Excerpts from Kuby Immunology:

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Chronic inflammation may also lead to formation of a granuloma, a tumor-like mass consisting of a central area of
activated macrophages surrounded by activated lymphocytes. The center of the granuloma often contains
multinucleated giant cells formed by the fusion of activated macrophages. These giant cells typically are surrounded
by large modified macrophages that resemble epithelial cells and therefore are called epithelioid cells.

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The influx and activation of macrophages in the DTH response is important in host defense against parasites and
bacteria that live within cells, where circulating antibodies cannot reach them. The heightened phagocytic activity
and the buildup of lytic enzymes from macrophages in the area of infection lead to nonspecific destruction of cells,
and thus of the intracellular pathogen. Generally, the pathogen is cleared rapidly with little tissue damage. However,
in some cases, especially if the antigen is not easily cleared, a prolonged DTH response can itself become
destructive to the host as the intense inflammatory response develops into a visible granulomatous reaction. A
granuloma develops when continuous activation of macrophages induces the macrophages to adhere closely to one
another, assuming an epithelioid shape and sometimes fusing to form multinucleated giant cells (Figure 16-18).
These giant cells displace the normal tissue cells, forming palpable nodules, and release high concentrations of lytic
enzymes, which destroy surrounding tissue. In these cases, the response can damage blood vessels and lead to
extensive tissue necrosis. The response to Mycobacterium tuberculosis illustrates the double-edged nature of the
DTH response. Immunity to this intracellular bacterium involves a DTH response in which activated macrophages
wall off the organism in the lung and contain it within a granuloma-type lesion called a tubercle. Often, however, the
concentrated release of lytic enzymes from the activated macrophages within tubercles damages lung tissue. Some
examples of truly hypersensitive conditions, in which tissue damage far outweighs any beneficial effects, are
described in Chapter 17.

Immune Responses Can Contribute to Bacterial Pathogenesis

The ability of some bacteria to survive intracellularly within infected cells can result in chronic antigenic activation
of CD4+ T cells, leading to tissue destruction by a cell-mediated response with the characteristics of a delayed-type
hypersensitivity reaction (see Chapter 14).Cytokines secreted by these activated CD4+ T cells can lead to extensive
accumulation and activation of macrophages, resulting in formation of a granuloma. The localized concentrations
of lysosomal enzymes in these granulomas can cause extensive tissue necrosis. Much of the tissue damage seen with
M. tuberculosis is due to a cell-mediated immune response.

Tuberculosis
The ability of some bacteria to survive intracellularly within infected cells can result in chronic antigenic activation
of CD4+ T cells, leading to tissue destruction by a cell-mediated response with the characteristics of a delayed-type
hypersensitivity reaction (see Chapter 14).Cytokines secreted by these activated CD4+ T cells can lead to extensive
accumulation and activation of macrophages, resulting in formation of a granuloma. The localized concentrations
of lysosomal enzymes in these granulomas can cause extensive tissue necrosis. Much of the tissue damage seen with
M. tuberculosis is due to a cell-mediated immune response.

Upon infection with M. tuberculosis, the most common clinical pattern, termed pulmonary tuberculosis, appears in
about 90% of those infected. In this pattern, CD4+ T cells are activated within 2–6 weeks after infection, inducing
the infiltration of large numbers of activated macrophages. These cells wall off the organism inside a granulomatous
lesion called a tubercle (Figure 17-10). A tubercle consists of a few small lymphocytes and a compact collection of
activated macrophages, which sometimes differentiate into epithelioid cells or multinucleated giant cells. The
massive activation of macrophages that occurs within tubercles often results in the concentrated release of lytic
enzymes. These enzymes destroy nearby healthy cells, resulting in circular regions of necrotic tissue,which
eventually form a lesion with a caseous (cheeselike) consistency (see Figure 17-10). As these caseous lesions
heal, they become calcified and are readily visible on x-rays, where they are called Ghon complexes.

Recent studies have revealed high levels of IL-12 in the pleural effusions of tuberculosis patients. The high levels of
IL-12, produced by activated macrophages, are not surprising, given the decisive role of IL-12 in stimulating TH1-
mediated responses (see Figure 12-12). In mouse models of tuberculosis, IL-12 has been shown to increase
resistance to the disease. Not only does IL-12 stimulate development of TH1 cells, but it also may contribute to
resistance by inducing the production of chemokines that attract macrophages to the site of infection.When IL-12 is
neutralized by antibody to IL-12, granuloma formation in tuberculous mice is blocked.

Helminth Egg Infections

A chronic state can then develop in which the adult worms persist and the unexcreted eggs induce cell-mediated
delayed-type hypersensitive reactions, resulting in large granulomas that are gradually walled off by fibrous
tissue.Although the eggs are contained by the formation of the granuloma, often the granuloma itself obstructs the
venous blood flow to the liver or bladder.

Chronic Granulomatous Disease (CGD)

CHRONIC GRANULOMATOUS DISEASE (CGD)
CGD is a genetic disease that has at least two distinct forms: an X-linked form that occurs in about 70% of patients
and an autosomal recessive form found in the rest. This disease is rooted in a defect in the oxidative pathway by
which phagocytes generate hydrogen peroxide and the resulting reactive products, such as hypochlorous acid, that
kill phagocytosed bacteria. CGD sufferers undergo excessive inflammatory reactions that result in gingivitis,
swollen lymph nodes, and nonmalignant granulomas (lumpy subcutaneous cell masses); they are also susceptible to
bacterial and fungal infection. CGD patients are not subject to infection by those bacteria, such as pneumococcus,
that generate their own hydrogen peroxide. In this case, the myeloperoxidase in the host cell can use the bacterial
hydrogen peroxide to generate enough hypochlorous acid to thwart infection. Several related defects may lead to
CGD; these include a missing or defective cytochrome (cyt b558) that functions in an oxidative pathway and defects
in proteins (phagocyte oxidases, or phox) that stabilize the cytochrome. In addition to the general defect in the killer
function of phagocytes, there is also a decrease in the ability of mononuclear cells to serve as APCs. Both processing
and presentation of antigen are impaired. Increased amounts of antigen are required to trigger T-cell help when
mononuclear cells from CGD patients are used as APCs.
The addition of IFN-_ has been shown to restore function to CGD granulocytes and monocytes in vitro. This
observation prompted clinical trials of IFN-_ for CGD patients. Encouraging increases in oxidative function and
restoration of cytoplasmic cytochrome have been reported in these patients. In addition, knowledge of the precise
gene defects underlying CGD makes it a candidate for gene therapy, and replacement of the defective cytochrome
has had promising results (see below).