Immunology

1. Cytokines and Chemokines
Objectives
• General Properties of Cytokines
and Chemokines
• Six Families of Cytokines
• Cytokine Antagonists
• Cytokine-Related Diseases
• Cytokine-Based Therapies
Dr. Refif S. Al-Shawk
Lec 1
2021-2022

2. Learning objectives
After reading this lecture, you should be able to:
• Define cytokines and chemokines
• describe the general properties of cytokines and chemokines
• Demonstrate and classify the cytokine families
• Explain the common features of each family that used by innate and
adaptive immune cells and give examples for each family
• Explain Cytokine antagonists, cytokine related diseases and cytokine-based
therapies.

3. Cytokines
• Low-molecular weight regulatory proteins or
glycoproteins
• Secreted by WBC and various other cells
• Assist in regulating development of immune effector
cells
• Referred to as Interleukins
• IL-1 through IL-37 have been described

4. Chemokines
Subpopulation of cytokines that share the specific
purpose of mobilizing immune cells from one organ, or
from one part of an organ, to another.
• Subpopulation of cytokines
• Mobilize immune cells from one area to another
• Class of chemoattractants

5. Cytokines Are Described by Their
Functions and the Distances at Which
They Act
• Cytokines can be described according to the distance between the secreting
cell and the recipient cell.
• Cytokines that must pass through the bloodstream before reaching their
target are referred to as endocrine.
• Those that act on cells near the secreting cell, such that the cytokine merely
has to diffuse a few angstroms to a nearby cell, are referred to as paracrine.
• Sometimes, a cell needs to receive a signal through its own membrane
receptors from a cytokine that it, itself, has secreted. This type of signaling is
referred to as autocrine.
• Many cytokines act over a short distance in an autocrine or paracrine
fashion.

6. Cytokines can be
classified on the basis of
the distance between the
cell secreting the
signaling ligand & the
cell receiving that
chemical signal :
Of note, the T-cell
interleukin IL-2 acts
effectively in all three
modes.

7. Cytokines Exhibit the Attributes of Pleiotropy,
Redundancy, Synergism, Antagonism, and
Cascade Induction
• A cytokine that induces different biological effects depending on the nature
of the target cells is said to have pleiotropic activity
• Whereas two or more cytokines that mediate similar functions are said to be
redundant.
• Cytokine synergy occurs when the combined effect of two cytokines on
cellular activity is greater than the additive effects of the individual cytokines.
• In some cases, the effects of one cytokine inhibit or antagonize the effects
of another.
• Cascade induction occurs when the action of one cytokine on one target
cell induces that cell to produce one or more additional cytokines

9. General Properties of Cytokines
and Chemokines:
 Cytokines bind to specific receptors
on the membranes of target cells,
triggering signal transduction
pathways that ultimately alter enzyme
activity and gene expression. The
susceptibility of a target cell to a
particular cytokine is determined by
the presence of specific membrane
receptors and exhibit very high
affinity for one another.

10. Cytokines Have
Numerous Biological
Functions
 The total number of
proteins with cytokine
activity grows daily “as
research continues to
uncover new ones”.
 Table 12-1 summarizes the
biological functions of
some commonly
encountered cytokines.

11.  Cytokines belong to 6 families
 Interleukin 1 (IL-1)
 Hematopoietin family (Class I)
 Interferon family (Class II)
 Chemokine family
 Tumor necrosis family
 Interleukin 17 (IL-17)
 Based on structural studies
 All have molecular mass less than 30kDa
 All have similarities and few rarely act alone

12. The six major cytokine families

13. Cytokines of the IL-1 Family
Promote Proinflammatory Signals
• Cytokines of the interleukin 1 (IL-1) family are typically secreted very early in the
immune response by dendritic cells, monocytes, and macrophages following recognition
by innate receptors of viral, parasitic, or bacterial antigens.
• IL-1 family members are generally proinflammatory.
• IL-1 also has systemic (whole body) effects and signals the liver to produce other
cytokines, such as the type I interferons (IFN-α and IFN-β), IL-6, and the chemokine
CXCL8.
• These proteins further induce multiple protective effects, including the destruction of
viral RNA and the generation of a systemic fever response (which helps to eliminate
many temperature-sensitive bacterial strains).
• In addition, IL-1 serves as an intermediary between the innate and adaptive immune
systems by helping to activate both T and B cells.
• Members of the IL-1 cytokine family include IL-1α and IL-1β
• IL-1 family also includes IL-18 and IL-33.

15. Class 1 Cytokines Share a Common
Structural Motif But Have Varied Functions
• The cellular origins and target cells of class 1 cytokines are extremely
diverse.
• For example, class 1 cytokines signal the onset of T- and B-cell
proliferation (e.g., IL-2), regulate helper T-cell functions (e.g., IL-4), call
for B-cell differentiation to plasma cells and antibody secretion (e.g., IL-
6), or initiate the differentiation of particular leukocyte lineages (e.g., GM-
CSF, G-CSF).
{The class 1 cytokine family is the largest family of cytokines, and members
mediate diverse effects, including proliferation, differentiation, and antibody
secretion}

17. Class 2 Cytokines Are Grouped into
Three Families of Interferons
The class 2 cytokine (interferon) family includes the following:
• The type I interferons (IFN-α and IFN-β), which mediate early antiviral
responses.
• The type II interferons (such as IFN-γ), which activate macrophages, interact
with cells of the adaptive immune system, and support the generation of T 1
cells.
• The type III interferons (IFN-λ), which are secreted by plasmacytoid dendritic
cells and regulate viral replication and host cell proliferation.

19. TNF Family Cytokines May Be Soluble or Membrane-
Bound
• Members of the tumor necrosis factor (TNF) family of cytokines have been shown to regulate the
development, effector function, and homeostasis of cells of the skeletal and neuronal systems, as well as the
immune system.
• Although some TNF family members are soluble proteins, others are transmembrane proteins, In some
cases, the same cytokine exists in both soluble and membrane-bound forms.
• There are two members having the same name of the TNF family: TNF-α and TNF-β. Both of these are
secreted as soluble proteins.
• TNF-α (frequently referred to simply as TNF) is a proinflammatory cytokine, produced in response to
infection, inflammation, and environmental stressors by activated macrophages, and also by lymphocytes,
fibroblasts, and keratinocytes (skin cells).
• TNF-β is produced by activated lymphocytes and can deliver a variety of signals. On binding to
neutrophils, endothelial cells lead to increased expression of MHC and of adhesion molecules.
• Fas ligand (FasL), induces apoptosis.
• Thus members of the membrane-bound TNF cytokine family regulate lymphocyte functions from development
to death and everything in between, highlighting their importance in both basic and clinical immunology.
• It is therefore not surprising that TNF cytokine pathways are the targets of some of the most effective drugs
(to counter diseases of the immune system).

20. The IL-17 Family of Cytokines Is the
Most Recently Identified
• IL-17A, the first member of the IL-17 family to be detected, is released by
activated T cells and its receptors are found on neutrophils, keratinocytes,
and other nonlymphoid cells.
• IL-17A binding to a cell instructs it to secrete cytokines that support a
proinflammatory state. The T cells secreting these cytokines belong to a
unique lineage, the TH 17 cell subset, which appears to occupy a locus at
the interface of innate and adaptive immunity
• interleukins 17A, 17B, 17C, 17D, and 17F. Signaling
through most members of this family culminates in the
generation of inflammation.

21. Chemokines Induce the Directed
Movement of Leukocytes
• Structurally related family of small cytokines that bind to cell
surface receptors and induce the movement of leukocytes
up a chemokine concentration gradient and toward the
chemokine source.
• This soluble factor–directed cell movement is known as
chemotaxis, and molecules that elicit such movement are
referred to as chemoattractants.
• Leukocytes change their pattern of expression of
chemokine receptors during the course of an immune
response.

22. • Chemokines play two roles in inflammation
:
• Increased adhesion of leukocytes to
endothelium
• Migration of leukocytes through blood
vessels and toward the site of
infection or tissue damage.
• Chemokines are involved in the
development of lymphoid organs
• Chemokines are required for the
migration of DCs from sites of infection
into draining lymph nodes
• CXCL group: attract neutrophils
• CCL group: attract monocytes and
macrophages, to the site of infection.

23. Cytokines produced by cells during innate immune responses to
microbes stimulate the proliferation and differentiation of
lymphocytes in adaptive immune responses.
Examples of cytokines secreted by PAMP stimulated cells acting on B cells,
CD4+ T cells, and CD8+ T cells are given here:
• IL-12 stimulates the differentiation of naive CD4+ T cells to the Th1 subset
of effector cells.
• IL-1, IL-6, and IL-23 stimulate the differentiation of naive CD4+ T cells to the
Th17 subset of effector cells.
• IL-25 and IL-33 stimulate the differentiation of naive CD4+ T cells to the Th2
subset of effector cells.
• IL-15 promotes the survival of memory CD8+ T cells.
• IL-6 promotes the production of antibodies by activated B cells .

24. Cytokine Related
Diseases
• Bacterial Septic Shock
 Certain bacteria: Staphyloccocus aureus,
E. coli, Klebsiella pneumoniae …..
 Symptoms: drop in blood pressure, fever,
diarrhea, blood clotting
 Endotoxins (cell wall) bind TLRs on
dendritic cells and macrophages leading
them to produce
○ Over-produce IL-1β and TNF-α
○ Cytokine imbalance causes
abnormal temp, abnormal
respiration, capillary leakage, tissue
injury, organ failure
○ Neutralization by monoclonal
antibodies may help
• Bacterial Toxic Shock
• Microorganisms produce toxins
that act as Superantigens
• Bind simultaneously to Class
II MHC and T cell receptor,
activating T cell despite
antigenic specificity ,,induce
extremely high levels of TNF-
α and IL-1β
• Symptoms similar to sepsis

25. Cytokine Antagonists
 Number of proteins can inhibit cytokine
activity
 Can bind to receptor but fail to activate
the cell, thus blocking the active cytokine
from binding, OR
 Can bind to cytokine, inhibiting its ability
to bind to the cognate receptor
A naturally occurring cytokine antagonists
that modulate and refine the power of
particular cytokine responses, as well as
the ways in which various pathogens have
hijacked cytokine responses to their own
ends.
 Regulatory T cells, which express high
levels of CD25 on their membrane
surfaces, have been shown to release sIL-
2R upon activation. Since these T cells
serve the function of down-regulating
ongoing immune responses, (soluble IL-2
receptors serve the physiological function
of soaking up excess IL-2 ) thus reducing
the amount of the cytokine that is
available.
 Epstein-Barr virus (EBV), for example,
produces an IL-10–like molecule (viral IL-
10 or vIL-10) that binds to the IL-10
receptor. Just like host-derived IL-10, this
viral homologue suppresses TH1-type cell
-mediated responses that would otherwise

26. • The first success with this class of biologic agents came with a soluble form of the
TNF receptor and anti-TNF antibodies, which bind to and neutralize TNF. These
agents are of great benefit in many patients with rheumatoid arthritis, Crohn’s
disease, and psoriasis.
• Antibodies to the IL-6 receptor have been successfully used for juvenile and adult
arthritis.
• Antagonists of other proinflammatory cytokines, such as IL-1, the p40 chain that
is present in both IL-12 and IL-23, and IL-17, are now approved for various
inflammatory diseases, and many others are in clinical trials.
• In addition to these biologic agents, small molecule inhibitors of JAK kinases
(important intracellular signaling mediators of a variety of cytokine receptors) are
also approved to inhibit cytokine actions in rheumatoid arthritis.
A large number of cytokines and their receptors involved in inflammation
are being targeted by specific antagonists for the treatment of chronic T
cell–mediated inflammatory diseases

27. Cytokine-Based Therapies
 Soluble TNF-α receptor and monoclonal antibodies against TNF-α ??
have been used to treat rheumatoid arthritis and ankylosing
spondylitis in more than a million patients. Which reduce proinflamatory
cytokine cascades; help to alleviate pain, stiffness, and joint swelling; and
promote healing and tissue repair.
 The recombinant form of IL-1R receptor?? has been shown to be
relatively effective in the treatment of rheumatoid arthritis.
 Monoclonal antibodies directed against the IL-2 Receptors ?? are also
in clinical use for the prevention of transplantation rejection reactions

28. • Referrences :
• Kuby immunology 8th edition, 2019
• Cellular and molecular immunology 9th edition , 2018 by Abul K. Abbas

29. Further reading for interest (‫ﻃﻼع‬ٔ‫ﻼ‬‫)ﻟ‬

30. Immune Responses: The Outcomes of
Immune System Recognition
• Changes in Protein Expression Facilitate Migration of Leukocytes into Infected Tissues(Alterations in the
expression of adhesion molecules and chemokine receptors facilitate the movement of immune cells to
the sites of immune activity)
• Activated Macrophages and Neutrophils May Clear Pathogens without Invoking Adaptive
Immunity(Changes in the protease specificity of their proteasomes optimize the capacity of dendritic cells
to mediate antigen presentation)
• Antigen Activation Optimizes Antigen Presentation by Dendritic Cells(The nature of the innate immune
receptor engaged in a dendritic cell determines what cytokines the dendritic cell secretes. These in turn
determine the type of T-cell response that it initiates)
• Cytokine Secretion by Dendritic Cells and T Cells Can Direct the Subsequent Immune Response(The
nature of the innate immune receptor engaged in a dendritic cell determines what cytokines the dendritic
cell secretes. These in turn determine the type of T-cell response that it initiates)
• Antigen Stimulation by T and B Cells Promotes Their Longer-Term Survival (Antigen activation increases
the life span of T and B lymphocytes by inhibiting apoptosis)
• Antigen Binding by T Cells Induces Their Division and Differentiation (Different subclasses of T cells
secrete different cytokines that direct varying aspects of immune effector responses)
• Antigen Binding by B Cells Induces Their Division and Differentiation(B-cell differentiation results in
differentiation to antibody-secreting cells and memory B cells and the production of antibodies of different
classes and enhanced binding affinity)

33. • Properties of the major subsets of CD4+ helper T cells. Naive CD4+ T cells
may differentiate into distinct subsets of effector cells in response to antigen,
costimulators, and cytokines.

34. Classical and alternative
macrophage activation.
• Different stimuli activate tissue
macrophages to develop into
functionally distinct populations.
• Classically activated macrophages
are induced by microbial products
and cytokines, particularly IFN-γ,
and are microbicidal and involved in
potentially harmful inflammation.
• Alternatively activated
macrophages are induced by IL-4
and IL-13 produced by Th2 cells
and other leukocytes and function
to control inflammation and to
promote tissue repair and fibrosis.
• Some investigators divide the M2
macrophage population into
subpopulations, some of which are
mainly anti-inflammatory and others

35. • A large number of cytokines and their receptors involved in inflammation are being targeted by
specific antagonists for the treatment of chronic T cell–mediated inflammatory diseases (Table
19.5).