The progression of some diseases may depend on the balance between the TH1 and TH2 subsets. In humans, a well-studied example of this phenomenon is leprosy, which is caused by Mycobacterium leprae, an intracellular pathogen that can survive within the phagosomes of macrophages. Leprosy is not a single clinical entity; rather, the disease presents as a spectrum of clinical responses, with two major forms of disease, tuberculoid and lepromatous, at each end of the spectrum. In tuberculoid leprosy, a cell-mediated immune response forms granulomas, resulting in the destruction of most of the mycobacteria, so that only a few organisms remain in the tissues. Although skin and peripheral nerves are damaged, tuberculoid leprosy progresses slowly and patients usually survive. In lepromatous leprosy, the cell-mediated response is depressed and, instead, humoral antibodies are formed, sometimes resulting in hypergammaglobulinemia. The myco-bacteria are widely disseminated in macrophages, often reaching numbers as high as 1010 per gram of tissue. Lepromatous leprosy progresses into disseminated infection of the bone and cartilage with extensive nerve damage.
The development of lepromatous or tuberculoid leprosy depends on the balance of TH1 and TH2 cells (Figure 12-14). In tuberculoid leprosy, the immune response is characterized by a TH1-type response with delayed-type hypersensitivity and a cytokine profile consisting of high levels of IL-2, IFN-7, and TNF-p. In lepromatous leprosy, there is a TH2-type immune response, with high levels of IL-4, IL-5, and IL-10. This cytokine profile explains the diminished cell-mediated immunity and increased production of serum antibody in lep-romatous leprosy.
There is also evidence for changes in TH-subset activity in AIDS. Early in the disease, TH1 activity is high, but as AIDS progresses, some workers have suggested, there may be a shift from a TH1-like to a TH2-like response. In addition, some pathogens may influence the activity of the TH subsets. The Epstein-Barr virus, for instance, produces vIL-10, which has
Correlation between type of leprosy and relative Th1 or Th2 activity. Messenger RNA isolated from lesions from tuberculoid and lepromatous leprosy patients was analyzed by Southern blotting using the cytokine probes indicated. Cytokines produced by Th1 cells predominate in the tuberculoid patients, while cytokines produced by TH2 cells predominate in the lepromatous patients. [From P. A. Sielingand R. L. Modlin, 1994, Immunobiology 191:378.]
IL-10-like activity and, like cellular IL-10, tends to suppress TH1 activity by cross-regulation. Some researchers have speculated that vIL-10 may reduce the cell-mediated response to the Epstein-Barr virus, thus conferring a survival advantage on the virus.
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