2. Cytokine
• The development of an effective immune response involve
cells from;
• Lymphoid lineage cells include T, B, and NK cells
• Myeloid lineage cells include granulocytes and macrophages,
endothelial and epithelial cells, adipocytes, and connective tissue,
stromal cells, fibroblasts etc.
• 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 (Interferon-alpha, an interferon type I), was identified in
1957 as a protein that interfered with viral replication
• The term "cytokine" is derived from a combination of two Greek
words - "cyto" meaning cell and "kinos" meaning movement.
3. Cytokine continue……
• Cytokines are small secreted proteins (~5–20 kDa) released by cells
that have a specific effect on the interactions and communications
between cells.
• They stimulate the movement of cells towards sites of inflammation,
infection and trauma.
• They are important regulators of both the innate and adaptive
immune response.
• The most current terminology used to describe cytokines is
"immunomodulating agents" or agents that modulate or alter the
immune system response.
• Cytokines exist in peptide, protein and glycoprotein forms.
4. Cytokine continue……
• Cytokine is a general name; other names include;
lymphokines (cytokines produced by lymphocytes)
monokines (cytokines produced by monocytes)
chemokines (cytokines with chemotactic activities)
interleukins (cytokines made by one leukocyte and
acting on other leukocytes)
Discussed late
• There are both pro-inflammatory cytokines and anti-
inflammatory cytokines.
5. • Cytokines act only on cells
bearing specific receptors.
• Expression of cytokines and
their receptors is highly
regulated.
6. Properties of Cytokine
• Cytokines exhibit the attributes of:
Autocrine action
Endocrine action
Paracrine action
Pleiotropy
Redundancy
Synergy
Antagonism
cascade
induction
• Permit them to regulate cellular activity in a coordinated and
interactive way.
7. Properties of Cytokine
• Cytokines may act
on the cells that secrete them
(autocrine action)
on nearby cells (paracrine action)
in some instances on distant cells
(endocrine action)
8. Pleiotropism refers to the ability of one cytokine having multiple effects on
diverse cell types
Redundancy refers to the property of multiple cytokines having the same
or overlapping functional effects.
Synergy refers to the property of two or more cytokines having greater than
additive effects..
“Independent action” occurs when two cytokines induce distinctive sets of host
response genes whose combined effector functions synergistically inhibit viral
replication
“cooperative action” occurs when treatment with two cytokines synergistically
enhances the expression levels of anti-viral genes normally induced to lower levels by
one, or both, of the individual cytokines
Antagonism refers to the ability of one cytokine inhibiting the action of
another.
• Can inhibit action of cytokines by acting directly on receptors, by affecting
production of cytokines or by binding to cytokines and preventing their
subsequent action
9. • Cascade effect; cytokines can stimulate the production of other
cytokines.
• During a cytokine storm, various inflammatory cytokines are
produced at a much higher rate than normal.
• This overproduction of cytokines causes positive feedback on
other immune cells to occur, which allows for more immune cells
to be recruited to the site of injury that can lead to organ damage
e.g., Covid-19 story
• Induced cytokine
• Production allows both innate and adaptive cells to rapidly sense
perturbations during infection and inflammation, responding to
distinct IL-1 family members and STAT activators with
effector cytokine production
13. Cytokines play key roles in regulating hematopoiesis, innate immunity and
acquired immunity.
14. Cytokines Properties
• 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
10–12M.
• Because their affinities are so high,
cytokines can mediate biological effects at
picomolar concentrations.
15.
16.
17. • Cytokine network.
• Several different cell types coordinate their efforts as part of the immune
system, including B cells, T cells, macrophages, mast cells, neutrophils,
basophils and eosinophils.
• Each of these cell types has a distinct role in the immune system and
communicates with other immune cells using secreted cytokines.
• Macrophages phagocytose foreign bodies and are antigen-presenting
cells, using cytokines to stimulate specific antigen dependent responses
by B and T cells and non-specific responses by other cell types.
• T cells secrete a variety of factors to coordinate and stimulate immune
responses to specific antigen, such as the role of helper T cells in B cell
activation in response to antigen.
• The proliferation and activation of eosinophils, neutrophils and basophils
respond to cytokines as well.
Figure from previous slide
18.
19.
20. Cytokines……..
• There is significant evidence showing that certain
cytokines/chemokines are involved in not only the initiation but also
the persistence of pathologic pain by directly activating nociceptive
sensory neurons.
• Certain inflammatory cytokines are also involved in nerve-
injury/inflammation-induced central sensitization and are related to
the development of contralateral hyperalgesia/allodynia.
21. Cytokines Principal Source Primary Activity
GM-CSF Th cells Growth and differentiation of monocytes and
dendritic cells
IL-1α
IL-β
Macrophages and other
antigen
presenting cells (APCs)
Costimulation of APCs and T cells, inflammation
and fever, acute phase response,
hematopoiesis
IL-2 Activated Th1 cells, NK
cells
Proliferation of B cells and activated T cells, NK
functions
IL-3 Activated T cells Growth of hematopoietic progenitor cells
IL-4 Activated T cells B cell proliferation, eosinophil and mast cell
growth and function, IgE and class II MHC
expression on B cells, inhibition of monokine
production
IL-5 Th2 and mast cells Eosinophil growth and function
IL-6 Activated Th2 cells,
APCs, other
somatic cells
Acute phase response, B cell proliferation,
thrombopoiesis, synergistic with IL-1 and TNF
on
T cells
Selected cytokines and their primary activities
22. IL-7 Thymic and marrow
stromal cells
T and B lymphopoiesis
IL-8 macrophages, somatic
cells
Chemoattractant for neutrophils and T cells
IL-9 T cells Hematopoietic and thymopoietic effects
IL-10 Activated Th2 cells, CD8+
T and B
cells, macrophages
Inhibits cytokine production, promotes B cell
proliferation and antibody production,
suppresses cellular immunity, mast cell growth
IL-11 Atromal cells Synergistic hematopoietic and thrombopoietic
effects
IL-12 B cells, macrophages Proliferation of NK cells, IFN production,
promotes cell-mediated immune functions
IL-13 Th2 cells IL-4-like activities
IL-18 Macrophages potent inducer of interferon-+ by T cells and NK
cells
IFN-α
IFN-β
Macrophages,
neutrophils and
some somatic cells
Antiviral effects, induction of class I MHC on all
somatic cells, activation of NK cells and
macrophages
23. IFN-γ Activated Th1 and NK
cells
Induces of class I MHC on all somatic cells,
induces class II MHC on APCs and somatic
cells, activates macrophages, neutrophils, NK
cells, promotes cell-mediated immunity,
antiviral effects
MIP-1α Macrophages Chemotaxis
MIP-1β Lymphocytes Chemotaxis
TGF-β T cells, monocytes Chemotaxis, IL-1 synthesis, IgA synthesis, inhibit
proliferation
TNF-α macrophages, mast cells,
NK
cells, sensory neurons
Cell death, inflammation, pain
TNF-β Th1 and Tc cells phagocytosis, NO production, cell death
24. Lymphokines
• 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.
26. Function 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
27. Monokines
• A monokine is a type of cytokine produced primarily by
monocytes and macrophages.
• Examples include interleukin 1 and tumor necrosis factor-alpha
(TNFβ).
• Other monokines include alpha and beta interferon, and colony
stimulating factors.
• Monokines can function as chemoattractants for guiding
neutrophil migration
28. chemokines
• Are a large family of structurally homologous cytokines that stimulate
leukocyte movement and regulate the migration of leukocytes from
the blood to tissues.
• Chemokine receptors are cytokine receptors found on the surface of
certain cells that interact with a type of cytokine called a chemokine.
• Following interaction with their specific chemokine ligands,
chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions
(calcium signaling).
• This causes cell responses, including the onset of a process known as
chemotaxis that traffics the cell to a desired location within the
organism.
• Chemokine receptors are G protein-coupled receptors containing 7
transmembrane domains that are found predominantly on the
surface of leukocytes.
29. Typical structure of a chemokine receptor has seven transmembrane
domains and a characteristic "DRY" motif in the third intracellular domain.
Chemokine receptors are usually linked to a G-protein through which they
signal.
30.
31.
32. Major biological functions of chemokines and receptors
• Homeostasis and development: e.g. CXCL12 (SDF-1) is constitutively
expressed in bone marrow-derived stromal cells, promotes proliferation of B
cell progenitors , and mobilizes the emigration of hematopoietic precursors to
the bone marrow during embryogenesis.
• In trafficking of lymphocytes and dendritic cells: Lymphocyte homing to
lymphoid and nonlymphoid tissues and recirculation between secondary
lymphoid organs critically depend on the chemokines present in different sites.
CCL19 and CCL21 (which bind to CCR7), and CXCL13 (which binds to CXCR5), are
expressed in the lymphatic vessels, high endothelial venules (HEVs) and
secondary lymphoid organs, and promote the entry of antigen-presenting cells
(APCs), T cells and B cells into these organs.
• Inflammation: participate in and control the process of a number of acute
and chronic inflammatory conditions by promoting the infiltration and
activation of inflammatory cells into injured or infected Tissues, eg Members of
the CXC chemokines
33. • Atherosclerosis: an inflammatory disease, in which chemokines play a central
role in leukocyte recruitment, angiogenesis, and more intriguingly in the
proliferation of vascular smooth muscle cells and their migration into plaques,
e.g. CCL2, CCL3,CCL4, CCL5, CCL11 and CXCL8
• Chemokines and angiogenesis: Chemokines act either as positive or negative
regulators of angiogenesis eg CXCL1, -2, -3, -5, -6, -7, and -8.
• Allergy: contributing to allergic disorders, in particular to allergic airway
inflammation such as allergic rhinitis and asthma
• Chemokines and tumor growth: Chemokines secreted by tumours not only
attract infiltrating cells into tumour sites but may also contribute to tumour cell
growth e.g. CXCL1, -2, and -3) and CXCL8.
• CXCR4 and cancer metastasis: selected chemokine receptors are often up-
regulated in a large number of common human cancers, including those of the
breast, lung, prostate, colon, and melanoma.
• Microbial infection: Chemokines are expressed at high levels in virtually every
kind of microbial infection examined.
34.
35.
36.
37. MHC
•Major Histocompatibility Complex
• Cluster of genes found in all mammals
• Its products play role in discriminating self/non-self
• Participant in both humoral and cell-mediated immunity
•In Human MHC Is Found On Chromosome 6
• Referred to as HLA complex
•In Mice MHC Is Found On Chromosome 17
• Referred to as H-2 complex
38. • Class I MHC Genes Found In Regions A, B and C In Humans (K and D In
Mice)--- polygenecity
• Class II MHC Genes Found In Regions DR, DP and DQ (IA and IE In
Mice)--- polygenecity
• Class I and Class II MHC Share Structural Features
• Both involved in APC
• Class III MHC Have No Structural Similarity To Class I and II
• For example TNF, heat shock proteins, complement components
Class I, II and III MHC
39.
40.
41. •MHC products are highly polymorphic
• Vary considerably from person to person
•However, crossover rate is low
• 0.5% crossover rate
• Inherited as 2 sets (one from father, one from mother)
• Haplotype refers to set from mother or father
•MHC alleles are co-dominantly expressed
• Both mother and father alleles are expressed
•Inbred mice haplotypes are designated with italic superscript
• For example H-2b
• Designation refers to entire set of H-2 alleles
MHC Genes Are Polymorphic
42. Diversity of HLA molecules in human population is caused by copy
number variation in concert with polymorphism
44. •several hundred allelic variants have been identified in
humans
•However, up to 6 MHC I And 12 MHC II Molecules Are
expressed in an individual
•enormous number of peptides needs to be presented using
these MHC molecules
•To achieve this task MHC molecules are not very specific for
peptides (unlike TCR and BCR)
•Promiscuous Binding Occurs
• A peptide can bind a number of MHC
• An MHC molecule can bind numerous peptides
Class I And II Specificity
45. •MHC Is One Of The Most Polymorphic Complexes Known
•Alleles Can Differ Up To 20 a/a
•Class I Alleles In Humans: 240 A, 470 B, 110 C
•Class II Alleles In Humans: HLA-DR 350 , 2 !
•HLA-DR
• genes vary from 2-9 in different individuals!!!,
• 1 gene ( can combine with all products increasing number of
APC molecules)
•DP (2 , 2 ) and DQ (2 , 3 )
Class I And II Diversity And Polymorphism
46. There are no rearrangements
•Thus, MHC proteins (from the “haplotype”) constitute a
life-long cell surface character for any vertebrate.
• This circumstance is very different from Ig’s which are constantly
being generated in response to new foreign proteins and
carbohydrates in the environment.
•The loci which specify MHC’s are polymorphic.
• Many alleles may exist at a locus:
• HLA A locus has ~60 alleles
• HLA B locus ~110 alleles
• HLA C locus ~40 alleles
• The high level of allelism creates diversity within a species (thus
restricting allografting) but does not produce diversity within an
individual.
47. •Peptides presented through MHC I Are endogenous proteins
•As few as 100 Peptide/MHC complex can activate TC
•Peptide Features
• size 8-10 a/a, preferably 9
•Peptides bind MHC due to presence of specific a/a found at
the ends of peptide. For example Glycine @ Position 2
Class I MHC Peptides
48.
49. •Peptides presented through MHC II are Exogenous
• Processed through endocytic pathway
•Peptides are presented to TH
•Peptides are 13-18 a/a Long
•Binding Is Due To Central 13 a/a
• Longer peptides can still bind MHC II
•MHC I peptides fit exactly, not the case with MHC II peptides
Class II MHC Peptides
50. •Expression is regulated by many cytokines
• IFN, IFN, IFN and TNF Increase MHC expression
•Transcription factors that increase MHC gene expression
• CIITA (Transactivator), RFX (Transactivator)
•Some viruses decrease MHC expression
• CMV, HBV, Ad12
•Reduction of MHC may allow for immune system evasion
MHC Expression
