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Chapter 12- cytokines!

Chapter 12- cytokines!. Where we’re going We’ll learn just a few cytokines- IL2,4, IFN γ , TNF α We’ll learn a few basic types of cytokines We’ll learn about pleiotrophy, redundancy, synergy, and antagonism We’ll learn about some of the steps, and a few more kinases

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Chapter 12- cytokines!

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  1. Chapter 12- cytokines! Where we’re going • We’ll learn just a few cytokines- IL2,4, IFNγ, TNFα • We’ll learn a few basic types of cytokines • We’ll learn about pleiotrophy, redundancy, synergy, and antagonism • We’ll learn about some of the steps, and a few more kinases • You’ll be even further convinced that the immune system is a simple thing (ha!)

  2. Overview • Cell signaling molecules- we’ve seen them before- IL2, IL7, IFNγ • Bind to the surface, and produce internal changes- signal transduction. • LOTS of them! • Most work by autocrine or paracrine action- vs endocrine

  3. Cytokines will be mostly autocrine and paracrine

  4. Notice the big player here!

  5. A typical cytokine

  6. In general, they’re not vey big, lots of alpha helices; 133 aa ~ 14,000 molecular weight.

  7. Note the 2 major players: Th and Mphages. They affect inflammation and adaptive immunity!

  8. You don’t have to learn these!

  9. Cytokines fall in 4 families, receptors in five (???) We’ll talk about the receptor families

  10. We’ll spend most of our time here!

  11. Explaining redundancy and antagonism

  12. Same signal gets transduced!

  13. So why have these? Receptors can readily differ by cell type, and response will differ by cell type.

  14. Redundancy

  15. Antagonism, but How would you know??? There must be some unique aspect of the signal, contributed by the α subunit!

  16. 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 γ chain- an X-linked form of SCID.

  17. The low affinity receptor is probably an artifact- just b/c it can bind at low affinity doesn’t mean it does at physiological concentrations.

  18. IL2, IL3, IFNgamma, etc. JAK= just another kinase, or Janus kinase (two faces) STAT now has an affinity for JAK, and gets phosphorylated

  19. IFN gamma bound to its receptor

  20. Evil viral strategiesViruses make compounds that competitively inhibit binding of cytokine to its receptor, or act as soluble, fake receptors, reducing response.

  21. IL-10 may push response to Th2- doesn’t destroy EBV

  22. The Th1 and Th2 story • Th1- think “mostly cell mediated response”- activated Mphages, Tc’s, 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?)

  23. 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

  24. 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,

  25. These are Northern blots- mRNA levels

  26. Some bad conditions are basically cytokine responses • Septic shock- LPS induces massive Mphage response, IL1, TNF alpha, fever, shock; Ab’s agains TNF alpha can protect. • Same w/ toxic shock- activated T cells activate Mphages, -> IL1, TNF’s

  27. Things we can do w/ cytokines • Use them therapeutically- IFN’s IL2- BUT- side-effects can be bad. • Block their actions w/ Ab’s or analogs.

  28. 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.

  29. 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)

  30. 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.

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