Chronic And Cell-Mediated Inflammation
Following the changes in permeability, the activation of complement and the influx of polymorphs, the last arrivals at sites of inflammation are the ‘mononuclear cells’: lymphocytes and monocytes (bottom left). Lymphocytes are usually specific in their attack, and only cause harm when attack is not called for (i.e. when the target is ‘self’ or a transplant), but monocytes and macrophages are equipped with enzymes that they normally use in the process of mopping up dead tissue cells and polymorphs, but which can also damage healthy cells, including other macrophages. When the stimulus is persistent, the result may be a growing mass of macrophages, or granuloma (bottom right), the hallmark of chronic inflammation.
These changes can occur in the absence of any specific immune response (e.g. reactions to foreign bodies; top right), but they are often greatly augmented by the activity of specific T lymphocytes (left) which, by secreting cytokines, attract and immobilize monocytes and activate macrophages. When this process is predominantly beneficial (as in healed tuberculosis) we speak of ‘cell-mediated immunity’ (CMI); when it is harmful (as in contact sensitivity or schistosomal cirrhosis) it is termed ‘type IV hypersensitivity’, the underlying mechanism being the same and the difference one of emphasis (compare with Fig. 21). Confusingly, direct killing by cytotoxic T cells is also called ‘cell-mediated immunity’, although because it mainly affects virus-containing cells, a better name would be ‘cell-mediated autoimmunity’ or, in the case of organ grafts, ‘cell-mediated transplant rejection’.
In any case, it is rare for one type of tissue damage to occur in isolation, interaction of cells and sharing of biochemical pathways being a feature of immune mechanisms, useful and harmful alike.
Cell-mediated immunity (CMI) Contact between recirculating T cells and antigen leads to cytokine secretion with attraction and activation of monocytes and other myeloid cells (for further details see Fig. 21). In the case of persistent antigens, particularly with intracellular infections such as tuberculosis, leprosy, brucellosis, leishmaniasis, schistosomiasis (the egg granuloma), trichinosis and fungi such as Histoplasma spp., chronic inflammation may result. The principal cell type associated with CMI has long been thought to be the TH1 cell, via the release of IFNγ and other macrophage activating factors. However, more recently, attention has focused on the T17 cell (see Fig. 21), which seems to play a key part in mediating tissue damage in several infectious and autoimmune diseases, principally via recruitment of granulocytes.
Delayed-type hypersensitivity (DTH) One of the key features of CMI, antigen-specific memory, can be tested in vitro by measuring lymphocyte proliferation or the release of cytokines such as IFNγ, or in vivo by the response to antigen injected into the skin. A positive DTH response consists of a reddened swelling 2–3 days later, the Mantoux or Heaf tests for tuberculosis being typical examples. While DTH frequently correlates with protective immunity, this is not invariably the case. Sometimes basophils are prominent, giving a quicker response known as ‘Jones Mote’ hypersensitivity.
Contact sensitivity In this variant of DTH, antigens (usually plant or chemical molecules) react with proteins in the skin and stimulate a TH and TC cell response. The result is an eczema-like reaction with oedema and mononuclear cell infiltration 1–2 days later. Contact sensitivity to nickel in watches or jewellery is one of the most common forms of contact allergic dermatitis.
Chronic non-immunological inflammation Materials that are phagocytosed but cannot be degraded, or that are toxic to macrophages, such as talc, silica, asbestos, and the cell wall peptidoglycan of group A streptococci, will give rise to granulomas even in T-cell-deprived animals, and are therefore considered to be able to activate macro- phages without the aid of T cells. A number of chronic degenerative diseases (e.g Alzheimer’s disease in brain, and atherosclerosis in vessels) are associated with T-independent macrophage inflammatory responses, although it remains unclear whether the inflammatory response is a primary cause of disease, or a secondary response to some other underlying pathology. The controversial reports that antioxidants increase lifespan may perhaps be due to their ability to dampen down macrophage-mediated tissue damage.
Cancer Chronic inflammation associated with infection is strongly associated with the development of cancer. Examples include Helico- bacter pylori, which gives rises to ulcers and strongly increases the risk of developing stomach cancer. Similarly, chronic infection with hepatitis B or C viruses often leads to liver cancer. The mechanisms that link inflammation and cancer include increased angiogenesis, the formation of new blood vessels that provide nutrients and oxygen for tumour cells to grow.
Granulomas, aggregates of macrophages, lymphocytes, and a variety of other cell types, are an important feature of several chronic infections, most notably tuberculosis. They are initiated and maintained principally by the recruitment of macrophages by T cells into a site of persistent antigen or toxic material. Immune complexes are also a stimulus for granuloma formation.
Tissue damage within a granuloma is caused principally by lysosomal enzymes released by macrophages, and by reactive oxygen species produced by the oxidative burst (see Fig. 9). The centre of older granulomas therefore often consists of necrotic (dying) tissue. However, as granulomas grow, they frequently damage the surrounding organ, e.g. by obstructing and rupturing blood vessels, or airways in the lung in tuberculosis.
Epithelioid cells are large cells found in palisades around areas of necrotic tissue. They are thought to derive from macrophages, specialized for enzyme secretion rather than phagocytosis.
Giant cells are formed by fusion of macrophages; they are particularly prominent in ‘foreign-body’ granulomas.
Eosinophils are often found in granulomas, perhaps attracted by antigen–antibody complexes, but also under the influence of T cells.
Fibrosis around a granuloma represents an attempt at ‘healing’. Long- standing granulomas, e.g. healed tuberculosis, may eventually calcify, e.g. the well-known Ghon focus in the lung X-ray of many healthy people.
Granulomas are found in several diseases, some of known and some of unknown aetiology, suggesting an irritant or immunological origin. A few of the better known are listed below.
Sarcoidosis is characterized by granulomas in the lung, skin, eye, etc. An interesting but paradoxical feature is a profound deficiency of other cell-mediated T-cell immunity (e.g. a loss of Mantoux test responses) and often an increased Ig level and antibody responsiveness.
Crohn’s disease (regional ileitis) is somewhat similar to sarcoidosis, but usually restricted to the intestine. It is associated with pronounced T-cell infiltration into the intestinal wall, and hence was thought to be due to autoimmunity against gut proteins, perhaps stimulated by cross- reacting bacteria. However, Crohn’s disease is associated with a genetic defect in the bacterial-sensing NOD proteins (see Fig. 5), and may be more similar to chronic granulomatous disease in deriving from a failure to effectively clear chronic bacterial infection from the gut. Ulcerative colitis may have a similar aetiology.
Temporal arteritis is a chronic inflammatory disease of arteries, with granulomas in which giant cells are prominent.
Primary biliary cirrhosis In this rare autoimmune disease (see also Fig. 38), granulomas form around the bile ducts. The disease is believed to result from cross-reaction between a bacterial antigen and a mitochondrial ‘self antigen’.
Eosinophilic granuloma Sometimes eosinophils outnumber the other cells in a granuloma; this is particularly seen in worm infections and in rare bone conditions.
Chronic granulomatous disease (CGD) An immunodeficiency disease, characterized by a defect in granulocyte function, which leads to chronic bacterial infection and granuloma development (see Fig. 33).