Ch05

Clinical Immunology & SerologyA Laboratory Perspective, Third Edition

Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company

Cytokines

Chapter Five


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.



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.



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.



Cytokines The major cytokine families include tumor

necrosis factors (TNF), interferons (IFN),

chemokines, transforming growth factors

(TGF), colony-stimulating factors (CSF) and

interleukins.



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.



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.



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.



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).



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.



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.



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).



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.



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.



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.



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.



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.



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.



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.



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.



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).



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).



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.



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.



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.



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).



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.



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.



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.



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.



CytokinesFigure 5-5

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