Cytokines and Inflammatory Response Lecture Notes PDF

Cytokines and the inflammatory response Dr. Simone Sandiford [email protected]  What are cytokines? Small proteins synthesised and released by various cells of the body usually in response to an activating stimulus during an i...

Cytokines and the inflammatory response Dr. Simone Sandiford [email protected]  What are cytokines? Small proteins synthesised and released by various cells of the body usually in response to an activating stimulus during an immune response  Why are cytokines released? Cytokines are released by cells of the immune system in response to PAMPs and DAMPs and this alters the activation state and behaviour of other cells Cytokines influence the development of effector cells Cytokines trigger the maturation and differentiation of immune cell subsets into more specialized effector cells Enable effector cells to fight particular types of infections Detection of an infection by PRRs is translated to most appropriate immune response Abbas, Basic Immunology 6th edition Figure 6.7  Cytokines They are pleiotropic and redundant Immune cells release a particular blend of cytokines depending on cell type and activation status More than 100 cytokines have been identified See Janeway Immunobiology 9th edition Appendix III Broadly categorised into four main functional groups Interleukins Chemokines Interferons Colony simulating factors  Activity of cytokines Act by autocrine, paracrine or endocrine mechanisms One cytokine can influence the effect of other cytokines additive, synergistic or antagonistic properties Some cytokines Influence the synthesis of other cytokines Induce the formation of other inflammatory mediators Induce receptors for other cytokines on their target cells Activity of cytokines  Cytokine receptors Only cells with appropriate cytokine receptors can respond to a particular cytokine Cytokine receptors can be divided into five families Immunoglobulin superfamily receptors Class I cytokine receptors Class II cytokine receptors TNF receptor superfamily Chemokine receptor family Coico et al. Immunology a short course 7th edition figure 12.5  Common cytokine receptor chains Receptors consist of multiple subunits and one subunit may be common to some family members Redundancy of cytokines is partially due to the nature of the cytokine receptor Coico et al. Immunology a short course 7th edition figure 12.6  X linked severe combined immunodeficiency (X-SCID) X-SCID is due to defects in the common gamma chain Shared by IL 2, 4, 7, 9, 15, 17, 21 Blockade of multiple cytokine pathways important for development and function Absent T cells and natural killer cells, nonfunctional B cells Coico et al. Immunology a short course 7th edition figure 12.6 Disorder is fatal in the first two years of life if not treated definitively  Interleukins (ILs) Originally named because they signal between leukocytes Have a variety of functions including causing other cells to divide and differentiate Produced by different immune cells along with other cell types Classified based on function Pro-inflammatory - IL-1, IL-6, TNF- Inhibitory/anti-inflammatory -TGF-β, IL-10 Growth factors - IL-2, IL-7  TNF-α is a cytokine with many functions TNF-α triggers local containment of infection but induces shock when released systemically TNF-α has many functions: Prothrombotic Promotes leukocyte adhesion Macrophage activation Modulates haematopoiesis and lymphocyte development Male et al. Immunology 9th edition Figure 3.3  Chemokines Group of chemotactic cytokines that direct the movement of leukocytes in the body Different chemokines cause different types of leukocytes to accumulate IL-8/CXCL8 attracts neutrophils Eotaxin/CCL11 and MCP-1/CCL2 attract monocytes Some chemokines activate cells to carry out particular functions Signalling induced by IL-8 in neutrophils augments respiratory bust Janeway Immunobiology 9th edition Figure 3.4 Properties of selected chemokines Janeway Immunobiology 9th edition Figure 3.28  Interferons (IFNs) Termed coined because these cytokines interfere with viral replication Many different subtypes secreted by different cell types which all display antiviral activity Type I IFNs – e.g. IFNα, IFNβ Type II IFNs – IFNγ  Interferons (IFNs) IFNα and IFNβ produced by viral infected cells IFNγ released by activated Th1 cells Male et al. Immunology 8th edition Figure 1.6 Antiviral action of interferon  Colony stimulating factors (CSFs) Cytokines primarily involved in directing the division and differentiation of bone marrow stem cells Control how many leukocytes of each type are released from the bone marrow Granulocyte colony stimulating factor (G-CSF) Granulocyte-macrophage colony stimulating factor (GM-CSF) Macrophage colony stimulating factor (M-CSF)  Cytokines and the immune responses – innate and adaptative Acute inflammation T cell priming Development of specialised T-cell responses The end of the immune response Important characteristics of cytokines of the innate and (adaptive) immune system Abbas, Basic Immunology 6th edition Figure 2.15  T cell priming Occurs in the lymph nodes Antigen is presented by dendritic cells and recognised by T cells expressing the appropriate receptor DCs secrete co-stimulatory cytokines which help initiate T-cell responses Abbas, Basic Immunology 6th edition Figure 3.5 T cell development in responses to different types of microbes Abbas, Basic Immunology 6th edition Figure 6.3 Functions of cytokines involved in T cell mediated immunity Abbas, Basic Immunology 6th edition Figure 6.4  The end of the immune response When pathogen is cleared, levels of IL-1, type 1 IFNs, and TNF-α are reduced Recognition of apoptotic cells by macrophages leads to the production of anti- inflammatory cytokines IL-10 and TGF-β which promote Placek et al Epigenetic reprogramming of immune cells in tissue repair injury, repair and resolution J Clin Invest. 2019 Significant cytokines of the immune system Helbert Immunology for Medical Students 3rd edition Table 24.2  Cytokine storm Severe immune reaction in which the body releases too many cytokines into the blood too quickly Can occur because of an infection, autoimmune condition, other diseases or immunotherapies Can be life threatening and lead to multiple organ failure Cytokine storm - Ebola Cytokine storm – COVID-19  Inflammation – a response to tissue damage Latin inflammare (to set on fire) Major component of the body’s defence mechanism Protective response involving host cells, blood vessels and proteins Principle components: Increased blood supply to the infected area Increased capillary permeability permitting larger molecules to escape from the capillaries Migration of leukocytes out of the venules into the surrounding tissues  Inflammation Inflammation is NOT a synonym for infection Infection is the invasion of a host by a disease-causing pathogen Inflammation is the RESPONSE of the organism to the pathogen  Cardinal signs of acute inflammation Heat (calor) Redness (rubor) Swelling (tumor) Pain (dolor) Loss of function (functio laesa) Lawrence et. al Nature Reviews Immunology 2002  Acute vs. chronic inflammation Acute inflammation Chronic inflammation Complete elimination of a Incomplete elimination of a pathogen followed by resolution pathogen of the damage Persistent antigenic stimulus Disappearance of leukocytes and Cytotoxic effects of the full regeneration of tissue pathogen itself function  Acute inflammation Cells of the innate immune system respond to pathogens by secreting cytokines Phagocyte recognition of bacteria using Toll-like receptors (TLRs) for example leads to secretion of IL-1, TNF-α, G-CSF and IL-6 Stimulate local inflammation In viral infections: IFN type 1 secretion predominates Abbas, Basic Immunology 6th edition Figure 2.15 Pro-inflammatory cytokines enhance antigen presentation and development of Th1 responses Cytokines secreted by macrophages in response to bacterial pathogens Janeway Immunobiology 9th edition Figure 3.27  Migration of leukocytes to inflamed tissues Process of leukocyte migration is controlled by cytokines Chemokines activate circulating leukocytes causing them to bind to the endothelium and initiate migration across the endothelium Migration of leukocytes is known as diapedesis Male et al. Immunology 8th edition Figure 1.18  The phase arrival of different populations of leukocytes into a site of infection Phased arrival of different populations leads to acute and chronic inflammation having different cells Acute inflammation Higher numbers of neutrophils and activated helper T cells Chronic inflammation Higher proportions of macrophages, cytotoxic T cells and B cells Male et al. Immunology 8th edition Figure 6.2  Acute-phase response Cytokines produced by macrophages and dendritic cells have long ranged effects IL-1β, IL-6, TNF- help to coordinate the body’s responses to infection Endogenous pyrogens Acute phase response Janeway Immunobiology 9th edition Figure 3.33  Acute phase proteins Mimic the action of antibodies but have broad specificity for PAMPs Depend on the presence of cytokines for their production Produced within 2 days of an infection C reactive protein PRR that binds to phosphocholine portion of bacterial and fungal cell walls Opsonises bacteria and activates complement system Bacterial infections typically trigger higher levels of CRP than viral ones Mannose binding lectin PRR which activates the complement system Present in low levels in healthy individuals, production increases during acute phase response  Mediators of inflammation The kinin system generates powerful vasoactive mediators The plasmin system is important for tissue remodelling and regeneration Mast cells, basophils and platelets release a variety of inflammatory mediators Histamine, serotonin (vasoactive) Leukotrienes and prostaglandins (slow reacting inflammatory mediators) Male Immunology 9th edition Table 3.1  Learning objectives Define the term cytokine List the major categories of cytokines and examples of cytokines in each category Discuss the role of cytokines in immune responses Discuss the acute inflammatory response and highlight the role of cytokines in this process  Required reading Introduction to the Immune System – Chapter 1 - Immunology 9th editions – Soluble mediators of immunity section on cytokines and inflammation Mechanisms of Innate Immunity – Chapter 3 – Immunology 9th edition https://www.pfizer.com/news/articles/inside_a_cytokine_storm_whe n_your_immune_system_is_too_strong https://www.newscientist.com/definition/cytokine-storm/ https://www.thesun.co.uk/news/2917810/elephant-man-drug- testing-trial-tgn1412/  Additional reading The induced responses of innate immunity – Chapter 3 – Janeway Immunobiology 9th edition Cytokines in the immune system – Chapter 24 – Helbert Immunology for medical students 3rd edition http://www.npr.org/sections/goatsandsoda/2014/08/26/342451672/ how-ebola-kills-you-its-not-the-virus  Tutorial Tutorial questions are posted on VLE. Additionally, the articles in the required reading section will be discussed in the tutorial session.