| Inflammatory mediators contribute to the immune response
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| All the cells involved can synthesize and secrete a wide variety of different types of soluble chemical substances termed inflammatory mediators. Since some of these mediators are present in the blood, they are also known as humoral components and include acute-phase reactants such as C-reactive protein (CRP) (see Chapter 3) and components of the complement system.
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| Complement is activated in a series of sequential steps
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| page 507 |  | | page 508 |
The complement system consists of a series of proteins that are normally present in the inactive form. The components of the system are sequentially activated, in a cascade, after contact with surfaces or particles that have a specific molecular composition or configuration. Please refer to Figure 36.1 throughout the following explanation of complement activation:
- The activation of the first component leads to the unlocking of serine protease activity;
- The activation of the next component in the sequence is achieved by it being cleaved by the first component into two unequally sized fragments;
- The larger of the resulting fragments exhibits serine protease activity and attaches to the activating surface, while the smaller fragment has distinctive biologic activities, which include the facilitation of phagocytosis (termed opsonization), the attraction of cells (chemotaxis), and the stimulating degranulation of mast cells (anaphylatoxin activity);
- This series of activation events is then repeated with further early components, thereby creating a cascade effect;
- By activating the next component, the large enzymatically active fragment of the previous component is itself inactivated. When components further down the sequence - the so-called 'late' components of the pathway - are activated, instead of demonstrating enzyme activity they show the ability to coalesce with each other and with subsequently activated components, to form a multimolecular
complex that can breach the integrity of the bacterial surface that bears the molecular complex - which had activated the complement cascade in the first place.
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Table 36-1.
Cells involved in inflammation. |
| Body_ID: None |
| Cells involved in inflammation |
| Body_ID: T036001.50 |
| Circulating | Tissue based |
| Body_ID: T036001.100 |
| Polymorphonuclear leukocytes | neutrophil | |
| Body_ID: T036001.150 |
| | eosinophil | |
| Body_ID: T036001.200 |
| | basophil | |
| Body_ID: T036001.250 |
| | | mast cell |
| Body_ID: T036001.300 |
| Mononuclear phagocytes | monocyte | macrophage |
| Body_ID: T036001.350 |
| Lymphocytes | | |
| Body_ID: T036001.400 |
| Platelets | | |
| Body_ID: T036001.450 |
| Endothellal cells | | |
| Body_ID: T036001.500 |
| Cytokines have several characteristics in common
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| Cytokines are soluble mediators of the inflammatory and immune response. They are produced by a variety of cells and tissues, are peptides or glycoproteins in nature, and are active at concentrations between 10-9-10-15 molar. They act by interacting with receptors on the surfaces of their target cells. The majority act within short distances of the site of their production (paracrine action) or on the cells that produced them (autocrine action). A few, however, are capable of acting on cells distant to their site of production. They show significant overlap in their functions (redundancy) and they may act on multiple cell types (pleiotropy); they also have potential for interaction via the effects they mediate (for cytokine signaling, see Chapter 38).
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| Cytokines may be classified into families or by their principal effect
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| Figure 36.1 The complement cascade. Activating stimuli bear surfaces that trigger complement activation, and to which the activated component can attach itself. The late components of the cascade do not show enzymatic activity. Instead, they coalesce to form a polymeric macromolecule (the membrane attack complex), which can insert itself into the activating surface (the cell wall in the case of bacteria), breach its integrity and cause osmotic lysis. |
| page 508 | | | page 509 |
Cytokines can be grouped into families:
- interferons (IFNs): while IFN-α and IFN-β have a role in protection against viral replication, IFN-g plays a significant part in regulating the specific immune response (SIR);
- interleukins (ILs): currently there are in excess of 20 interleukins recognized, all of which participate in regulating the cells involved in both nonspecific and specific immune responses;
- chemokines: these are a family of cytokines that bring about chemokinesis - movement in response to chemical stimuli. Interest has increased dramatically in the receptors for these mediators since some appear to act as coreceptors for infection, in particular HIV infection of lymphocytes. Some overlap in activity with cytokines can be seen with IL-8 which demonstrates chemokine properties. In general cytokines are more practically grouped by their principal effects or roles, examples of which are shown below:
- proinflammatory cytokines: tumor necrosis factor (TNF)-α, IL-1, IL-6, IL-8 and other chemokines, IL-12 and IL-15;
- anti-inflammatory: transforming growth factor (TGF)-β and IL-10;
- immunostimulatory: for cellular responses IL-2 and IFN-γ; for humoral, including allergic, responses: IL-4, IL-13, TGF-b, and IL-10.
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| As will be seen later, the specific immune response is driven by direct cell interactions together with the effects of cytokines. Cells and soluble mediators of the nonspecific immune response participate in the initiation of these responses and then help to deal with the antigen.
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| Arachidonic acid metabolites
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| The prostaglandins (PGs) and leukotrienes (LTs) form another group of inflammatory mediators. On each stimulation, the nonspecific immune response follows the same sequence of nonspecific and stereotypical events.
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