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.
Granulomatous diseases
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).
