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SEROLOGYTRANSCRIPT
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company
Cytokines
Chapter Five
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Cytokines are small soluble proteins that
regulate the immune system’s innate immunity
and the adaptive response to infection.
Cytokines are induced in response to specific
stimuli, such as bacterial lipopolysaccharides,
flagellin, capsular anigens, toxins, and other
bacterial products.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Cytokine production occurs through the
ligation of cell adhesion molecules or through
the recognition of foreign antigens by host
lymphocytes.
The effects of cytokines in vivo include
regulation of growth, differentiation, and gene
expression by many different cell types,
including leukocytes.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Cytokines exert their effects through
autocrine stimulation (i.e., affecting the same
cell that secreted it), paracrine stimulation
(i.e., affecting a target cell in close proximity),
and occasionally by systemic or endocrine
activities.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The major cytokine families include tumor
necrosis factors (TNF), interferons (IFN),
chemokines, transforming growth factors
(TGF), colony-stimulating factors (CSF) and
interleukins.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The pleiotropic (i.e., having many different
effects) nature of cytokine activity relates to
the widespread distribution of cytokine
receptors on many cell types and the ability of
cytokines to alter expression of numerous
genes. Eg. IL-2 activates T cells, B cells and
NK cells.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Many different cytokines may share receptors
and properties—that is, they activate some of
the same pathways and genes. (redundancy)
Eg. B cells may be regulated by IL-2, IL-4, and
IL-5.
Figure 5-1 in the text illustrates some of the
different actions of cytokines.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The pattern of cytokine expression can also
determine whether the host will be able to
mount an effective defense against and
survive certain infections.
Numerous immunodeficiency syndromes and
leukemias are caused by defects in cytokines
or their receptors/signal transduction circuits.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Cytokines involved in the innate immune
response are responsible for many of the
physical symptoms attributed to inflammation,
such as fever (IL-1), swelling, pain, and
cellular infiltrates into damaged tissues.
The innate immune response is nonspecific
but occurs within hours of first contact with
microorganisms (see Chapter 1).
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The main function of the innate immune
response is to recruit effector cells to the
area.
Cytokines involved in triggering this
response are interleukin-1, tumor necrosis
factor-α, interleukin-6 chemokines,
transforming growth factor-β, and interferons,
both α and β.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The IL-1 family consists of IL-1α, IL-1β, and
IL-1RA (IL-1 receptor antagonist to turn off the
immune response when no longer needed).
IL-1α and IL-1β are proinflammatory cytokines
produced by monocytes and macrophages.
IL-1β is responsible for most of the systemic
activity attributed to IL-1, including fever,
activation of phagocytes, and production of
acute phase proteins.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines IL-1 acts as an endogenous pyrogen and
induces fever in the acute phase response
through its actions on the hypothalamus.
IL-1 also induces the production of vascular
cell-adhesion molecules as well as
chemotaxins and colony-stimulating factors
(CSFs).
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines TNF-α is the most prominent member of the
TNF superfamily, which consists of at least 19
different peptides that have diverse biological
functions.
TNF-α causes vasodilation and increased
vasopermeability.
The main trigger for TNF-α production is the
presence of lipopolysaccharide, found in gram-
negative bacteria.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines TNF-α secreted by activated monocytes and
macrophages can activate T cells through its
ability to induce expression of MHC class II
molecules, vascular adhesion molecules, and
chemotaxins, in a similar manner to IL-1.
TNF-α is the central mediator of pathological
processes in RA and other inflammatory
illnesses, such as Crohn’s disease.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines IL-6, triggered by IL-1, is a pleiotropic
cytokine, affecting inflammation, acute phase
reactions, immunoglobulin synthesis, and the
activation states of B cells and T cells.
IL-6 stimulates B cells to proliferate and
differentiate into plasma cells and induces
CD4+ T cells to produce greater quantities of
both pro- and anti-inflammatory cytokines.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Shared expression of chemotaxin receptors
among different types of leukocytes allows for
the co-localization of multiple cell types to the
damaged tissue and helps to broaden the
response to tissue damage.
The gradient of chemokine concentration
enables the leukocyte to migrate into the
tissue in the direction of increasing chemokine
concentration.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokine receptors Adhesion molecules : During migration, wbc
inserts integrins into its plasma membrane.
These allow wbc to bind to selectins on
surface of endothelium
CCR5 and CXCR4 are chemokine receptors
that function as attachment sites for HIV on
CD4+ leucocytes. Those with certain
polymorphisms in these receptors are long-
term nonprogressors.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The transforming growth factor beta (TGF-
β) superfamily induces antiproliferative
activity in a wide variety of cell types.
Active TGF-β is primarily a regulator of cell
growth, differentiation, apoptosis, migration,
and the inflammatory response.
Thus, it acts as a control to help down-
regulate the inflammatory response when no
longer needed.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Interferons were originally so named because
they interfere with viral replication.
However, it is the type I interferons consisting
of IFN-α and IFN-β that function primarily in
this manner.
These interferons are produced by dendritic
cells and induce production of proteins and
pathways that directly interfere with viral
replication and cell division.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Type I IFN activates natural killer cells and
enhances the expression of MHC class I
proteins, thus increasing the recognition and
killing of virus-infected cells.
The type I interferons are also active against
certain malignancies and other inflammatory
processes.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines There are three main subclasses of Th cells:
Th1, Th2, and Treg (T regulatory cells).
Once the T-cell receptor (TCR) captures
antigen, clonal expansion of those particular
CD4+ T helper cells occurs.
Differentiation into Th1, Th2, or Treg cell
lineages is influenced by the spectrum of
cytokines expressed in the initial response
(see Fig . 5-4).
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Dendritic cells in damaged tissues produce IL-
12 in response to certain stimuli, such as
mycobacteria, intracellular bacteria, and
viruses.
IL-12 is also produced by macrophages and B
cells and has multiple effects on both Th1 cells
(release of gamma interferon) and natural
killer cells (promotes cytolysis).
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Th1 cytokines: IFN-γ is the principal
molecule produced by Th1 cells, and it affects
genes involved in regulation and activation of
CD4+ Th1 cells, CD8+ cytotoxic lymphocytes,
NK cells, IL-12R, and IL-18R
IFN-γ also stimulates antigen presentation by
APC using MHC I and MHC II molecules.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Th1 cytokines: IL-2: Th1 cells also secrete
IL-2 in addition to IFN-γ. IL-2 is also known as
the T-cell growth factor.
IL-2 drives the division and differentiation of
both T and B cells and induces lytic activity in
NK cells.
IL-2 alone can activate proliferation of Th2
cells and helps to generate IgG1- and IgE-
producing cells.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Th2 cytokines: Th2 cells are primarily
responsible for antibody-mediated immunity.
IL-4 is one of the key cytokines regulating Th2
immune activities and helps drive antibody
responses in allergies, autoimmune diseases,
and fighting off parasites.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Th2 cytokines: IL-10 has anti-inflammatory
and suppressive effects on Th1 cells.
It is produced by monocytes, macrophages,
CD8+ T cells, and Th2 CD4+ T cells.
It inhibits antigen presentation by
macrophages and dendritic cells (IL-10 serves
as an antagonist to IFN-γ by down-regulating
MHC gene transcription) while it stimulates
CD8+ T cells (CTL).
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines Treg cytokines: Tregs are CD4+ CD25+ T
cells that are selected in the thymus.
They play a key role in establishing peripheral
tolerance to a wide variety of self-antigens,
allergens, tumor antigens, transplant antigens,
and infectious agents.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines T-cell suppression occurs through IL-10
inhibition of proinflammatory cytokines and
inhibition of costimulatory molecule expression
on antigen-presenting cells (APCs).
TGF-β down-regulates the function of APCs
and blocks proliferation and cytokine
production by CD4+ T cells.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines The colony stimulating factors (CSFs)
include IL-3, erythropoietin (EPO) and
granulocyte (G-CSF), macrophage (M-CSF),
and granulocyte-macrophage (GM-CSF)
colony-stimulating factors.
In response to inflammatory cytokines such as
IL-1, the different colony-stimulating factors act
on bone marrow cells and promote specific
colony formation for the various cell lineages.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
Cytokines See Figure 5-5 for a summation of the
maturation of white blood cell lineages under
the influence of colony-stimulating factors.
Erythropoietin (EPO) regulates RBC
production in the bone marrow but is primarily
produced in the kidneys.
RBC proliferation induced by EPO improves
oxygenation of the tissues and eventually
switches off EPO production.
Clinical Immunology & SerologyA Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis Company
CytokinesFigure 5-5