Transcript Immunology
Immunology Chapter 13 • • • • • • • 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 – – – – 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)