Immunology Chapter 13

1. ImmunologyChapter 13 • Richard L. Myers, Ph.D. • Department of Biology • Southwest Missouri State • Temple Hall 227 • Telephone: 417-836-5307 • Email: rlm967f@mail.smsu.edu

2. 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

3. 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

4. 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

5. Fig 13-4 Kuby

7. Interleukins and other cytokines • Many cytokines are called interleukins • because they are secreted by leukocytes • and act upon other leukocytes • there are over 20 identified to date • Other cytokines known by a common name • interferons • tumor necrosis factors

8. TNF-a

9. Function of cytokines • Generally function as intracellular messenger molecules • evoke a specific biological activity • Two principle producers are 1) macrophages and 2) TH cells • Rarely act alone • Often induce the synthesis of other cytokines

10. When a cytokine binds to its receptor, it induces numerous physiological responses • development of 1) cellular and 2) humoral immune responses • induction of the inflammatory response • regulation of hematopoiesis • control of cellular proliferation and differentiation • induction of wound healing

11. Cytokine receptor families or Class I IFN-a,b,g Interferon or Class II

12. 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

13. 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

14. 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

15. 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

16. Cytokines and disease • Defects in cytokine regulatory networks have been implicated in disease • overexpression • underexpression • A variety of cytokine abnormalities may lead to disease

17. Bacterial septic shock • Results from overproduction of cytokines • By gram-negative cells • Symptoms include • drop in blood pressure • fever • diarrhea • blood clotting • LPS causes macrophages to overproduce IL-1 and TNF-a

18. 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

19. 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

20. 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

21. 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

22. Assignment • Read Chapter 14, Complement • Review question 5 (pg 355)