Diseases Caused by Cytokine Mediated Inflammation

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In immune-mediated inflammation, TH1 and TH17 cells secrete cytokines that recruit and activate leukocytes. IL-17, produced by TH17 cells, promotes neutrophil recruitment; interferon-y (IFN-y), produced by TH1 cells, activates macrophages; and tumor necrosis factor (TNF) and chemokines, produced by T lymphocytes and other cells, are involved in the recruitment and activation of many types of leukocytes. Tissue injury results from the products of activated neutrophils and macrophages, such as lysosomal enzymes, reactive oxygen species, nitric oxide, and proinflammatory cytokines (see Chapter 10).

Cytokine-mediated inflammation

Th1 Mediated Damage

T cell-mediated cytotoxicity

CD8+ CTLs

Cell killing and tissue injury

FIGURE 18-5 Mechanisms of T cell-mediated diseases. A, In cytokine-mediated inflammatory reactions, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. APC, antigen-presenting cell. B, In some diseases, CD8+ CTLs directly kill tissue cells.

TABLE 18-4 T Cell-Mediated Diseases

Disease

Specificity of Pathogenic T Cells

Principal Mechanisms of Tissue Injury

Rheumatoid arthritis

Collagen?

Citrullinated self proteins?

Inflammation mediated by TH17 (and TH1?) cytokines Role of antibodies and immune complexes?

Multiple sclerosis

Protein antigens in myelin (e.g., myelin basic protein)

Inflammation mediated by TH1 and TH17 cytokines Myelin destruction by activated macrophages

Type 1 diabetes mellitus

Antigens of pancreatic islet p cells (insulin, glutamic acid decarboxylase, others)

T cell-mediated inflammation Destruction of islet cells by CTLs

Inflammatory bowel disease

Enteric bacteria Self antigens?

Inflammation mediated by TH17 and TH1 cytokines

Autoimmune myocarditis

Myosin heavy chain protein

CTL-mediated killing of myocardial cells Inflammation mediated by TH1 cytokines

Examples of human T cell-mediated diseases are listed. In many cases, the specificity of the T cells and the mechanisms of tissue injury are inferred on the basis of the similarity with experimental animal models of the diseases.

Vascular endothelial cells in the lesions may express increased levels of cytokine-regulated surface proteins such as adhesion molecules and class II MHC molecules. The inflammation associated with T cell-mediated diseases is typically chronic, but bouts of acute inflammation may be superimposed on a background of chronic inflammation. Delayed-type hypersensitivity (DTH) is an example of such inflammatory reactions and is described later. Chronic inflammatory reactions often produce fibrosis as a result of the secretion of cytokines and growth factors by the macrophages.

Many organ-specific autoimmune diseases are caused by interaction of autoreactive T cells with self antigens, leading to cytokine release and inflammation. This is believed to be the major mechanism underlying rheumatoid arthritis, multiple sclerosis, type 1 diabetes, psoriasis, and other autoimmune diseases (Table 18-4). Some of these are described in more detail at the end of the chapter.

T cell reactions against microbes and other foreign antigens may also lead to inflammation and tissue injury at the sites of infection or antigen exposure. Intracellular bacteria such as Mycobacterium tuberculosis induce strong T cell and macrophage responses that result in granuloma-tous inflammation and fibrosis (described below); the inflammation and fibrosis may cause extensive tissue destruction and functional impairment, in this case in the lungs. Tuberculosis is a good example of an infectious disease in which tissue injury is mainly due to the host immune response (see Chapter 15). A variety of skin diseases that result from topical exposure to chemicals and environmental antigens, called contact sensitivity, are due to inflammatory reactions, presumably triggered by neoantigens formed by the binding of the chemicals to self proteins. Both CD4+ and CD8+ T cells may be the source of cytokines in contact sensitivity reactions. Examples of contact sensitivity include the rashes of poison ivy and poison oak (in which T cells react against chemicals made by the plants called urushiols) and rashes induced by contact with a variety of chemicals, such as thiuram, which is used in the manufacture of latex gloves. Some of these reactions become chronic and clinically are called eczema. T cell responses against intestinal bacteria are believed to underlie some forms of inflammatory bowel disease.

The classical T cell-mediated inflammatory reaction is called delayed type hypersensitivity, and is described next.

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Responses

  • jill
    What diseases are related to cytokine mediated?
    4 years ago

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