In all of these conditions, tissue injury is mediated by the same mechanisms that normally function to eliminate infectious pathogens—namely, antibodies, effector T lymphocytes, and various other effector cells. The fundamental problem in these diseases is that the immune response is triggered and maintained inappropriately. Because the stimuli for these abnormal immune responses are difficult or impossible to eliminate (e.g., self antigens, persistent microbes, or environmental antigens), and the immune system has many intrinsic positive feedback loops (which normally promote protective immunity), once a hypersensitivity reaction starts, it is difficult to control or terminate it. Therefore, these diseases tend to be chronic and debilitating, and are therapeutic challenges. Since inflammation is a major component of the pathology of these disorders, they are sometimes grouped under the term immune-mediated inflammatory diseases.
Hypersensitivity reactions can be subdivided into four types based on the principal immune mechanism responsible for injury; three are variations on antibody-mediated injury, and the fourth is T-cell mediated (
Table 5.2 ). The rationale for this classification is that the mechanism of http://ebooksmedicine.net immune injury is often a good predictor of the clinical manifestations and may help to guide the therapy. However, this classification of immune-mediated diseases is not perfect, because several immune reactions may coexist in any one disease.
The main types of hypersensitivity reactions are as follows:
In immediate (type I) hypersensitivity, often called allergy, the injury is caused by TH2 cells, IgE antibodies, and mast cells and other leukocytes. Mast cells release mediators that act on blood vessels and smooth muscle as well as cytokines that recruit and activate inflammatory cells.
Antibody-mediated disorders (type II hypersensitivity) are caused by secreted IgG and IgM antibodies that bind to fixed tissue or cell surface antigens. Antibodies injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation. Antibodies also may interfere with cellular functions and cause disease without cell or tissue injury.
In immune complex–mediated disorders (type III hypersensitivity), IgG and IgM antibodies bind antigens, usually in the circulation, and form antigen-antibody complexes that deposit in vascular beds and induce inflammation. The leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals.
T cell–mediated (type IV) hypersensitivity disorders are caused mainly by immune responses in which T lymphocytes of the TH1 and TH17 subsets produce cytokines that induce inflammation and activate neutrophils and macrophages, which are responsible for tissue injury. CD8+ CTLs also may contribute to injury by directly killing host cells.
Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody bound to the surface of mast cells. The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy. Many allergens are environmental substances that certain individuals are predisposed to developing allergic  reactions against. TH2 cells and IgE are responsible for the clinical and pathologic manifestations of the reaction. Immediate hypersensitivity may occur as a local reaction that is merely annoying (e.g., seasonal rhinitis, hay fever), severely debilitating (asthma), or even fatal (anaphylaxis).
Sequence of Events in Immediate Hypersensitivity Reactions
Most hypersensitivity reactions follow a stereotypic sequence of cellular responses (