Cytokines are small protein molecules that are secreted by immune cells and other cells to regulate the immune system and inflammatory response. There are over 200 identified cytokines including interleukins, interferons, tumor necrosis factors, and colony stimulating factors. Cytokines act in autocrine, paracrine, or endocrine fashion through cell surface receptors. They have pleiotropic, redundant, synergistic, and antagonistic properties and can induce cytokine cascades. The major histocompatibility complex proteins present antigen peptides and help the immune system distinguish self from non-self. Diseases have been associated with alleles of these histocompatibility genes.

1. CYTOKINES
• Cytokine: Any low-molecular-weight
regulatory protein or glycoprotein secreted by
immune cells or other cells of the body in
response to an stimuli.
• Cytokines through interaction with specific
cell surface receptors, regulate the
development or function of another cell.
• Cytokines are proteins with specific roles in
communication between cells of the immune
system.

2. • Presently, about 200 cytokines have been
identified.
• Many cytokines are referred to as
“interleukins” because they are secreted by
some leukocytes and act on other leukocytes.

3. MODE OF ACTION OF CYTOKINES
Cytokines may act in one of the following 3
ways:
1) Autocrine when a cytokine acts on the cell
which produced it.
2) Paracrine when it acts on another target cell
in the vicinity.
3) Endocrine when the cytokine secreted in
circulation acts on a distant target.

4. AUTOCRINE ACTION

5. PARACRINE ACTION

6. ENDOCRINE ACTION

7. Cytokine Properties.
1. Cytokines can be Pleiotropic:

8. 2. Cytokines can be Redundant

9. 3. Cytokines can be Synergistic

10. 4. Cytokines can be Antagonistic

11. 5. Cytokine Cascade Induction
• Certain cytokines induce a pyramid of effects,
including a cascade of cytokine secretion.
• The action of one cytokine on a target cell
induces that cell to produce one or more
cytokines.
• This, in turn, may induce other target cells to
produce other cytokines.

13. TYPES OF CYTOKINES
• INTERLEUKINS: (IL-1 to IL-38)
• INTERFERONS: (INF- α, INF-β, INF- γ)
• TUMOUR NECROSIS FACTORS: (TNF- α, TNF- β)
• TUMOUR GROWTH FACTORS: (TGF- β1)
• COLONY STIMULATING FACTORS:
- MONOCYTE-COLONY STIMULATING FACTOR (M-CSF)
- GRANULOCYTE- COLONY STIMULATING FACTOR (G-CSF)
- GRANULOCYTE-MACROPHAGE STIMULATING FACTOR (GM-CSF)

14. INTERLEUKIN-1
• IL-1 is intensely produced by
tissue macrophages, monocytes, fibroblasts,
and dendritic cells, but is also expressed by B
lymphocytes, NK cells, microglia, and epithelial cells.
• They form an important part of the inflammatory
response of the body against infection.
• These cytokines increase the expression of adhesion
factors on endothelial cells to enable transmigration
(also called diapedesis) of immunocompetent cells,
such as phagocytes, lymphocytes and others, to sites of
infection.

15. • They also affect the activity of
the hypothalamus, the thermoregulatory
center, which leads to a rise in body
temperature (fever) .
• That is why IL-1 is called an
endogenous pyrogen.
• Besides fever, IL-1 also
causes hyperalgesia (increased pain
sensitivity), vasodilation and hypotension.

16. CLASSIFICATION: Cytokine Families
1. Hematopoietin family.
2. Interferon (IFN) family.
3. Chemokine family.
4. Tumor Necrosis Factor (TNF) family.

17. 1. Hematopoietin family.
• Cytokines of the hematopoietic system
include
- Interleukins (ILs) (IL-2, IL-3, IL-4, IL-5, IL-6, IL-6,
IL-7, IL-9.)
- Colony-Stimulating Factors (CSFs),
- Erythropoietin (EPO) and
- Thrombopoietin (TPO)

18. Cytokine Function in hematopoiesis
Erythropoietin (EPO) Red blood cell production
Granulocyte-macrophage colony stimulating
factor (GM-CSF)
Stimulation of diverse set of granulocyte-
macrophage colonies
Granulocyte-colony stimulating factor (G-
CSF)
granulocytic colony stimulation
Interleukin-2 (IL-2) T-cell proliferation
Interleukin-3 (IL-3) Granulocyte, macrophage, eosinophil,
megakaryocyte and erythroid colony formation
Interleukin-5 (IL-5) B-cell differentiation and eosinophil regulation
Interleukin-6 (IL-6) B-cell differentiation
Interleukin-7 (IL-7) T-lymphocyte induction
Interleukin-11 (IL-11) Stimulation of megakaryocytes and
plasmacytoma cell lines
Leukemia inhibitory factor (LIF) Differentiation and suppression of clonogenicity
of leukemic cells
Macrophage-colony stimulating factor (M-
CSF)
Macrophage colony stimulation
Stem cell factor (SCF) Proliferation of mast cells and stem cells
Thrombopoietin (TPO) Regulation of platelet production; stimulation of
megakaryocytes with IL-3 and SCF

19. 2. INTERFERONS FAMILY.
• IFNs are class of proteins known as cytokines,
molecules used for communication between
cells to trigger the protective defenses of
the immune system that help eradicate
pathogens especially viruses.
• Certain symptoms of infections, such
as fever, muscle pain and "flu-like symptoms",
are also caused by the production of IFNs and
other cytokines.

20. • They are typically divided among three
classes: Type I IFN, Type II IFN, and Type III
IFN.
• IFNs belonging to all three classes are
important for fighting viral infections and for
the regulation of the immune system.

22. 3. CHEMOKINES (Chemotactic cytokines)
• Chemokines are small protein molecules that
are produced by the cells of the immune system.
• These act as chemo-attractants, leading to the
migration of immune cells to an infection site so
they can target and destroy invading bodies such
as microbes.
• Eg: The chemokines that attract Macrophages
to the site of inflammation are CCL2, CCL3

23. • Chemokines have been classified into four
main subfamilies:
- CXC,
- CC,
- CX3C
- XC

24. 4. TUMOR NECROSIS FACTOR FAMILY :
• Also called cachexin, or cachectin
• Produced chiefly by activated macrophages,
although it can be produced by many other
cell types such as CD4+ Lymphocytes, NK
Cells, Neutrophils, Mast Cells, Eosinophils.
• TNF is able to induce fever, apoptotic cell
death, cachexia, inflammation and to
inhibit tumorigenesis and viral replication.

25. • TNF is an important endogenous pyrogen,
together with IL-1, it is responsible for many
of the hematological changes in septic shock.
• A local increase in concentration of TNF will
cause the cardinal signs of Inflammation to
occur:
- Heat,
- Swelling,
- Redness,
- Pain,
- Loss of function.

26. • Whereas high concentrations of TNF
induce shock-like symptoms.
• The prolonged exposure to low
concentrations of TNF can result in cachexia,
a wasting syndrome.
• This can be found, for example,
in cancer patients.

27. HLA SYSTEM AND MAJOR
HISTOCOMPATIBILITY COMPLEX
• HLA stands for Human Leucocyte Antigens
because these are antigens or genetic proteins
in the body that determine one’s own tissue
from non-self (histocompatibility)
• (The HLA complex helps the immune system
distinguish the body's own proteins from
proteins made by foreign invaders such as
viruses and bacteria.)
• First discovered on the surface of leucocytes.

28. • Subsequently, it was found that HLA are
actually gene complexes of proteins on the
surface of all nucleated cells of the body and
platelets.
• Since these complexes are of immense
importance in matching donor and recipient
for organ transplant, they are called Major
Histocompatibility Complex (MHC) or HLA
complex.

29. • In humans, the MHC complex consists of more
than 200 genes located close together
on chromosome 6.
• Genes in this complex are categorized into
three basic groups:
- CLASS I
- CLASS II
- CLASS III

31. 1) MHC class I genes:
- HLA-A
- HLA-B
- HLA-C
2) MHC class II genes:
- HLA-DPα1
- HLA-DPβ1
- HLA-DQα1
- HLA-DQβ1
- HLA-DRα1
- HLA-DRβ1
- HLA-DRβ2

32. • Some histocompatibility complex genes have
hundreds of identified versions (alleles), each
of which is given a particular number.
• Example: HLA-B GENE has other
variants/alleles such as HLA-B27.
• The variants/alleles has further subtypes-
HLA-B2701, HLA-B2702, HLA-B2703.

33. Class I MHC antigens
MHC class I genes:
- HLA-A
- HLA-B
- HLA-C
• The proteins produced from these genes are present
on the surface of almost all cells.
• On the cell surface, these proteins are bound to
protein fragments (peptides) that have been
exported from within the cell.
• MHC class I proteins display these peptides to the
immune system.

34. • If the immune system recognizes the peptides
as foreign (such as viral or bacterial peptides),
it responds by triggering the infected cell to
self-destruct.
• CD8+ (i.e. T suppressor) lymphocytes carry
receptors for class I MHC; these cells are used
to identify class I antigen on them.

35. CD8+ T CELL
TCR
ANTIGEN
MHC-1
TUMOUR CELL

36. Class II MHC antigens
• MHC class II genes provide instructions for
making proteins that are present almost
exclusively on the surface of certain immune
system cells.
• Like MHC class I proteins, these proteins
display peptides to the immune system.
• Class II MHC is identified by B cells and CD4+
(i.e. T helper) cells.

37. CD4+ T CELL
TCR
ANTIGEN
MHC-2
MACROPHAGE

38. Class III MHC antigens
• Class III MHC antigens are some components
of the complement system (C2 and C4) coded
on HLA complex but are not associated with
HLA expression and are not used in antigen
identification.

39. PATHOLOGY OF HLA GENES
• More than 100 diseases have been associated with
different alleles of histocompatibility complex genes.
• For example, the HLA-B27 allele increases the risk of
developing an inflammatory joint disease
called ankylosing spondylitis.
• Many other disorders involving abnormal immune
function and some forms of cancer have also been
associated with specific HLA alleles.
• However, it is often unclear what role
histocompatibility complex genes play in the risk of
developing these diseases.