* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Inflammation and immunity
Complement system wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Molecular mimicry wikipedia , lookup
Immune system wikipedia , lookup
Adaptive immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Inflammation wikipedia , lookup
Innate immune system wikipedia , lookup
Inflammation and immunity NR Webster PhD FRCA FRCP HF Galley PhD FIMLS The inflammatory response Key points The main features of the inflammatory response are: HF Galley PhD FIMLS Academic Unit of Anaesthesia and Intensive Care, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD Humans must defend themselves against viruses, bacteria, fungi, protozoa, parasites and tumour cells as well as physical, chemical or traumatic damage – inflammation is the body’s reaction to such an event. The body must also respond to injury by healing and repairing the damaged tissue. Many effector mechanisms capable of defending the body against such antigens and agents have developed and these are mediated by soluble molecules or by cells of the immune system. Three major events occur during this response: (i) an increased blood supply to the tissue; (ii) increased capillary permeability caused by retraction of the endothelial cells; and (iii) leucocytes migrate out of the capillaries into the surrounding tissues. The virulence of micro-organisms and the induction of inflammation depend on their ability to replicate in the body and to destroy cellular structures. During growth and multiplication, micro-organisms can produce and release exotoxins which are potent injuring agents. Other micro-organisms, after destruction or lysis, release from phospholipid and lipopolysaccharide envelopes, toxins known as endotoxins (lipopolysaccharide or LPS). Viruses do not produce exotoxins or endotoxins but use cells for their own replication and damage cell structures leading to cell death. The main purpose of inflammation is to bring fluid, proteins and cells from the blood into the damaged tissues. Tissues are normally bathed in extracellular fluid lacking most of the proteins and cells present in blood, since the majority of proteins are too large to cross the endothelium. Therefore, mechanisms are required to allow cells and proteins to gain access to extravascular sites. 54 British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003 © The Board of Management and Trustees of the British Journal of Anaesthesia 2003 Innate and acquired immunity are both important in the inflammatory response. The inflammatory response is both useful and potentially harmful. The inflammatory response is carefully regulated by complex and interlinked chemical messengers which act like local hormones. Many different cell types are involved in the inflammatory response. There is considerable overlap in the actions of soluble mediators of inflammation. NR Webster PhD FRCA FRCP Academic Unit of Anaesthesia and Intensive Care, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD Tel: 01224 273207 Fax: 01224 273066 E-mail: [email protected] (for correspondence) 1. Vasodilation to increase the blood flow to the infected area. 2. Increased vascular permeability to allow diffusible components to enter the site. 3. Cellular infiltration by chemotaxis, or the directed movement of inflammatory cells through the walls of blood vessels to the site of injury. 4. Activation of cells of the immune system and enzyme systems. The movement of leucocytes to a site of injury requires adhesive interactions between leucocytes and endothelial cells. The nature and magnitude of the leucocyte–endothelial cell interaction taking place within post-capillary venules is determined by a variety of factors, including expression of adhesion molecules on leucocytes and/or endothelial cells, the presence of products of leucocytes (e.g. superoxide) and endothelial cells (e.g. nitric oxide), and the physical forces generated by the movement of blood along the vessel wall. Extravasation is a complex event, dependent not only on adhesion molecule expression and activation, but also on cytoskeletal re-organisation and alteration in membrane fluidity. Innate and adaptive immunity Innate immunity prevents entry of micro-organisms into tissues or, once they have gained entry, eliminates them prior to the occurrence of disease. It is non-specific and does not require prior exposure to antigen. Examples include mechanical barriers at body surfaces (skin, mucous membranes), antibacterial substances in secretions (lysozyme, low pH in stomach) and prevention of stasis (ciliary activity, coughing, vomiting). DOI 10.1093/bjacepd/mkg014 Inflammation and immunity Acquired immunity requires prior exposure to antigen and involves antibodies and lymphocytes. An immune response must: (i) recognise a micro-organism as foreign or non-self; (ii) respond by production of specific antibodies and specific lymphocytes; and (iii) mediate the elimination of microorganisms. The key cells are B- and T-cell lymphocytes. B-cell lymphocytes B-cells make antibodies of the same specificity, i.e. able to react with the same antigenic determinants. Antibodies are immunoglobulins (150,000–900,000 kDa), which act by one end of the molecule binding to antigens (the Fab portion) and the other end (Fc) being responsible for effector functions. There are 5 classes of immunoglobulin – IgM, IgG, IgA, IgD and IgE. Immunoglobulins occur in serum and in secretions from mucosal surfaces and are produced by plasma cells found mainly within lymph nodes. B lymphocytes evolve into plasma cells under the influence of T-cell cytokines. marginating and entering tissue pools, where they survive for 1–2 days. Cells of the circulating and marginated pools can exchange with each other. Neutrophils contain cytoplasmic granules full of antimicrobial or cytotoxic substances, proteinases, hydrolases and cytoplasmic membrane receptors. The enzyme myeloperoxidase (MPO) catalyses the conversion of hydrogen peroxide to hypochlorous acid. Proteases such as elastase and cathepsin G hydrolyse proteins in bacterial cell walls. Lysosomal proteases are potentially very destructive to normal tissue and regulation is mediated by protease inhibitors such as macroglobulin and antiprotease which bind to the active sites of proteases. The protease:antiprotease balance is important in the pathogenesis of some diseases. Phagocytosis Phagocytosis is a complex process composed of several morphological and biochemical steps: 1. Recognition and binding to the phagocyte surface. T-cell lymphocytes 2. Ingestion (engulfment). There are two types of T-cells, T-helper (Th) cells and T-cytotoxic (Tc) cells. Th-cells secrete cytokines (chemical regulators of the immune response, see below), which activate various phagocytic cells, B-cells, Tc-cells, macrophages and various other cells. Tc-cells do not secrete cytokines but have cytotoxic activities, including the elimination of cells displaying antigen, i.e. altered self cells, such as virus-infected cells, foreign tissue grafts and tumour cells. Circulating Th-cells are capable of unrestricted cytokine expression and are prompted into a more focused pattern of cytokine production depending on signals received at the outset of infection. The cells can be classified according to the pattern of cytokines they produce and Th1-cells secrete cytokines which push the system towards cellular immunity (cellular cytotoxicity) while Th2cells are associated with humoral or antibody-mediated immunity. The local balance of cytokines, particularly early in the inflammatory response, is therefore an important determinant of subsequent Th immune responses and may dictate the final outcome of the septic insult. 3. Phagosome and then phagolysosome formation (fusion of phagosome with lysosomes). 4. Killing and degradation of ingested cells or other material. 5. Respiratory burst – simultaneously with the recognition and particle binding there is a dramatic increase in oxygen consumption associated with production of superoxide and other oxygen radicals. Neutrophils – central cells in acute inflammation Neutrophils (polymorphonuclear leucocytes or PMNs) constitute the ‘first line of defence’ against infectious agents. Upon release into the circulation from bone marrow, the cells are in a non-activated state and have a half-life of only 4–10 h before An essential part of the killing process of neutrophils is the production of free radicals – reactive oxygen intermediates and reactive nitrogen intermediates. Upon activation, neutrophils and mononuclear phagocytes have increased oxygen consumption (the respiratory burst) when oxygen is reduced by NADPH-oxidase to superoxide anion which can interact with hydrogen peroxide or a variety of transition metals to form hydroxyl radical. Superoxide anion can pass through cell membranes via anion channels and may exert its toxicity by penetration to important sites where it is converted to hydrogen peroxide and the more toxic hydroxyl radical. Reactive oxygen species also promote the margination of neutrophils by triggering the expression of adhesion molecules on endothelial cells. Reactive oxygen species are implicated in a variety of pathological conditions (e.g. ARDS, hyperoxia, asbestosis, silicosis, paraquat toxicity, bleomycin toxicity, cigarette smoking, ionising radiation and others). Reactive nitrogen intermediates such as nitric oxide are also produced. Three isoforms of the enzyme nitric oxide synthase British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003 55 Inflammation and immunity (NOS) have been identified but, in inflammation, the inducible form (iNOS or type II NOS) is probably the most important. Stimuli causing the induction of iNOS formation include the cytokines IFN-γ, IL-1β, IL-6, GM-CSF (granulocyte-macrophage colony stimulatory factor) and platelet activating factor as well as LPS. Although nitric oxide itself exerts many effects, it also reacts with superoxide to form the highly toxic peroxynitrite anion. Biological functions of macrophages Macrophages are involved at all stages of the immune response. They act as a rapid protective mechanism which can respond before T-cell-mediated amplification has taken place. In addition, through antibody-dependent cell-mediated cytotoxicity, they are able to kill or damage extracellular targets. They also take part in the initiation of T-cell activation by processing and presenting antigen. Finally, and perhaps most importantly, they are central effector and regulatory cells of the inflammatory response. Macrophages are important producers of arachidonic acid metabolites and, on phagocytosis, release up to 50% of their arachidonic acid from membrane phospholipid which is immediately metabolised into prostaglandins, thromboxanes and leucotrienes. Macrophages secrete not only cytotoxic- and inflammation-controlling mediators but also substances participating in tissue reorganisation such as enzymes (e.g. hyaluronidase, elastase, collagenase), enzyme inhibitors (e.g. antiproteases) and regulatory growth factors. and endothelial cells. A wide range of cytokines has been identified and many have overlapping and complementary activities. Increasing numbers of cytokines are being discovered. Broad groupings of cytokine families are now known including interleukins (ILs), tumour necrosis factors (TNFs), interferons (IFNs) and colony stimulating factors (CSFs). Another way of grouping cytokines is by their action – either pro-inflammatory or antiinflammatory. The importance of the balance between these two opposing actions – in many ways similar to the coagulation system with procoagulants and profibrinolytics and anti-coagulants – is now becoming better appreciated. Cytokines make up a major class of soluble intercellular signalling molecules and possess typical hormonal activities in that: (i) they are secreted by a single cell type, react specifically with other cell types (target cells) and regulate specific vital functions controlled by feedback mechanisms; (ii) they act at short range in a paracrine or autocrine manner; and (iii) they interact first with high-affinity cell surface receptors (distinct for each type or even subtype) and regulate gene transcription. This altered transcription (which can be enhanced or inhibited) results in changes in cell behaviour. Target cells may be in any body compartment (sometimes a long distance from the site of secretion). Other types of cytokine act mostly on neighbouring cells in the micro-environment where released. During paracrine secretion, some cytokines may escape cell binding and spill over into the general circulation. Cytokines are synthesised, stored and transported by various cell types, not only those of the immune system. Table 1 Components of inflammation Regulation of the inflammatory response The inflammatory response must be well ordered and controlled and a variety of interconnected cellular and soluble mechanisms are activated when tissue damage and infection occur. Examples include cytokines, by-products of the plasma enzyme systems (complement, the coagulation, kinin and fibrinolytic pathways), lipids (prostaglandins, leukotrienes, platelet activating factor), and vasoactive mediators. Once leucocytes have arrived at a site of inflammation, they release mediators which control the later accumulation and activation of other cells. The main humoral and cellular components involved in the amplification and propagation of both acute and chronic inflammation are shown in Table 1. Cytokines are soluble proteins which regulate host-cell function through interaction with specific receptors. They are produced by neutrophils, lymphocytes, monocytes/macrophages 56 Process Antigen recognition Specific Non-specific Effector cells and molecules B and T lymphocytes Antibodies Professional phagocytes Non-professional phagocytes Complement pathway Coagulation cascade Amplification Complement system Arachidonic acid products Platelet activating factor (PAF) Bradykinin Serotonin Cytokines Growth factors Antigen destruction Neutrophils Macrophages Complement system Perforins Reactive oxygen and nitrogen species British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003 Inflammation and immunity Table 2 Main types of cytokines Table 3 Cytokines involved in inflammatory reactions Cytokine type Individual cytokine examples Group Lymphokines Macrophage activating factor Macrophage chemotactic factor Histamine releasing factors Pro-inflammatory cytokines TNF-α IL-1 IL-6 IL-8 Anti-inflammatory cytokines IL-4 IL-10 IL-13 Interleukins IL-1, IL-2, etc. Tumour necrosis factors TNF-α,TNF-β Interferons IFN-α, IFN-β, IFN-γ Colony stimulating factors G-CSF, GM-CSF Polypeptide growth factors Epidermal growth factor Nerve growth factor Vascular endothelial growth factor Transforming growth factors TGF-α,TGF-β α-Chemokines IL-8 Platelet factor 4 β-Chemokines Monocyte chemo-attractant protein 1 (MCP-1) Macrophage inflammatory protein 1 (MIP-1α) RANTES Stress proteins Individual cytokines Table 4 Mediators of inflammation Heat shock proteins Superoxide dismutase Function Mediators Increased vascular permeability Histamine Serotonin Bradykinin C3a and C5a PgE2, prostacyclins, LTC4 and LTD4 Vasoconstriction TXA2, LTB4, LTC4 and LTD4 C5a Smooth muscle contraction C3a and C5a Histamine LTB4, LTC4, LTD4 and TXA2 Serotonin Platelet activating factor (PAF) Bradykinin Increased endothelial cell stickiness Endotoxin, IL-1 and TNF-α LTB4 Mast cell degranulation C3a and C5a Chemotaxis C5a LTB4 IL-8 and other chemokines PAF Histamine Pyrogens IL-1, IL-6 and TNF-α PgE2 Pain PgE2 Bradykinin RANTES, regulated upon activation normal T expressed and presumably secreted chemokine. The main types of cytokines are listed in Table 2. They control the direction, amplitude, and duration of immune responses and the remodelling of tissues. Individual cytokines have multiple, overlapping and sometimes contradictory, functions depending on local concentration, cell type they are acting on, and the presence of other mediators. Thus, the information which an individual cytokine conveys depends on the pattern of regulators to which a cell is exposed, and not on just one cytokine. Because of the potent and profound biological effects of cytokines, it is not surprising that their activities are tightly regulated, mainly at the levels of secretion and receptor expression. From the point of view of inflammation, there are two main groups of cytokines: pro-inflammatory and anti-inflammatory (Table 3). Pro-inflammatory cytokines up-regulate inflammatory reactions. Anti-inflammatory cytokines are generally T-cellderived cytokines and down-regulate inflammatory reactions. TNF-α and IL-1 have a central role in inflammatory response since administration of their antagonists, such as IL1 receptor antagonist (IL-1ra), soluble fragment of IL-1 receptor, or monoclonal antibodies to TNF-α and soluble TNF receptor, block various responses in models of inflammation. Some have also been used in the treatment of human chronic inflammatory states such as rheumatoid arthritis. On the other hand, anti-inflammatory cytokines (IL-4, IL-10, IL-13) are responsible for the down-regulation of inflammation. They suppress the production of pro-inflammatory cytokines and their strong anti-inflammatory activity may suggest a role in the management of many inflammatory conditions. IL-10 has been extensively investigated in both healthy volunteers and in patients with both chronic and acute inflammatory diseases. Patients with rheumatoid arthritis, inflammatory bowel disease, and hepatitis C infections have received IL-10 for extended periods (up to several months). The safety profile in British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003 57 Inflammation and immunity patients receiving IL-10 has been very good to date, with no evidence of an increased susceptibility to either bacterial or viral infections. Future clinical studies in acute inflammatory diseases will need to address the unresolved issues of the quantitative importance of IL-10’s anti-inflammatory and immunosuppressive properties in critically ill patients. It is possible that treatment targeted to increasing tissue levels rather than plasma concentrations will be more useful. Mediators of inflammation Once leucocytes have arrived at a site of infection or inflammation, they release mediators which control the later accumulation and activation of other cells. Inflammatory mediators are soluble, diffusible molecules that act locally at the site of tissue damage and infection and, when present at high enough concentrations, at more distant sites. Bacterial products and toxins can act as exogenous mediators of inflammation; for example, endotoxin can trigger complement activation, resulting in the formation of anaphylatoxins C3a and C5a resulting in vasodilation and increased vascular permeability. Endogenous mediators of inflammation are produced from within the immune system itself, as well as by other systems. For example, they can be derived from molecules normally present in the plasma in an inactive form such as peptide fragments of some components of complement, coagulation and kinin systems. Mediators of inflammatory responses are also released at sites of injury by a number of cell types that either contain them as preformed molecules within storage granules (e.g. histamine) or which can rapidly switch on the machinery 58 required to synthesise the mediators when they are required (e.g. to produce metabolites of arachidonic acid). The early phase mediators, produced by mast cells and platelets, are especially important in acute inflammation and include histamine, serotonin and other vasoactive substances (Table 4). Platelets may contribute to inflammatory responses as a consequence of tissue injury through several mechanisms including: (i) release of vasoactive amines and other permeability factors; (ii) release of lysosomal enzymes; (iii) release of coagulation factors which lead to localised and generalised fibrin deposition; and (iv) formation of thrombi which result in blocking of vessels and capillaries. There is considerable functional redundancy of the mediators of inflammation and this explains why certain new treatment options although appearing promising in the laboratory and in animal models have not been so successful in human sepsis. Key references Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J Anaesth 1996; 77: 110–7 Galley HF,Webster NR.The immuno-inflammatory cascade. Br J Anaesth 1996; 77: 11–6 Oberholzer A, Oberholzer C, Moldawer LL. Interleukin-10: a complex role in the pathogenesis of sepsis syndromes and its potential as an anti-inflammatory drug. Crit Care Med 2002; 30: S58–63 Westendorp RG, Langermans JA, Huizinga TW et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–3 Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM.The plateletactivating factor signalling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 2002; 30: S294–301 See multiple choice questions 40–44. British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 2 2003