directly.
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• Subclasses of Th cells: Th1, Th2, Th17 • TNF-a - Can cause cell death and
and T Regulatory cells (Treg cell). Each has broad pro-inflammatory
has a specific function and produces a effects
different set of cytokines.
• TNF-b - Kills chronically infected
• Once T cell receptor (TCR) captures
cells, activates macrophages,
antigen, clonal expansion of those
and lymphoid tissue
particular CD4+ T helper cells occurs.
development
Differentiation into Th1, Th2 or Treg cell
lineage is influenced by spectrum of Th2 Cytokines
cytokines expressed in initial response.
• Activate humoral responses (antibodies
produced by b cells)

• Strong presence of
eosinophils/basophils/ mast cells

• IL-4 - polarizes helper T cells to

type 2 phenotype, promotes
mast cell growth and
development in the bone
marrow, stimulates
eosinophils, and activates B
cells

• IL-5 - Drives eosinophil

development in the bone
marrow

• IL-13 - Signals B cells to make

IgE antibodies

• IL-25 - Amplifies Th2 response

by inducing IL-4/IL-5/IL-13 and
activates type innate
lymphoid cells

• IL-10 - Enhances B cell

Th1 Cytokines
activation/ antibody
• Cellular Immunity against intracellular production, suppresses Th1
pathogens cytokine expression

• IL-2 - Critical for T cell survival/ Th17 Cytokines

proliferation and differentiation
• Controls fungi/bacteria via ability to
• IL-12 - Activates natural killer recruit neutrophil response
cells and helps helper T-cells to • Overly active Th17 response leads to
be more Type 1-like irritable bowel syndrome
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• IL-17 - Stimulates production of • Function: Major macrophage
chemokine IL-8 (CXCL8) which is a strong activator, and increases
neutrophil chemoattractant expression of MHC class 1 and 2
• IL-22 - Acts on epithelial cells in gut/
skin/ lung to promote cell proliferation
and tissue healing, and production of
anti-microbial peptides
• IL-23 - Helps polarize helper T-cells to
Th17 phenotype

Treg Cytokines

• IL-10 Enhances B cell activation/

Antibody production. Suppresses Th1
cytokine expression

• TGF-b

• Promotes tissue repair/ wound

healing

• Has anti-inflammatory
properties
IL-2
• Promotes Treg development
• T cell cell growth factor
• Inhibits B cell proliferation
• It drives the growth and differentiation
• Inhibits activated macrophages
of both T and B cells and induces lytic
IMPORTANT NOTES activity in NK cells

Type 2 IFN • IL-2 alone can activate proliferation of

Th2 cells and helps to generate IgG1- and
• Interferon gamma (Immune
IgE-producing cells
interferon) – secreted by T cells
and NK cells • Secreted by Th1 cells in addition to IFN-
• This is the principal molecule γ. It drives the growth and differentiation
produced by Th1 cells, which of both T and B cells and induces lytic
affects the RNA expression levels activity in NK cells.
of more than 200 genes
• The clonal expansion of activated T
• most potent activator of
helper cells is necessary in mounting an
macrophages and boosts their
adequate immune response to any
tumoricidal activity.
immunologic challenge.
• involved in regulation and
activation of CD4+ Th1 cells,
CD8+ cytotoxic lymphocytes,
and NK cells.
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bone marrow cells at different
developmental stages and promote
specific colony formation for various cell
lineages.

• IL-3 is a multilineage CSF that induces

CD34+ bone marrow stem cells to form T
and B cells during the differentiation
cycle.

• GM-CSF acts to drive toward other

WBCs. If M-CSF is activated, the cells
becomes macrophage, and so on.

• G-CSF enhances the function of

neutrophils and decrease the IFN-γ
production and increases IL-4
TNF-B production in T cells.

• Known as lymphotoxin, produced by T • IL-3 in conjunction with GM-CSF, drives

cells the development towards basophil, and
addition of IL-5 will develop into
• For killing and endothelial activation eosinophils.
IL-3

• Known as multi-colony-stimulating
factor. It promotes hematopoiesis.

• It stimulates Myeloid, lymphoid, and

erythroid lineage

ERYTHROPOIETIN and COLONY-

STIMULATING FACTOR
• The CSFs includes:

• Erythropoietin (EPO)

• Granulocyte-colony stimulating
factor (G-CSF)

• Macrophage-colony stimulating
factor (M-CSF)

• Granulocyte-macrophage-
colony stimulating factor (GM-
CSF)

• In response to inflammatory cytokines

such as IL-1, the different CSFs acts on
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