Immunology Serology Lecture Notes  Synergic interactions – cytokines

complement and enhances one

CYTOKINES
another
 Cytokines are chemical  Antagonism – one cytokine
messengers that regulate the counteracts the action of another
immune system.  Cascade induction – a cytokine
o Small proteins produced by secreted by a specific type of cell
different cell types that can activate target cells to produce
influence the hematopoietic additional cytokines.
and immune systems o Produce a spectrum of
o Produced in response to the activities that lead to the
binding of stimuli such as rapid generation of both
bacterial lipopolysaccharides, innate and adaptive immune
flagellins or other bacterial response.
products. o Hypercytokinemia –
massive overproduction and
Effects of Cytokines In Vivo dysregulation of cytokines
 Autocrine – affecting the same cell “cytokine storm”
 Paracrine – affecting a target cell in  Tularemia, Influenza
close proximity A
 Endocrine – targets a distant cell Cytokines in the Innate Immune
trough the bloodstream Response
 Initially, cytokines were named
based on their activities and the type  Responsible for many of the physical
of cells from which they were first symptoms attributed to inflammation
isolated from. Major Major Anti-
o Lymphocytes – lymphokines Proinflammatory Inflammatory
o Monocytes – monokines Cytokines Cytokines
 Now, cytokines are grouped into TNF-alpha TGF-beta
families: IL-1 IL-10
o Tumor necrosis factor (TNF) IL-6 IL-13
o Interferon (IFN) IFN-y (gamma) IL-35
o Transforming Growth factor
(TGF) Interleukin 1 – (IL-1)
o Colony stimulating factor
(CSF)  IL-1a, IL-1b, ILRA (receptor
o Interleukins (IL) antagonist)
o IL-1a, IL-1b –
Functionally, Cytokines may exhibit: proinflammatory cytokines
produced by monocytes,
 Pleiotrophy – a single cytokines
macrophages, and dendritic
can have many different actions
cells
 Redundancy – when different
 Induced by the presence of microbial
cytokines activate some of the same
pathogens, bacterial
pathways and genes
lipopolysaccharides, or other
cytokines.
  Induces the production of vascular Interleukin 6 (IL-6)
cell adhesion.
 Single protein produced by both
 Induces the production of CSFs in
lymphoid and nonlymphoid cells.
the bone marrow.
 Part of the cytokine cascade that
 IL-1a – remains inside the cells,
plays a role in response to
released after cell death and can
lipopolysaccharides and acute-
help attract inflammatory cells to
phase reactions.
areas where cells and tissues are
 Stimulates B-cells to proliferate and
being killed or damaged.
differentiate into plasma cells and
 IL-b – responsible for most of the
induces CD4+ T cells to produce
systemic activity attributed to IL-1
greater quantities of both pro and
(fever, activation of phagocytes and
anti-inflammatory cytokines.
production of APRs)
 IL-1RA – cytokine inhibitor,
antagonist to IL-1
Chemokines

 Family of cytokines that enhances

Tumor Necrosis Factor (TNF)
 TNF-a – most prominent member of
the TNF superfamily
o Causes vasodilation and
increased vasopermeability
o Main trigger for production is
the presence of
lipopolysaccharides which is
found in G(-) bacteria
o Secreted by activated
monocytes and
macrophages – can activate
T cells
 Enhances antigen
presentation and
activate T cells to
respond to the
pathogen
 when secreted at higher levels, TNF
can have deleterious systematic
effect (ex. Septic shock)
 TNFR1 – binds soluble TNF-a
primary mediator of TNF-a signal
transduction in most cell types.
motility and promote migration of
many types of WBC toward a
chemokine source via the process
known chemotaxis.
 Play key roles in the initiation and
development of inflammatory
response in numerous disease
process
Transforming Growth Factor – b (beta)
 Originally characterized as a factor
that induce growth arrest in tumor
cells
 Identified as a factor that induces
antiproliferative activity
 Regulators of cell growth,
differentiation, apoptosis, migration,
and inflammatory response
 Downregulates inflammatory
response when no longer needed
Interferon

 Interferes with viral replication

 Produced by the dendritic cells and
induce production of proteins and
 pathways that interfere with viral
replication and cell division
 Type 1 FN – activates NK cells and
enhances expression of class I MHC
proteins.
Cytokines in the Adaptive Immune
Response
 Mainly secreted by T cells,
especially Th cells and affect T- and
B- cell function more directly
 3 subclasses:
o T helper 1 (Th1)
o T helper 2 (Th2)
o T regulatory cells
 Another subset, Th17, affect both
innate and adaptive immune
response.
Th1 (T helper 1)
 Dendritic cells in damaged tissues
produce IL-12 in response to certain
stimuli such as mycobacteria,
intracellular bacteria, and viruses
o Also produced by
macrophages and B cells
o Has multiple effects on both
T cells and NK cells
o Binds to its receptor on naïve
T cells and causes the
expression of new set of
genes, including those that
determine maturation into the
Th1 lineage.
 (T cell is made from
bone marrow)
IFN-y (gamma)
 Principal molecule produced by Th1
cells
 Stimulates antigen presentation by
class I and II MHC molecules
o Increased expression of
class I and II MHC molecules
on antigen-presenting cells
increases the likelihood of
antigen capture and
involvement of additional
lymphocytes.
 Most potent activator of
macrophages and boosts their
tumoricidal activity
 Involved in regulation and activity of
Interleukin-2 (39 mins)
 “T-cell growth factor”
 Drives the growth and differentiation
of both T and B cells and induces
lytic activity in NK cells
 IL-2 and IFN-y induce the
development of Th1 cells, which in
turn, induces macrophage activation
and delayed type hypersensitivity
 Can activate proliferation of Th2
cells and helps generate IgG1 and
IgG1 and IgE producing cells
Th2 Cytokines
 Responsible for antibody-mediated
immunity
 Important regulators of the immune
response
Interleukin-4 (under Th2)
 Key cytokine regulating Th2 immune
activities and helps drive antibody
responses in a variety of diseases
 IL-4 activity on naïve T cells turns on
the genes that generate Th2 and
turns off the genes that promote Th1
  Stimulates the production of IgG2
and IgE
Interleukin-10 (IL-10)
 Produced by monocytes,
macrophages, CD8+ T cells, and
Th2 CD4+ T cells and has anti-
Clinical Assays for Cytokines
inflammatory and suppressive
effects on Th1 cells.
 Inhibits antigen presentation by
macrophages and dendrite cells
 Inhibition of IFN-y production via
suppression of IL-12 synthesis
(antagonist)
Cytokines associated with T regulatory
Cells
 CD4+ and CD25+ T cells, iTregs
 Play a key role in establishing
peripheral tolerance to a wide variety
of self-antigens, allergens, tumor
antigens, transplant antigens, and
infectious agents.
 Responsible for producing IL-10 and
TGF-b expression in adaptive T
regulatory cells
o IL-3, EPO, G-CSF, M-CSF,
GM-CSF,
o IL-3 – a multilineage CSF
that incudes bone marrow
stem cells to form T and B
cells
 Useful in the prognosis and
diagnosis of treating autoimmune
diseases
 ELISpot Assay – employs the
ELISA technique on in vitro activated
peripheral WBCs
 Multiplexed ELISAs – several
detector antibodies bound to
individual microwells or antibody
microarrays and allow for
simultaneous detection of several
cytokines from serum or plasma
 Microbead assays – simultaneous
detection of multiple cytokines in a
single tube.

Th17 Cytokines in Innate and Adaptive

Immune response

 Secretes IL-17 family of cytokines

 Key cytokines that differentiate T
cells to maintain them as Th17 cells
are TGF-b and IL-6
 Th17 plays

Hematopoietic Growth Factors

 CSF (Colony Stimulating factors) –

primary mediators of hematopoiesis