Pathological immune-complex deposition is seen in other situations in which antigen persists. One is when an adaptive antibody response fails to clear the infecting pathogen, as occurs in subacute bacterial endocarditis or chronic viral hepatitis. In these situations, the replicating pathogen is continuously generating new antigen in the presence of a persistent antibody response, with the consequent formation of abundant immune complexes. These are deposited within small blood vessels and result in injury in many tissues and organs, including the skin, kidneys, and nerves.
Immune-complex disease also occurs when inhaled allergens provoke IgG rather than IgE antibody responses, perhaps because they are present at relatively high levels in the air. When a person is reexposed to high doses of such allergens, immune complexes form in the walls of alveoli in the lungs. This leads to the accumulation of fluid, protein, and cells in the alveolar wall, slowing blood:air exchange of O2 and CO2, compromising lung function. This type of reaction is more likely to occur in occupations such as farming, in which there is repeated exposure to hay dust or mold spores, and the resulting disease is known as farmer’s lung. If exposure to antigen is sustained, the lining of the lungs can be permanently damaged.
14-16 Hypersensitivity reactions can be mediated by TH1 cells and CD8 cytotoxic T cells.
Unlike the immediate hypersensitivity reactions, which are mediated by antibodies, cellular hypersensitivity reactions such as delayed-type hypersensitivity reactions are mediated by antigen-specific effector T cells. We have already seen the involvement of TH2 effector cells and the cytokines they produce in the chronic response of IgE-initiated allergic reactions. Here we consider the hypersensitivity diseases caused by TH1 and CD8 cytotoxic T cells (Fig. 14.19). These cells function in hypersensitivity in essentially the same way as when they respond to a pathogen (described in Chapter 9), and the responses can be transferred between experimental animals by purified T cells or cloned T-cell lines. Much of the chronic inflammation seen in some of the allergic diseases described earlier is due to cellular hypersensitivity reactions mediated by antigen-specific TH1 cells acting in concert with TH2 cells.
The prototypic delayed-type hypersensitivity reaction is the Mantoux test— the standard tuberculin test that is used to determine whether an individual has previously been infected with Mycobacterium tuberculosis. In the Mantoux test, small amounts of tuberculin—a complex extract of peptides and carbohydrates derived from M. tuberculosis—are injected intradermally. In people who have been exposed to the bacterium, either by infection or by immunization with the BCG vaccine (an attenuated form of M. tuberculosis), a local T-cell-mediated inflammatory reaction evolves over 24–72 hours. The response is caused by TH1 cells, which enter the site of antigen injection, recognize complexes of peptide:MHC class II molecules on antigen-presenting cells, and release inflammatory cytokines such as IFN-γ, TNF-α, and lymphotoxin. These stimulate the expression of adhesion molecules on endothelium and increase local blood vessel permeability, allowing plasma and accessory cells to enter the site, thus causing a visible swelling (Fig. 14.20). Each of these phases takes several hours and so the fully developed response only appears 24–48 hours after challenge. The cytokines produced by the activated TH1 cells and their actions are shown in Fig. 14.21.
Very similar reactions are observed in allergic contact dermatitis (also called contact hypersensitivity), which is an immune-mediated local inflammatory reaction in the skin caused by direct skin contact with certain antigens. It is important to note that not all contact dermatitis is immune-mediated and allergic in nature; it can also be caused by direct damage to the skin by irritant or toxic chemicals.