Download Immunology

Immunology
Chapter 13
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Richard L. Myers, Ph.D.
Department of Biology
Southwest Missouri State
Temple Hall 227
Telephone: 417-836-5307
Email: [email protected]
Homepage:
http://creative.smsu.edu/biology/
myersr/index.html
• TopClass: http://creative.smsu.edu
Cytokines
• A group of low molecular weight
compounds control communication between
lymphoid, inflammatory and hematopoietic
cells
– collectively called cytokines
– for cell-to-cell communication
– sometimes called immune hormones
• Regulatory proteins that bind to specific
receptors on the surface of target cells
– elicit biochemical changes
– alters the pattern of gene expression in targets
Cytokine activities
• Autocrine action
– binding to the membrane of the secreting cell
• Paracrine action
– binding to receptors on a close target cell
• Endocrine action
– binding to target cells in distant parts of the
body
Regulation by cytokines
• Pleiotropy
– different biological effects on different cells
• Redundancy
– two or more cytokines mediate same function
• Synergy
– combined effect is greater than either alone
• Antagonism
– one offsets effects of another
Fig 13-4 Kuby
Interleukins and other cytokines
• Many cytokines are called interleukins
– because they are secreted by leukocytes
– and act upon other leukocytes
– there are approximately 20 identified to date
• Other cytokines known by a common name
– interferons
– tumor necrosis factors
• TNF-a
Function of cytokines
• Generally function as intracellular
messenger molecules
– evoke a specific biological activity
• Two principle producers are macrophages
and TH cells
• Rarely act alone but with many others
• Often induce the synthesis of other
cytokines
• When a cytokine binds to its receptor, it
induces numerous physiological responses
– development of cellular and humoral immune
responses
– induction of the inflammatory response
– regulation of hematopoiesis
– control of cellular proliferation and
differentiation
– induction of wound healing
Cytokine receptor families
or Class I
Interferon
or Class II
IFN-a,b,g
IL-2 receptor
• Three chain structure
• Has a, b and g chains
• Expressed on activated
T cells in three forms
– low affinity
– intermediate affinity
– high affinity
IL-2 facts
• Most studied of cytokine receptors
• Chain a has different structure
– expressed only by activated cells
– referred to as T-cell activation (TAC) antigen
• Signal transduction requires both b and g
• CD4 and CD8 express high-affinity IL-2
receptors and proliferate in response to IL-2
Cytokine signal transduction
• Recently, a unifying model was proposed
• Class I and II signal because of a cytokine
induced dimerization of receptor subunits
– allows for engagement of intracellular signaling
machinery
• Then JAK kinases (tyrosine kinases)
interact with dimerized receptors
– these phosphorylate each other and
transcription factors (STATs)
• STATs translocate to the nucleus and
activate gene transcription
Signal transduction
• Binding induces dimerization
• JAK interacts with tyrosine
kinases and phosphorylates
kinases
• Also STAT transcription
factors
• STATs dimerize and
translocate to nucleus
• Activate transcription of
specific genes
See Fig 13-9 Kuby
Cytokines and disease
• Defects in cytokine regulatory networks
have been implicated in disease
– overexpression
– underexpression
• A variety of cytokine abnormalities may
lead to disease
Bacterial septic shock
• Results from overproduction
of cytokines
• By gram-negative cells
• Symptoms include
–
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drop in blood pressure
fever
diarrhea
blood clotting
• LPS causes macrophages to
overproduce IL-1 and TNF-a
Bacterial toxic shock
• Some microorganisms produce
toxins that act as “superantigens”
• Staphylococcus aureus is a good
example
• It produces several superantigens
like enterotoxins, exfoliating and
TSST-1 toxins
• Excessive activation of T cells
produce excess cytokine
Superantigen binding
• Superantigens bind simultaneously
to a class II MHC and to the Vb
domain of the TCR
• They are not internalized,
processed and presented by APCs
• Binding is outside of the binding
cleft
• They can activate large numbers of
T cells irrespective of specificity
Superantigens
bind to MHCs
• Crystal structures show
that molecules like TSST-1
bind to a chains of class II
MHCs
• Binding of superantigen
does not interfere with
antigen binding site
Others
• Cytokines may be produced in different
levels in some types of cancer
– IL-6 overproduction in cardiac myxoma,
myeloma, cervical and bladder cancer cells
• Trypanosoma cruzi will cause Chagas’
disease
– immunosuppression results because the a
subunit of the IL-2 receptor is not made
Assignment
• Read Chapter 14,
Complement
• Review question 5 (pg
355)