Inflammation: a brief overview
Inflammation is defined as increased vascular permeability accompanied by an infiltration of ‘inflammatory’ cells, initially polymorphonuclear leucocytes (usually neutrophils) and later macrophages, lymphocytes and plasma cells. Vascular permeability may be increased (resulting in oedema) by a number of agents, which include complement fragments such as C3a, C5a, factor Ba and C2 kinnin. Some fragments (C3a, C5a and C567) also attract neutrophils and mobilize them from the bone marrow; cytokines generated by activated DCs, T cells and macrophages, such as IL- 1, IL- 6, TNF and IL- 12, have similar properties, as well as activating vasodilation to increase blood flow (resulting in erythema). Inflammatory chemokines also attract a variety of cells to migrate into tissues.
The triggering of mast cells via IgE is also a method of causing inflammation, due to release of histamine and leukotrienes (which are quite distinct from cytokines) that increase vascular permeability and attract eosinophilic polymorphonuclear leucocytes too.
The inflammatory cytokines (IL- 1, IL- 6 and TNF) also provoke increased synthesis of particular serum proteins in the liver. The proteins are known as acute- phase proteins and include proteins that act as mediators (as in opsonization – C3 and C4 complement components, C- reactive protein [CRP]), enzyme inhibitors (α1- antitrypsin) or scavengers (haptoglobin); the increased serum concentrations of such proteins are helpful in resolving inflammation. In practical terms, serial measurements of CRP give a useful indication of the extent and persistence of inflammation; since the half- life of CRP is only a few hours, changes in serum levels reflect rapid changes in inflammation (such as after antibiotic therapy) sufficiently quickly to be clinically useful. This is in contrast to fibrinogen (another acute- phase protein and the major factor in the erythrocyte sedimentation rate, ESR), where changes are much slower and therefore not useful clinically.
Unfortunately, the recognition of antigen by antibodies, B cells or T- effector cells can cause incidental tissue damage as well as the intended destruction of the antigen. Reactions resulting in tissue damage are often called hypersensitivity reactions; Gell and Coombs defined four types (Table 1) and this classification (though arbitrary) is still useful to distinguish types of immunological mechanisms. Most hypersensitivity reactions are not confined to a single type: they usually involve a mixture of mechanisms.
Table1. Types of hypersensitivity – mechanism, examples of disease and relevant therapy
Immediate hypersensitivity (type I) reactions are those in which antigen interacts with preformed antigen- specific IgE bound to tissue mast cells or basophils. IgE responses are usually directed against antigens that enter at epithelial surfaces, i.e. inhaled or ingested antigens. Specific IgE production requires helper T cells and is regulated by T- cell- derived cytokines; IL- 4 and IL- 13 stimulate IgE production, while IFN- y is inhibitory. The balance between help and suppression depends on many variables, including the route of administration of the antigen, its chemical composition, its physical nature, whether or not adjuvants were employed and the genetic background of the animal. Following the interaction of cell- surface IgE and allergen, activation of the mast cell causes the release of pharmacologically active substances. Type I reactions are rapid; for example, if the anti gen is injected into the skin, ‘immediate hypersensitivity’ can be seen within 5–10 minutes as a ‘wheal- and- flare reaction’, where the resulting oedema from increased vascular permeability is seen as a wheal and the increased blood flow as a flare. In humans, there is a familial tendency towards IgE- mediated hypersensitivity, although the genes related to this ‘atopic tendency’ do not determine the target organ or the disease. Clinical examples of type I reactions include anaphylactic reactions due to insect venoms, peanuts and drugs, as well as Type II reactions are initiated by antibody reacting with antigenic determinants that form part of the cell membrane. The consequences of this reaction depend on whether or not complement or accessory cells become involved, and whether the metabolism of the cell is affected (Fig. 1). IgM and IgG can be involved in type II reactions. The best clinical examples are some organ- specific autoimmune diseases (Table 1).
Fig1. Clinical consequences of cell- bound hypersensitivity. ITP, immune thrombocytopenic purpura.
Although type II reactions are mediated by autoantibodies, T cells are also involved. For example, in Graves’ disease, which is known to be due to autoantibodies stimulating thyroid- stimulating hormone (TSH) receptors, specific reactive T cells are present also. Although these T cells are instrumental in promoting antibody production (primary effect), they are unlikely to cause tissue damage since the lymphocytic infiltration is mild and consists of B cells too. Secondary autoantibodies to antigens are released following tissue damage such as the antibodies to thyroid peroxidase. In contrast, the autoreactive T cells cloned from patients with rheumatoid arthritis and multiple sclerosis have a primary role in tissue damage.
Type III reactions result from the presence of immune complexes in the circulation or in the tissues. Localization of immune complexes depends on their size, their charge, the nature of the antigen and the local concentration of complement. If they accumulate in the tissues in large quantities, they may activate complement and accessory cells and produce extensive tissue damage. A classic example is the Arthus reaction, where an antigen is injected into the skin of an animal that has been previously sensitized. The reaction of preformed antibody with this antigen results in high concentrations of local immune complexes; these cause complement activation and neutrophil attraction and result in local inflammation 6–24 hours after the injection. Serum sickness is another example: in this condition, urticaria, arthralgia and glomerulonephritis occur about 10 days after initial exposure to the antigen. This is the time when maximum amounts of IgG antibody, produced in response to antigen stimulation, react with remaining antigen to form circulating, soluble immune complexes (Fig. 2). As these damaging complexes are formed, the antigen concentration is rapidly lowered; the process only continues as long as the antigen persists and thus is usually self- limiting. Further clinical examples include systemic lupus erythematosus (SLE), glomerulonephritis and extrinsic allergic alveolitis.
Fig2. Immune complex formation in acute serum sickness.
Type IV reactions are initiated by T cells that react with antigen and release Th1 cytokines. Cytokines attract other cells, particularly macrophages, which in turn liberate lysosomal enzymes and Th17 cells. The resultant acute lesions consist of infiltrating lymphocytes, macrophages and occasionally eosinophil polymorphonuclear leucocytes. Chronic lesions show necrosis, fibrosis and, sometimes, granulomatous reactions. An understanding of mechanisms that lead to tissue damage helps to find relevant therapy (Table 1).
