Chapter 12- cytokines!

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Chapter 12- cytokines!

• Where were going
• Well learn just a few cytokines- IL2,4, IFN?,
  TNFa
• Well learn a few basic types of cytokines
• Well learn about pleiotrophy, redundancy,
  synergy, and antagonism
• Well learn about some of the steps, and a few
  more kinases
• Youll be even further convinced that the immune
  system is a simple thing (ha!)

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Overview

• Cell signaling molecules- weve seen them before-
  IL2, IL7, IFN?
• Bind to the surface, and produce internal
  changes- signal transduction.
• LOTS of them!
• Most work by autocrine or paracrine action- vs
  endocrine

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Cytokines will be mostly autocrine and paracrine
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Notice the big player here!
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A typical cytokine
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In general, theyre not vey big, lots of alpha
helices 133 aa 14,000 molecular weight.
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Note the 2 major players Th and Mphages. They
affect inflammation and adaptive immunity!
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You dont have to learn these!
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Cytokines fall in 4 families, receptors in five
(???) Well talk about the receptor families
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Well spend most of our time here!
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Explaining redundancy and antagonism
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Same signal gets transduced!
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So why have these? Receptors can readily differ
by cell type, and response will differ by cell
type.
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Redundancy
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Antagonism, but How would you know??? There must
be some unique aspect of the signal, contributed
by the a subunit!
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IL2 and strategies for response

• Intermediate and High-affinity receptors
• Signal 1 2- the Th, upon activation, makes a
  high affinity receptor, AND IL2!
• No ? chain- an X-linked form of SCID.

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The low affinity receptor is probably an
artifact- just b/c it can bind at low affinity
doesnt mean it does at physiological
concentrations.
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IL2, IL3, IFNgamma, etc.
JAK just another kinase, or Janus kinase (two
faces)
STAT now has an affinity for JAK, and gets
phosphorylated
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IFN gamma bound to its receptor
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Evil viral strategiesViruses make compounds
that competitively inhibit binding of cytokine to
its receptor, or act as soluble, fake receptors,
reducing response.
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IL-10 may push response to Th2- doesnt destroy
EBV
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The Th1 and Th2 story

• Th1- think mostly cell mediated response-
  activated Mphages, Tcs, but also opsonic and
  complement-fixing IgGs- defeat bacterial
  invaders.
• Th2- think mostly antibody response- Other
  antibody classes, including IgE, eosinophil
  activation (helps fight parasites?)

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Note that the decision to be a Th1 or Th2 can
depend upon local cytokine effects, but that
these are then amplified due to positive feedback
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The wrong response can kill you

• Leprosy- Mycobacterium leprae diseae comes in two
  types
• Tuberculoid- good type- cell-mediated response,
  activated Mphages, granuloma formation, slow
  progression, patient lives.
• Lepromatous- bad type- suppressed
  cell-mediated, Ab production that is not helpful.
  Actually grows in the Mphage!!!. Disseminated,
  nerve damage, bone and cartilage,

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These are Northern blots- mRNA levels
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Some bad conditions are basically cytokine
responses

• Septic shock- LPS induces massive Mphage
  response, IL1, TNF alpha, fever, shock Abs
  agains TNF alpha can protect.
• Same w/ toxic shock- activated T cells activate
  Mphages, -gt IL1, TNFs

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Things we can do w/ cytokines

• Use them therapeutically- IFNs IL2- BUT-
  side-effects can be bad.
• Block their actions w/ Abs or analogs.

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Things to know

• Definitions paracrine, autocrine, etc.
• Types of responses
• Typical response story- JAK,STAT, etc
• Th1 and Th2 Typical responses, major cytokines
  involved.
• Leprosy as an example.

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Major cytokine functions

• Inflammation IL1, TNF alpha, Mphage produced
• IL2- Th stimulation
• IL4 Th2 stimulation, Th1 suppression
• IL12 Th1 response stimulated.
• IFN gamma Mphage activation, Th2 suppression.
  (Fig. 12-12)

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Quiz on Wed

• Terms- affinity maturation, somatic hypermutation
• Antigen-independent and dependent stages of B
  cell maturation
• Th1 and Th2
• Recognize redundancy, pleiotropy, antagonism, and
  synergy when you see it.