Cytokine and chemokine 2021 (Prof. Moiz).pptx

Cytokines and Chemokines in Health and Disease Moiz Bakhiet, MD, Ph.D., Professor of Immunology and Consultant Neurologist 1 Biological aspects of cytokine function Cytokines are pleiotropic: act on variety of different cells and often produce different effects Endocrine Paracrine Autocrine 2 T cell...

Cytokines and Chemokines in Health and Disease Moiz Bakhiet, MD, Ph.D., Professor of Immunology and Consultant Neurologist 1 Biological aspects of cytokine function Cytokines are pleiotropic: act on variety of different cells and often produce different effects Endocrine Paracrine Autocrine 2 T cell activation Intercellular adhesion Lymphocyte function molecules (ICAM) associated Ag (LFA-1) CD40 MHC I APC CD40L CD4 (CD8) MHC II T cell TCR/CD3 CD28 B7.1 (B7.2) CD80 (CD86) CTLA4 3 Primary structures of MHC class I and class II The two MHC proteins have a similar secondary and tertiary structure with subtle functional differences Class I molecules are made up of one heavy chain (45 kD) and a light chain called ß2microglob ulin (12 kD) that contributes to the overall structure of the protein Class II molecule s do not contain ß2microglo bulin and consist of two (alpha and ß) chains of similar size (34 and 30 kD) 4 IL-2 IL-4 T-cell growth IL-3 & GM-CSF Hematopoietic stem cell growth Proliferation Th2 Th1 IL-5 IFN-g  Activates macrophages  Induces MHC  B-cell differentiation IL-12 B-cell growth IL-6 IL-1 B-cell maturation induces fever  Activates T-cells Induces IFN-g by NK cells  Endogenous and T-cells pyrogen IL-18  IFN-g inducing factor TNF-a IL-32 IL-10 Cytokine synthesis inhibitory factor IL-36/38  Proinflammatory  Member of IL-1 family IL-25  Induces leukocytosis, fever, Wt loss and necrosis of some tumors   Its encoding gene is closely linked with Anti-flammatory  Member of IL-1 family IL-37 lymphoyoxin or TNF-b IL-15 Shares biological activities with IL-2 IL-23, 27, 35 Ig class switch IgE synthesis Growth and differentiation IFN-g & IL-10 Composed of the IL-12 p40 subunit and a p19, p28 & a p35 TGF-b Inhibits growth of T cells and macrophages IL-13  Inhibit production of proinflammatory cytokines  B-cell prolif. & different.  Does not act on T-cells IL-14 B-cell growth factor IL-19, 20, 22, 26 IL-10 homologue 5 IL-7 Growth factor for pre B and pre T cells IL-8 Attracts neurophils IL-9 T cell growth factor IL-11 B cell and macrophage growth factor IL-16 T cell chemoatractant factor Secreted by CD8 and acts on CD4 IL-17 Secreted by activated memory CD4 cells Early initiator of T cell dependent inflammatory reactions IL-21 NK expansion Regulate lymphocyte function Interleukin 31 Produced by activated T cells induces dermatitis in mice Interleukin 33 Has structural similarity to IL-1 & IL-18 Interleukin 34 stimulates monocyte viability 6 Regulation of normal body functions, e.g. Metabolism Wound healing and tissue repair Inflammation Infections GI and liver disease Cardiovascular and atherosclerosis Rheumatology Hematological effects CNS diseases Lung injury Skin disease Cancer Septic shock 7 Schematic representation of processes involved in wound healing Wounding Platelet aggregation Cell immigration Removal of debris Cytokines Cell activation Secretion of growth factors Neovascularisation Cell proliferation Re-epithelialisation Granulation Formation of new tissues Wound Closure Scar tissue 8 Class I MHC Pathway 9 Class II MHC Pathway 10 Immune mediators contribute to the developmen of neuroinflammatory disorders: BBB y or m l e M ce l T 2 Th e +v ro Ab p ell c g n duci IFN-g ne uro n Th1 CD 8  TGF-b M Ac t rea ivated ctiv e T myeli ce l n l Adhesion molecule IL-10 on i t na i l ye m e d CNS myelin contains proteins differing in size, shape and composition as myelin basic protein (MBP), 11 proteolipid protein (PLP), myelin-associated glycoprotein (MAG), Myelin oligodendrocyte glycoprotein (MOG) Interferons Interferons are divided into two Types: Type I IFNs: Are all derived from the same gene and have retained sufficient structural homology to act via the same cell surface receptor. They mainly comprise IFN-a and IFN-b. They are major contributors to the first line of antiviral defense. They belong to the network of cytokines that are involved in the control of cellular function and replication and that become actively engaged in host defense during infection. Type I interferons are used in the clinic as antiviral and anti-tumor agents, and also to treat multiple sclerosis. 12 Type II IFN or IFN-g: Is a cytokine that displays molecular homology with type I IFNs, but shares some important biological activities. In addition to its antiviral activities, it is an important modulator of the immune system.  Induction of expression of MHC antigens  Activation of macrophages  Immunosuppression   Induction of production of other cytokines like TNF-a and IL-1 Maturation of B cells  Induction of cell death of effector T cells  Enhancement of natural cytotoxic activity   Promotion of proliferation and activation of astrocytes, which may then be primed to TNF-a production Recruitment of T cells into the CNS 13 Type III IFNs IL-28A, IL-28B and IL-29; alternatively named: IFN-lambda1 (IL-29) IFN lambda-2 (IL-28A) IFN-lambda3 (IL-28B) 14 IFN IFN signalling pathway Jak 2 P Jak 1 P Tr an sc P P P P fa ript cto ion r P Signal transduction (activated STAT) Cytoplasm Nucleus P P IFN-induced proteins ISRE ISRE: IFN-stimulatory response element 15 Chemokines are chemoattractant cytokines that form a large family of structurally related proteins The chemokine superfamily is divided into four groups based on structural, functional, and genetic criteria: 1. CXC (a-family): IL-8, MIP-2* 2. CC (b-family): MIP-1a, MIP-1b, MCP**, RANTES*** 3. C (Lymphotactin) 4. CX3C (Neurotactin/fractalkine) *Macrophage inflammatory protein **Monocyte chemotactic protein ***Comes later 16 a chemokines are potent chemotactic agents for monocytes, lymphocytes and other cell types such as basophils and eosinophils MIP-1a, MCP-1, and RANTES induce leukocyte migration and accumulation in inflammatory site MIP-2 has been functionally characterized as a major polymorphonuclear activating factor and chemoattractant 17 Regulated upon Activation, Normal T cell Expressed and Secreted New nomenclature: 18 Chemokine Nomenclature C Family CX3C Family CC Family CXC Family Reference Zlotnik, A. and Yoshie, O. (2000) Immunity 12:121. 19 20 21 22 23 24