Immune response and inflammation. March 2014 PSO13-C051m

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1 Immune response and inflammation March 2014 PSO13-C051m

2 The Immune System: Coordinated Defences Against External and Internal Threats Pathogens (bacteria, viruses, fungi, parasites) Immune responses arise from the coordinated actions of specialised organs, cells and molecules that: Monitor tissue homeostasis Protect against pathogens Eliminate damaged cells Immune cells develop from pluripotent stem cells in the bone marrow (and fetal liver), mature in bone marrow or the thymus gland, and differentiate in the spleen and lymph nodes Cells and molecules of the immune system recognise and remove foreign invaders Delves PJ et al. N Engl J Med. 2000;343:

3 The Immune System Has Two Arms Distinguished by the Speed and Specificity of the Response Immune System Cell Origin Bone marrow Foreign invader Innate immune responses Are mediated by phagocytic cells and other cells of myeloid lineage Rapid Use pattern-recognition receptors Do not change with repeated exposure Delves PJ, Roitt I. N Engl J Med. 2000;343: Parkin J, Cohen B. Lancet. 2001;357: Adaptive immune responses Are mediated by lymphocytes of lymphoid lineage Delayed Use highly specific antigen receptors/antibodies Specificity and speed of response improves with repeated exposure Generate immunological memory 3

4 Phagocytic Cells Are Key Cellular Components of the Innate Immune Response 1 Phagocytic cells express receptors on their cell surface that recognise pathogen-associated molecular patterns Macrophage Monocyte 2 Once recognised by phagocytic cells, a foreign invader is engulfed, attacked by proteases and reactive oxygen molecules, and eliminated Pathogen Phagocyte Neutrophil Dendritic cell Cytokines Proteases and reactive oxygen species 3 Delves PJ, Roitt I. N Engl J Med. 2000;343: Parkin J, Cohen B. Lancet. 2001;357: Phagocytic cells secrete cytokines to recruit additional cells to augment the innate immune response. Dendritic cells are phagocytes that present antigens to lymphocytes, thereby bridging the innate and adaptive immune responses 4

5 Innate Immunity: Cells and Functions Innate response 1 First line of immune defence Mediated by phagocytes and other cells of myeloid lineage Does not change with repeated exposure Less specific than adaptive response Macrophage Monocyte Neutrophil Dendritic cell Natural killer cell δ T cell Cell description Derived from blood-borne monocytes 1,2 Large phagocytic leukocytes 2 Kidney shaped/ oval nucleus 3 Irregular shape Granulocytes 5 Lobed nucleus 9 Antigen presenting cells 6 Cytotoxic lymphocyte 7 T cell receptor is made of chain and δ chain Functions Phagocytosis 2 Fixed macrophages: Removal of necrotic tissue 2 Histiocytes, Kupffer cells, microglial cells, osteoclasts 2 At the site of infection: differentiate into macrophages and dendritic cells 3 Elicit immune responses 3 Chemotaxis 4,5 First responder among inflammatory cells 4,5 Recruit antigen presenting cells to site of injury within minutes 4 Hallmark of acute inflammation 4 Bridge innate and adaptive immunity 6 Rapid response to infected and malignant cells 1 Border between innate and adaptive immunity 8 1. Delves PJ et al. N Engl J Med. 2000;343:37-49; 2. Mosser DM et al. Nat Rev Immunol. 2008;8: ; 3. Auffray C et al. Annu Rev Immunol. 2009;27: ; 4. Nathan C. Nat Rev Immunol. 2006;6: ; 5. Witko-Sarsat V et al. Lab Invest. 2000;80: ; 6. Adema GJ. Immunol Lett. 2009;122: ;7. Parkin J et al. Lancet. 2001;357: ; 8. Holtmeier W et al. Chem Immunol Allergy. 2005;86:

6 Lymphocytes Are Cellular Components of the Adaptive Immune Response Lymphocytes Differentiate Into Effector Cells in Peripheral Lymphoid Organs T-cell priming by dendritic cell Naïve T-cell Antigen presentation T-cell proliferation and differentiation into clones of effector cells B-cell encounters and processes antigen T-cell dependent response T-helper cell Antibody Secretes antibody TI antigen B-cell Secretes antibody T-cell independent (TI) response Parkin J, Cohen B. Lancet. 2001;357:

7 Adaptive Immunity: Cells and Functions Adaptive response 1 Mediated by lymphocytes of lymphoid lineage Delayed response Improve with repeated exposure B cell T cell Cell description Mature in bone marrow 1 Specialised B-cell receptor protein (membrane-bound antibody) present on cell surface 1 Clones 1 Functions Make antibodies 1 Develop into memory B cells or plasma B cells after activation by antigens 1 Mature in the thymus 1 T-cell receptor (TCR) made of 2 glycoprotein chains: α and or and δ 1 Helper T cell 2,4,5 Cytotoxic T cell 1, 3 Natural killer T cell 1 Express CD4 protein on their surface Activate and direct other immune cells Activation and growth of cytotoxic T cells B-cell antibody class switching Express CD8 proteins on their surface Destroy virally infected cells and possibly tumour cells On exposure to dysfunctional cells release the cytotoxins: perforin, granzymes, Destroy infected and malignant cells Involved in cellular cytotoxicity caspase enzymes 1. Delves PJ et al. N Engl J Med. 2000;343:37-49; 2. Reiner SL et al. Cell. 2007;29:33-36; 3. Parkin J et al. Lancet. 2001;357: ; 4. Martin-Orozco N et al Immunity : Weinstein JS Immunol Rev ; 247:

8 Cytokines Are Members of Families of Small Soluble Proteins That Mediate Intercellular Communication Cytokine Families Interleukins Interferons Tumour Necrosis Factor Transforming Growth Factor Colony-stimulating Factors Examples of Interleukin cytokine families IL-1 IL-2 IL-6 IL-12 IL-17 Cytokines Are an integral part of the signalling network between cells of the immune system Regulate the function of the immune system Are produced by many cell types of the innate and adaptive immune systems Bind to cell surface receptors on target cells Are pleiotropic Delves P, Roitt I. N Engl J Med. 2000;343: Ozaki K et al. J Biol Chem. 2002;277: Coondoo A. Indian J Dermatol. 2011;56:

9 Chemokines Are Small Signalling Molecules that Guide Cell Migration Monocyte Interior of blood vessel Chemokine gradient Neutrophil Chemokines Chemotaxis Inflamed tissue (skin, joint) Chemokines Are small molecules that guide immune cell migration Attract effector cells (predominantly neutrophils and monocytes) to sites of infection and tissue damage Contribute to wound healing, metastasis, angiogenesis, cell recruitment, lymphoid organ development and lymphoid trafficking Charo I, Ransohoff R. N Engl J Med. 2006;354: Cameron M, Klein D. 9

10 Cytokines Integrate Innate and Adaptive Immune Responses Cytokines produced by phagocytes govern differentiation of lymphocytes Dendritic cell Monocyte Cytokines Macrophage Neutrophil T-cell Cameron M, Klein D. Kopf M et al. Nat Rev Drug Discov. 2010;9: Cytokines and chemokines produced by lymphocytes control the activity and migration of phagocytes 10

11 The Cytokine Environment Regulates Lymphocyte Differentiation Into Functional Subsets Functional lymphocyte subsets are defined by the cytokines they produce IL-12 Th1 IFN-, TNF-α Cell-mediated immunity (intracellular bacteria, viruses) Dendritic cell IL-4 Th2 IL-12R IFN- R IL-4R IL-4, IL-5, IL-13 Humoral immunity (extracellular parasites) Naïve T helper cell IL-6 Th17 TGF- 1R IL-23R IL-17A*, IL-17F, IL-22 Cell-mediated inflammation Autoimmune diseases (extracellular pathogens, fungi) TGF- Treg IL-2R TGF- 1R TGF-, IL-10 Immunoregulation (peripheral tolerance) * IL-17A also produced by other cell types Leung S et al. Cell Mol Immunol. 2010;7: Zhu J et al. Ann Rev Immunol. 2010;28: ? Potential exists for identification of additional T-cell lineages 11

12 Inflammation Is an Orchestrated, Balanced Response Mediated by Cells and Cytokines Blood Vessel 2 Neutrophils from bone marrow travel in bloodstream to site of infection Inflamed Tissue (skin or joint) Macrophage Endothelial cell Neutrophil Red blood cell Cytokines, chemokines Other inflammatory mediators 3 Proinflammatory mediators, cytokines, and chemokines facilitate migration of neutrophils into inflamed tissue Increased vascular permeability 1 Recognition of pathogen by tissue-resident macrophages leads to cell activation and cytokine release 5 Pathogen Pathogen is destroyed or eliminated Medzhitov R. Nature. 2008;454: ; Cho JH, Gregersen P. N Engl J Med. 2011; 365: ; Nathan C. Nature. 2002;420: ; Parkin J, Cohen B. Lancet. 2001;357: Mast cell Dendritic cell Activated T lymphocytes invade tissue and launch an adaptive immune response that includes production of antibodies and proinflammatory mediators 6 Lymphocyte Infiltration of lymphocytes and continued release of cytokines can drive chronic inflammation and tissue destruction 12

13 Summary The immune system is an coordinated series of responses from organs, cells, and molecules that defends the body against foreign invaders The innate and adaptive arms of the immune system are mainly distinguished by differences in: Cells and cytokines Timing of response Specificity of response Cytokines functionally link phagocytic cells and lymphocytes Inflammation is an orchestrated, balanced response involving the innate and adaptive immune system Ongoing cytokine production can lead to chronic inflammation 13

specific B cells Humoral immunity lymphocytes antibodies B cells bone marrow Cell-mediated immunity: T cells antibodies proteins

specific B cells Humoral immunity lymphocytes antibodies B cells bone marrow Cell-mediated immunity: T cells antibodies proteins Adaptive Immunity Chapter 17: Adaptive (specific) Immunity Bio 139 Dr. Amy Rogers Host defenses that are specific to a particular infectious agent Can be innate or genetic for humans as a group: most microbes