There are three variants of type IV hypersensitivity reaction

Three variants of type IV hypersensitivity reaction are recognized (Fig. 26.1):

Fig. 26.1 Delayed hypersensitivity reactions

The characteristics of type IV reactions comparing contact, tuberculin, and granulomatous reactions.

These three types of DTH were originally distinguished according to the reaction they produced when antigen was applied directly to the skin (epicutaneously) or injected intradermally. The degree of the response is usually assessed in animals by measuring thickening of the skin. This local response is accompanied by evidence of T cell activation systemically, such as antigen-specific T cell proliferation and cytokine synthesis, such as interferon-γ (IFNγ).

A contact hypersensitivity reaction has two stages – sensitization and elicitation

Dendritic cells and keratinocytes have key roles in the sensitization phase

Antigen presenting cells (APC) in the skin include Langerhans’ cell (LCs), located in the suprabasal epidermis, and dermal dendritic cells (dDCs). Contact hypersensitivity is primarily an epidermal reaction, and epidermal LCs were considered to be the APC responsible for initiating contact sensitivity (Fig. 26.3). More recent studies have established that dDCs are essential for stimulating hapten-specific T cells.

Fig. 26.3 Langerhans’ cells

(1) These dendritic cells constitute 3% of all cells in the epidermis. They express a variety of surface markers, including Langerin and CD1. Here they have been identified in normal skin using an anti-CD1 monoclonal antibody (counterstained with Mayer’s hemalum). (L, Langerhans’ cell; K, keratinocyte.) × 312. (2) Electron micrograph of a Langerhans’ cell showing the characteristic ‘Birbeck granule’. This organelle is a platelike structure derived from cell membranes, often with a bleb-like extension at one end. × 132 000.

Langerhans’ cells (see Chapter 2) are specialized DCs which extend dendritic processes throughout the epidermis, allowing them to sample environmental antigens. LCs express MHC class II, CD1 and the C-type lectin, langerin (CD207), which is responsible for the development of Birbeck granules, the cell membrane-derived organelle characteristic of LCs (see Fig. 26.3). The majority of dermal DCs are Langerin⁻, but there is a small population of Langerin⁺ dDCs, which are distinct from LCs, but also migrate rapidly to draining lymph nodes on exposure to sensitizers and activate hapten-specific CD8⁺ T cells. Both LCs and dDCs take up hapten-modified proteins by micropinocytosis but they also absorb lipid-soluble haptens, which modify cytoplasmic proteins. Under the influence of IL-1 and TNF secreted by keratinocytes and other cells, these DCs undergo maturation and increase expression of MHC and co-stimulatory molecules. Both LCs and dDCs are inactivated by ultraviolet B, which can therefore prevent or alleviate the effects of contact hypersensitivity.

Sensitization stimulates a population of memory T cells

Sensitization takes 10–14 days in humans. Hapten-bearing LCs and dDCs bearing modified proteins migrate as veiled cells through the afferent lymphatics to the paracortical areas of regional lymph nodes, where they activate CD4⁺ and CD8⁺ T cells.

MHC class I-restricted CD8⁺ T cells are important in contact hypersensitivity responses in humans and mice and are the major effector cells for many allergens. For example, lipid-soluble urushiol from poison ivy enters the cytoplasm of APCs and haptened cytoplasmic proteins are processed through the MHC class I pathway, leading to the activation of allergen-specific CD8⁺ T cells. Hapten-specific CD4 T cells are also activated hapten–peptide conjugates in association with MHC class II molecules and become effector/memory CD4⁺ T cells, which contribute to the skin inflammation, or regulatory CD4⁺ T cells (Fig. 26.4).

Fig. 26.4 Sensitization phase of contact hypersensitivity

The hapten forms a hapten–carrier complex in the epidermis or within cytoplasm. Langerhans’ cells and dermal Dendritic cells internalize the antigen, undergo maturation, and migrate via afferent lymphatics to the paracortical area of the regional lymph node where peptide–MHC molecule complexes on the surface of the Langerhans’ cell can also be directly haptenated. As interdigitating cells, they present antigen to CD4⁺ and CD8⁺ T cells.

Activated T cells change the pattern of adhesion molecules on their surface by downregulating the chemokine receptor, CCR7, and CD62L.

Q. What effect will loss of CCR7 and CD62L have on T cell function?

A. CD62L promotes adhesion of lymphocytes to high endothelial venules and CCR7 allows the cells to respond to CCL21 expressed in secondary lymphoid tissues (see Fig. 6.15). Hence cells lacking these receptors will lose their propensity to traffic into lymph tissues.

The expression of leukocyte functional antigen-1 (LFA-1), very late antigen-4 (VLA-4), and the chemokine receptors CXCR3 and CCR5 is increased. As a result the activated/memory T cells remain within the circulation rather than trafficking through lymphoid tissue, and are able to bind to adhesion molecules on the endothelium of inflamed tissues.

Elicitation involves recruitment of CD4⁺ and CD8⁺ lymphocytes and monocytes

The application of a contact allergen leads to:

• rapid expression of proinflammatory cytokines; and

• recruitment of effector T cells and monocytes to the site (Fig. 26.5).

Fig. 26.5 Elicitation phase of contact hypersensitivity

Langerhans’ cells carrying the hapten–carrier complex (1) move from the epidermis to the dermis, where they present the hapten–carrier complex to memory CD4⁺ and CD8⁺ T cells (2). Activated CD4⁺ and CD8⁺ T cells release IFNγ, which induces expression of ICAM-1 (3) and, later, MHC class II molecules (4) on the surface of keratinocytes and on endothelial cells of dermal capillaries, and activates keratinocytes, which release proinflammatory cytokines such as IL-1, IL-6, and GM–CSF (5). Hapten specific CD8⁺ T cells induce apoptosis of keratinocytes expressing haptenated self-peptides (6). Non-antigen-specific T cells are attracted to the site by cytokines (7) and may bind to keratinocytes via ICAM-1 and MHC class II molecules. Activated macrophages are also attracted to the skin, but this occurs later. Thereafter the reaction starts to downregulate. This suppression is driven by eicosanoids such as prostaglandin E2 (PGE2),produced by activated keratinocytes and macrophages, and the inhibitory cytokines, IL-10 and TGFβ (8).

There is induction of mRNA for TNF, IL-1β, and GM–CSF in Langerhans’ cells within 30 minutes of exposure to allergen, and increased transcription of mRNA for IL-1α, macrophage inflammatory protein-2 (CXCL2), and interferon-induced protein-10 (CXCL10) by keratinocytes.

TNF and IL-1 are potent inducers of endothelial cell adhesion molecules, including:

• E-selectin and vascular cell adhesion molecule-1 (VCAM-1) within 2 hours; and

• ICAM-1 within 8 hours (Fig. 26.6).

Fig. 26.6 Cytokines, prostaglandins, and cellular interactions in contact hypersensitivity

Cytokines and prostaglandins are central to the complex interactions between Langerhans’ cells, CD8⁺ and CD4⁺ T cells, keratinocytes, macrophages, and endothelial cells in contact hypersensitivity. The act of antigen presentation (1) causes the release of a cascade of cytokines (2). This cascade initially results in the activation and proliferation of CD4⁺ T cells (3), the induction of expression of ICAM-1 and MHC class II molecules on keratinocytes and endothelial cells (4), and the attraction of further T cells and macrophages to the skin (3, 5). Subsequently, influx of FoxP3⁺ CD25⁺ CD4⁺ regulatory T cells inhibits T cell activation and function by direct CTLA4-mediated effects and secretion of IL-10 and TGFβ. IL-10 is also released by keratinocytes and mast cells, while keratinocytes and macrophages produce PGE, which inhibits IL-1 and IL-2 production. The combined effects of enzymatic and cellular degradation of the hapten–carrier complex, regulatory CD4⁺ T cells and suppressive cytokines and PGE released by skin cells lead to downregulation of the reaction.

VCAM-1 and ICAM-1 are the receptors for VLA-4 and LFA-1, respectively, on the surface of effector/memory T cells and contribute to their recruitment across the endothelium. These locally released cytokines and chemokines also produce a gradient signal for the movement of mononuclear cells towards the dermoepidermal junction and epidermis.

The earliest histological change, seen after 4–8 hours, is the appearance of mononuclear cells around blood vessels. Macrophages and lymphocytes invade the dermis and epidermis, peaking at 48–72 hours (Fig. 26.7).

Fig. 26.7 Histological appearance of the lesion in contact hypersensitivity

Mononuclear cells (M) infiltrate both dermis and epidermis. The epidermis is pushed outwards and microvesicles (V) form within it due to edema (E). H&E stain. × 130.

The recruitment of memory T cells is antigen non-specific, with less than 1% of infiltrating lymphocytes bearing hapten-specific αβ T cell receptors. However, the hapten-specific T cells are stimulated by dermal DCs expressing hapten–peptide complexes to expand and to increase the expression of adhesion molecules. This leads to the retention of hapten-specific T cells at the inflamed site.

Infiltrating lymphocytes include CD4⁺ TH1-like T cells secreting IFNγ, and up to 50% CD8⁺ T cells. CD8⁺ T cells are essential for inducing experimental allergic sensitivity through their direct cytolytic effect on keratinocytes and the release of IFNγ.

Effector αβ T cells are essential for experimental contact sensitivity in mice, but NK T cells and γδ T cells also contribute to the induction and elicitation of this response.

Interestingly, hapten-specific IgM antibodies from B-1 cells are also important during the elicitation phase in mice by activating complement and recruiting T cells to the challenge site.

Experiments in gene-targeted mice show that selectins, ICAM-1, and the integrins, LFA-1 and VLA-4, are all required for the elicitation of contact and delayed hypersensitivity.

Suppression of the inflammatory reaction is mediated by multiple mechanisms

The reaction to cutaneous application of sensitizer wanes after 48–72 hours. This is due to the removal of antigenic stimulus following degradation of the hapten–conjugate and a variety of inhibitory mechanisms (see Fig. 26.6) including:

The tuberculin skin test reaction involves monocytes and lymphocytes

The tuberculin skin test is an example of the recall response to soluble antigen previously encountered during infection. Dendritic cells infected with M. tuberculosis in the lung undergo maturation and migrate to the draining mediastinal lymph nodes where they activate CD4⁺ and CD8⁺ T cells.

Following intradermal tuberculin challenge in a previously infected individual, mycobacteria-specific memory T cells are recruited and activated by dermal DCs to secrete IFNγ, which activates macrophages to produce TNFα and IL-1. These proinflammatory cytokines and chemokines from T cells and macrophages act on endothelial cells in dermal blood vessels to induce the sequential expression of the adhesion molecules E-selectin, ICAM-1, and VCAM-1. These molecules bind receptors on leukocytes and recruit them to the site of the reaction.

The initial influx at 4 hours is of neutrophils, but this is replaced at 12 hours by monocytes and T cells. The infiltrate, which extends outwards and disrupts the collagen bundles of the dermis, increases to a peak at 48 hours. CD4⁺ T cells outnumber CD8⁺ cells by about 2:1. A few CD4⁺ cells infiltrate the epidermis between 24–48 hours.

Monocytes constitute 80–90% of the total cellular infiltrate. Both infiltrating lymphocytes and macrophages express MHC class II molecules, and this increases the efficiency of activated macrophages as APCs. CD1⁺ DCs also are present at 24–48 hours. Overlying keratinocytes express HLA-DR molecules 48–96 hours after the appearance of the lymphocytic infiltrate. These events are summarized in Figure 26.9.

Fig. 26.9 Tuberculin-type hypersensitivity

This diagram illustrates cellular movements following intradermal injection of tuberculin. Within 1–2 hours there is expression of E-selectin on capillary endothelium leading to a brief influx of neutrophil leukocytes. By 12 hours ICAM-1 and VCAM-1 on endothelium bind the integrins LFA-1 and VLA-4 on monocytes and lymphocytes, leading to accumulation of both cell types in the dermis. This peaks at 48 hours and is followed by expression of the MHC class II molecules on keratinocytes. There is no edema of the epidermis.

The circulation of immune cells to and from the regional lymph nodes is thought to be similar to that for contact hypersensitivity. The tuberculin lesion normally resolves within 5–7 days, but if there is persistence of antigen in the tissues it may develop into a granulomatous reaction.

Tuberculin-like DTH reactions are used practically in two ways

First, reaction to soluble antigens from a pathogen demonstrates past infection with that pathogen. Thus, tuberculin reactivity confirms past or latent infection with M. tuberculosis, but not necessarily active disease. However, subjects with latent tuberculosis infection have an increased lifelong risk of 7–10% for the reactivation of active tuberculosis.

Second, DTH responses to frequently encountered microbes are a general measure of cell-mediated immunity. This can be tested with intradermal injection of single antigens from common pathogens or vaccine antigens, such as Candida albicans or tetanus toxoid. Loss of recall responses to specific antigens occurs in a wide range of diseases and infections, including HIV infection, which impair T cell function, and during therapy with corticosteroids or immunosuppressive agents.

Epithelioid cells and giant cells are typical of granulomatous hypersensitivity

Epithelioid cells are large and flattened with increased endoplasmic reticulum (Fig. 26.10). They:

Fig. 26.10 Electron micrograph of an epithelioid cell

The epithelioid cell is the characteristic cell of granulomatous hypersensitivity. Compare the extent of the endoplasmic reticulum (E) in the epithelioid cell (1, × 4800) with that of a tissue macrophage (2, × 4800). (C, collagen; L, lysosome; M, mitochondria; N, nucleus; U, nucleolus)

(Courtesy of MJ Spencer.)

Giant cells are formed when epithelioid cells fuse to form multinucleate giant cells (Fig. 26.11), sometimes referred to as Langhans’ giant cells (not to be confused with the Langerhans’ cell discussed earlier). Giant cells have several nuclei at the periphery of the cell. There is little endoplasmic reticulum, and the mitochondria and lysosomes appear to be undergoing degeneration. The giant cell may therefore be a terminal differentiation stage of the monocyte/macrophage line.

Fig. 26.11 Clinical and histological appearances of the Mitsuda reaction in leprosy seen at 28 days

(1) The resultant skin swelling (which may be ulcerated) is much harder and better defined than at 48 hours. (2) Histology shows a typical epithelioid cell granuloma (H&E stain. × 60). Giant cells (G) are visible in the center of the lesion, which is surrounded by a cuff of lymphocytes. This response is more akin to the pathological granulomatous processes in delayed hypersensitivity diseases than the self-resolving tuberculin-type reaction. The reaction is due to the continued presence of mycobacterial antigen.

A granuloma contains epithelioid cells, macrophages, and lymphocytes

An immunological granuloma typically has a core of epithelioid cells and macrophages, sometimes with giant cells. In some diseases, such as tuberculosis, this central area may have a zone of necrosis, with complete destruction of all cellular architecture.

The macrophage/epithelioid core is surrounded by a cuff of lymphocytes, and there may also be considerable fibrosis (deposition of collagen fibers) caused by proliferation of fibroblasts and increased collagen synthesis. An example of a granulomatous reaction is the delayed Mitsuda reaction to dead M. leprae (see Fig. 26.11).

The three types of delayed hypersensitivity are summarized in Figure 26.1.

T cells bearing αβ TCRs are essential

Experiments with gene knockout mice have confirmed that T cells bearing αβ TCRs rather than γδ TCRs are essential for initiating delayed hypersensitivity reactions in response to infection with intracellular bacteria.

Sensitized αβ T cells, stimulated with the appropriate antigen and APCs, undergo lymphoblastoid transformation before cell division (Fig. 26.12). This forms the basis of the lymphocyte stimulation test as a measure of T cell function. Lymphocyte stimulation is accompanied by DNA synthesis and this can be measured by assaying the uptake of radiolabeled thymidine, a nucleoside required for DNA synthesis. Lymphocytes from a patient are stimulated in culture with the suspect antigen to determine whether it induces proliferation. It is important to stress that this is a test for T cell memory only, and does not necessarily imply the presence of protective immunity.

Fig. 26.12 Transformed lymphocytes

Following stimulation with appropriate antigen, T cells undergo lymphoblastoid transformation before cell division. Blast cells with expanded nuclei and cytoplasm (as well as one lymphocyte in the metaphase of cell division) are shown. The resulting cell division can be measured by the uptake of tritiated thymidine.

Following activation by APCs, T cells release a number of proinflammatory cytokines, which attract and activate macrophages. These include IFNγ, lymphotoxin-α, IL-3, and GM–CSF. The presence of memory T cells can be detected by antigen-specific IFNγ release assays.

This TH1-like pattern of cytokines is enhanced by activation of the naive T cells in the presence of IL-12 which is released by dendritic cells on exposure to bacterial products. IL-12 suppresses the cytokine response of TH2 cells.

IFNγ is required for granuloma formation in humans

The role of individual cytokines can be analyzed in gene knockout mice deficient for a single cytokine. For example, IFNγ gene knockout mice are unable to activate macrophages and control infection with M. tuberculosis (Fig. 26.13).

Fig. 26.13 The importance of IFNγ in the activation of macrophages

Mice deficient in IFNγ (gene knockout [gko] mice), infected with a sublethal dose of M. tuberculosis, are unable to activate macrophages in response to infection with an intracellular bacterium. Macrophages initially accumulate at the site of infection, but do not form typical granulomas. Uncontrolled infection (graph, left) causes widespread tissue necrosis and death (graph, right). (cfu, colony forming units of infectious agent in the liver.)

The absolute requirement of IFNγ for granuloma formation in humans is illustrated by the syndrome of Mendelian susceptibility to mycobacterial disease. Subjects deficient in the IFNγ receptor have markedly increased susceptibility to environmental mycobacteria and the vaccine strain, BCG, and fail to develop granulomas.

TNF and lymphotoxin-α are essential for granuloma formation during mycobacterial infections

TNF and the related cytokine, lymphotoxin-α, are both essential for the formation of granulomas during mycobacterial infections (Fig. 26.14), and act in part through the regulation of chemokine production.

Fig. 26.14 Macrophage differentiation

Bacterial products stimulate macrophages to secrete IL-12. Activation of T cells in the presence of IL-12 leads to the release of IFNγ and other cytokines, lymphotoxin (LT), IL-3, and GM–CSF. These cytokines activate macrophages to kill intracellular parasites. Failure to eradicate the antigenic stimulus causes persistent cytokine release and promotes differentiation of macrophages into epithelioid cells, which secrete large amounts of TNFα. Some fuse to form multinucleate giant cells.

Both macrophage- and T cell-derived TNF contribute to this process, but within granulomas activated macrophages become the major source of TNF, driving the differentiation of macrophages into epithelioid cells and the fusion of epithelioid cells to form giant cells (Figs 26.14 and 26.15). The maintenance of granulomas is also dependent on TNF. Consequently, inhibition of TNF activity suppresses the granulomatous inflammation in Crohn’s disease and sarcoidosis.

Fig. 26.15 The importance of TNF in the formation of granulomas

TNF is essential for the development of epithelioid cell granulomas. If BCG-injected mice are injected with anti-TNFα antibodies, they do not develop granulomas.

The immune response in leprosy varies greatly between individuals

Leprosy is a chronic granulomatous disease of skin and nerves caused by infection with M. leprae. It is divided clinically into three main types – tuberculoid, borderline, and lepromatous:

Fig. 26.16 The immunological spectrum of leprosy

The clinical spectrum of leprosy ranges from tuberculoid disease with few lesions and bacteria to lepromatous leprosy, with multiple lesions and uncontrolled bacterial proliferation. This range reflects host immunity as measured by specific cellular and antibody responses to M. leprae, and the tissue expression of cytokines.

In leprosy, protective immunity is usually associated with cell-mediated immunity, but this declines across the leprosy spectrum towards the lepromatous pole with an increase in mycobacteria and rise in non-protective anti-M. leprae antibodies.

The borderline leprosy reaction is a dramatic example of delayed hypersensitivity. Borderline reactions occur either spontaneously or following drug treatment. In these reactions, hypopigmented skin lesions containing M. leprae become swollen and inflamed (Fig. 26.17) because the patient is now able to mount a T cell response to the mycobacteria resulting in a delayed-type hypersensitivity reaction. The histological appearance shows a more tuberculoid pattern with an infiltrate of IFNγ-secreting lymphocytes. The process may occur in peripheral nerves, where Schwann cells contain M. leprae; this is the most important cause of nerve destruction in this disease. The lesion in borderline leprosy is typical of granulomatous hypersensitivity (see Fig. 26.17).

Fig. 26.17 Leprosy

(1) A borderline leprosy reaction. This small nerve is almost completely replaced by the granulomatous infiltrate. (2) Lepromatous leprosy. Large numbers of bacilli are present. (3) Borderline lepromatous leprosy. There are gross infiltrated erythematous plaques with well-defined borders.

((2) Courtesy of Dr Phillip McKee. (3) Courtesy of Dr S Lucas.)

In patients with a tuberculoid-type reaction, T cell sensitization may be assessed in vitro by lymphocyte proliferation or the release of IFNγ following stimulation with M. leprae antigens.

Granulomatous reactions are necessary to control tuberculosis

In tuberculosis, the granuloma provides the microenvironment in which lymphocytes stimulate macrophages to kill the intracellular M. tuberculosis. The formation and maintenance of granulomas are essential to control the infection.

In most (> 90%) subjects with latent tuberculosis infection, the mycobacteria remain dormant within small granulomas in the lung. There is, however, a balance between the effects of activated macrophages:

Fig. 26.w1 Chest radiograph of a patient with pulmonary tuberculosis

There is extensive parenchymal streaking, predominantly in the upper fields of the lungs. These changes are typical of chronic bilateral pulmonary tuberculosis. Some enlargement of the heart is also evident.

The histological appearance of the lesion is typical of a granulomatous reaction, with central caseous (cheesy) necrosis (Fig. 26.18). This is surrounded by an area of epithelioid cells with a few giant cells. Mononuclear cell infiltration occurs around the edge.

Fig. 26.18 Histological appearance of a tuberculous section of lung

This shows an epithelioid cell granuloma (E) with giant cells (G). Mononuclear cell infiltration can be seen (M). There is also marked caseation and necrosis (N) within the granuloma. H&E stain. × 75.

Granulomas surround the parasite ova in schistosomiasis

In schistosomiasis, which is caused by parasitic trematode worms (schistosomes), the host becomes sensitized to the eggs of the worms, leading to a typical granulomatous reaction in the parasitized tissue mediated essentially by TH2 cells (Fig. 26.19; see also Chapter 15). In this case the cytokines IL-5 and IL-13 are responsible for the recruitment of eosinophils and the formation of the granulomas around the ova. When the eggs have been deposited in the liver, the subsequent IL-13-dependent fibrosis causes hepatic scarring and portal hypertension.

Fig. 26.19 Histological appearance of the liver in schistosomiasis

The epithelioid cell granuloma surrounds the schistosome ovum (O) and eosinophils are prominent. H&E stain. × 300.

(Courtesy of Dr Phillip McKee.)

The cause of sarcoidosis is unknown

Sarcoidosis is a chronic disease of unknown etiology in which activated macrophages and non-caseating granuloma accumulate in many tissues, frequently accompanied by fibrosis (Fig. 26.20). The disease particularly affects lymphoid tissue and the lungs, as well as bone, nervous tissue, and skin. Enlarged lymph nodes may be detected in chest radiographs of affected patients (Fig. 26.w2 ). No infectious agent has been isolated, though mycobacteria have been implicated because of the similarities in the pathology.

Fig. 26.20 Histological appearance of sarcoidosis in a lymph node biopsy

The granuloma of sarcoidosis is typically composed of epithelioid cells (E) and multinucleate giant cells (G), but without caseous necrosis. There is only a sparse mononuclear cell infiltrate (M) evident at the periphery of the granuloma. H&E stain. × 240.

Fig. 26.w2 The chest radiograph of a patient with sarcoidosis

There is enlargement of the lymph nodes adjacent to the hilar (H) and paratracheal (L) areas of the lungs, with diffuse pulmonary infiltration characteristic of the disease.

One of the paradoxes of clinical immunology is that this disease is usually associated with depression of delayed hypersensitivity both in vivo and in vitro. Patients with sarcoidosis are anergic on testing with tuberculin; however, when cortisone is injected with tuberculin antigen the skin tests are positive, suggesting that cortisone-sensitive T inhibitory cells are responsible for the anergy.

Patients may present acutely with fever and malaise, though in the longer term those with pulmonary involvement develop shortness of breath caused by lung fibrosis. The diagnosis is often suggested by the clinical pattern and radiographic changes and confirmed by tissue biopsy. Angiotensin converting enzyme (ACE) and serum calcium levels are sometimes elevated because activated macrophages are a source of both ACE and 1,25-dihydroxy-cholecalciferol (the active metabolite of vitamin D₃).

The cause of Crohn’s disease is unknown

Crohn’s disease is a chronic inflammatory disease of the ileum and colon, in which lymphocytes and macrophages accumulate in all layers of the bowel. The granulomatous reaction and fibrosis cause stricture of the bowel and penetrating fistulas into other organs (see Fig. 7.17). Although the antigens initiating this granulomatous reaction are unknown, there appears to be defect in inflammasome-mediated intracellular signaling responses to bacterial products in Crohn’s disease. This may result an excessive T cell-driven immune response to microbial antigens in genetically predisposed individuals.

Infiltrating T cell show a restricted T cell receptor repertoire and the cytokine profile of pro-inflammatory TH17 cells, driven by IL-23, as well as TH1 T cells. These are responsible for macrophage activation and the release of inflammatory cytokines, such as IL-17, IL-21, IL-22, and TNF, reactive oxygen metabolites, and nitric oxide. These initiate and maintain the transmural intestinal inflammation.

Inhibition of TNF activity with antibody or soluble TNF receptor reduces inflammation in patients with Crohn’s disease, but this therapy may be associated with reactivation of tuberculosis in subjects with latent tuberculosis infection and with other granulomatous infectious diseases.