Section B – Cells and molecules of the innate immune system
B4 I NNATE IMMUNITY AND
Inflammation Inflammation is the process by which the body deals with an insult from physi- cal or chemical agents and invasion by microbes. It is recognized by its cardinal signs, including redness, heat, swelling and pain. The cells of the immune system contribute to the inflammatory response.
There are two types of inflammation based on the duration of the response and the prominent inflammatory cell type. Acute inflammation is generally of short duration, lasting from minutes to a few days, and is the result of an initial response by immune cells (primarily PMNs) to an infectious agent (mainly bacteria). Chronic inflammationmay last months to years, usually results from the persistence of a microbe in a viable or inert state, and involves lymphocytes, macrophages and plasma cells of the immune system.
An inflammatory response always results in some tissue damage. Moreover, cells of the immune system are important in the repair process that follows successful elimination of a microbe.
Apart from physical and chemical agents and microbes, immune mechanisms themselves can lead to inflammatory responses (hypersensitivity reactions), e.g.
allergies and granulomatous lesions (Section K). A summary of the main causes of acute inflammation is shown in Fig 1.
B4 – Innate immunity and inflammation 37
Microbial infection
Trauma Injury, burns etc.
Autoimmunity
Immune complexes → phagocytes Complement activation
T cell cytotoxicity Allergens
Tissue damage inflammatory mediators
and cytokines
Mast cell degranulation Toxins
(exotoxins, endotoxins) Complement
activation (classical and alternative)
Fig. 1. Causes of acute inflammation. The activation phase of the acute inflammatory response may be initiated by trauma, infection, allergy and autoimmune reactions, although the latter is more often associated with the chronic form of inflammation. While the initiating events may be different, the overall inflammatory response is similar, with the exception of inflammation caused by IgE/mast cell interactions where the response may be immediate and more systemic.
Acute inflammation is caused initially by the release of inflammatory mediators from microbes, damaged tissues, or other cells including mast cells and macrophages (Table 1). Complement cleavage products C3a, C4a and C5a may also be involved, as they trigger release of histamine from mast cells, which induces vascular changes leading to edema. Moreover, C5a is chemotactic for PMNs, and C3a, C4a and C5a increase neutrophil and monocyte adherence to endothelial cells. Tissue macrophages also play a role in generation of Initiation of acute
inflammatory responses
pro-inflammatory cytokines (including IL-1 and TNFα)via recognition, through their pattern recognition receptors (Topic B3), of structures associated with microbes.
Mast cells, which are distributed throughout the body (Topic B1), are central to the acute inflammatory process in that, on stimulation, they release histamine and other vasoactive amines that result in the vascular changes seen in acute inflammation. Other pro-inflammatory substances released by mast cells include IL-1, TNFα, leukotrienes, PAF and nitric oxide, some of which cause blood vessel dilation and edema and increase adhesion of neutrophils and monocytes to endothelium (see below). Vasoactive amines such as histamine can also have an effect on smooth muscle contraction, which is important in defense against worms in the intestine (Topic H2). Thus, while the inflamma- tory mediators associated with the initiating events of acute inflammation may be different, they share common pathways in the inflammatory process as a result of the intimate involvement of mast cells in this process.
Vascular changes The inflammatory mediators released by tissues, mast cells and macrophages cause dilation of the blood vessels (vasodilation), which increases blood flow and smooth muscle contraction. These inflammatory mediators also cause rapid alterations in the blood vessel endothelium and induce increased expression of cellular adhesion molecules, which assist in the transfer of blood leukocytes.
Overall, changes in tight junctions in endothelial cells occur that permit the passage of fluid (containing antibacterial proteins, clotting factors, and anti- bodies, etc.) and PMNs from the bloodstream to the site of release of these inflammatory mediators (Fig. 2), so as to combat the microbe and/or repair the damage. Vasodilation and increased blood flow result in the redness and heat, and the edema (fluid accumulation) results in swelling. Fluid accumulation together with tissue damage gives rise to the pain through specialized recep- tors. Overall, the mast cell plays a major role in acute inflammation initiated by injury or infection by microbes (Fig. 2).
PMNs leave the bloodstream as a result of their recognition of adhesion molecules displayed on the endothelial cells. The expression of these adhesion molecules is induced by pro-inflammatory cytokines released from macrophages. In particular, IL-1 and TNFα cause increased expression of ICAM-1 and VCAM-1, adhesion molecules central to the progression of acute 38 Section B – Cells and molecules of the innate immune system
Table 1. Source of inflammatory mediators resulting from microbial infection Source of initiating factors Mechanism of induction
Exotoxins Via damage to tissues:
Prostaglandins and leukotrienes have a direct effect on vascular endothelium
Via pattern recognition receptors:
Endotoxins (from Gram-positive Direct effects on macrophages to release
bacteria) proinflammatory cytokines (via toll receptors)
eg. IL-1, IL-6, IL-12, IL-18, TNFαand IFNγ Lipopeptides, etc. (from Gram-positive Direct effects of macrophages to release bacteria) proinflammatory cytokines (via toll receptors).
C3a derived by alternative or Causes mast cell degranulation classical pathways
inflammation. Adhesion molecules expressed on the surface of endothelial cells interact with their counter-receptor (ligand) on PMNs (e.g. ICAM-1 binds to LFA-1, VCAM-1 binds to VLA-4). This process involves the capture and rolling of PMNs, followed by their activation, flattening and extravasation (Fig. 3).
Once the offending insult, e.g. microbe, has been removed or controlled, inhibitors dampen inflammation and tissue repair mechanisms become acti- vated. Inhibitors of the pro-inflammatory cytokines include their soluble recep- Termination of
the response and repair
B4 – Innate immunity and inflammation 39
Tissue damage
Exotoxins
Mast cell
IgE/allergen
Microbe Macrophage
Endotoxins
PMN Endothelium of blood vessel wall
Prostaglandins Leukotrienes
Histamine, TNFα, Nitric oxide,
IL-1
IL-1, TNFα, Nitric oxide
C3a, C5a Classical/alternative pathway
Fluid, edema exudate Injury
Fig. 2. The mast cell in acute inflammation. Microbial products or direct physical damage to blood vessels and tissues leads to release of mediators, e.g. prostaglandins and leukotrienes, which like mast cell mediators (e.g. histamine) increase vascular permeability and vasodilation. Mast cells release their mediators following microbial activation of complement (classical and alternative pathways) and via IgE/allergen complexes. Microbial endotoxins also activate macrophages to release TNFαand IL-1, which have vasodilatory properties. The outcome of this barrage of mediators is the loosening of the endothelial tight junctions, increased adhesion of intravascular neutrophils (and monocytes) and their passage from blood vessels into the surrounding tissues where they can phagocytose the microbes. Serum proteins (fibrinogen, antibodies, etc.) also pass into the tissues and the accumulating fluid (edema) protects the damaged area during repair.
Capture Rolling Flattening Extravasation
Activation of endothelial
cells by inflammatory
mediators
LFA-1 VLA-4 ICAM-1 V-CAM 1
Endothelium
Fig. 3. Adhesion to endothelium and extravasation of neutrophils. Inflammatory mediators activate endothelial cells resulting in expression of adhesion molecules (e.g. ICAM-1 and VCAM-1). These capture leukocytes expressing LFA-1 and VLA-4 (e.g. PMNs) respectively causing them to roll, flatten and squeeze through tight junctions between the endothelial cells (extravasation) and into the tissues where inflammatory mediators are being released.
tors (e.g. receptors for IL-1, TNFα, IL-6 and IL-12), the anti-inflammatory cytokines (IL-4, IL-10 and TGFβ), components of the hemostasis and thrombosis system, and glucocorticoids.
The Th2 cytokine IL-4 downregulates the production of pro-inflammatory cytokines from Th1 cells and TGFβis a potent inhibitor of many immune func- tions. Protein C, a component of the hemostasis and thrombosis system, is an anti-inflammatory agent and functions by inhibiting cytokines such as TNFα.
Glucocorticoids are well known anti-inflammatory agents and inhibit produc- tion of nearly all pro-inflammatory mediators (Section G). Other hormones such as α-melanocyte-stimulating hormone reduce fever, IL-2 synthesis and prostaglandin production, while corticotrophin inhibits macrophage activation and IFNγsynthesis. The neuropeptides somatostatin and VIP reduce inflamma- tion by inhibiting T cell proliferation and migration.
As the inflammatory phase is neutralized by these anti-inflammatory mole- cules, repair of the damage begins. Various cells including myofibroblasts and macrophages, both of which make collagen, mend tissues. Macrophage products including epidermal growth factor, platelet-derived growth factor, fibroblast growth factor and transforming growth factor are important in the repair process.
40 Section B – Cells and molecules of the innate immune system
Section C – The adaptive immune system