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Chapter 21 : Pathology and Pathogenesis of Parasitic Disease

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Abstract:

This chapter focuses primarily on the question of how the balance between immune protection and immune pathology is regulated. A fundamental biological dilemma is that the host has to deal with many different infectious pathogens and, even for a single species of parasite, with different strains. Eosinophils, typically associated with the Th2 response, are involved in immediate hypersensitivity reactions to the filarial worm . Humans with visceral leishmaniasis have high circulating levels of IL-10, which may partly explain their inability to control the infection. The clinical manifestations of weight loss, hypothermia, hypoglycemia, and increased levels of liver-derived enzymes in the blood, together with hepatic necrosis, suggested that the IL-10 knockout (KO) mice died in response to an overwhelming systemic immune response, resembling that observed during septic shock. Schistosomiasis is caused by one of three major species of helminth parasites, , , and . Malarial infection provokes high levels of tumor necrosis factor (TNF) and other proinflammatory cytokines as well as causing markedly elevated immunoglobulin production activation of complement and redistribution of lymphocytes from the peripheral circulation to the spleen and other organs. Although our knowledge of cytokines and other immunological mediators has grown enormously in the last 15 years, the current list is undoubtedly a small fraction of the total number of host molecules involved in the pathogenesis of parasitic disease.

Citation: Wynn T, Kwiatkowski D. 2002. Pathology and Pathogenesis of Parasitic Disease, p 293-305. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch21

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Figure 1.

Resistance versus susceptibility to many intracellular organisms is regulated by a delicate balance between IFN-γ and IL- 10. The type, magnitude, location, and duration of the host response dictate a susceptible or resistant outcome following infection with and With all three intracellular pathogens, IFN-γ is required to induce resistance. Nevertheless, the protective response must also be carefully down-regulated in a timely manner to prevent the development of immune-mediated and potentially lethal tissue pathology. Here, the immunosuppressive cytokine IL-10 appears to play a dominant role. Because of the systemic nature of and infections, dysregulation in the type 1 response is more dangerous during these infections (bold line) than during an infection (dotted line), which tends to remain localized within granulomatous foci.

Citation: Wynn T, Kwiatkowski D. 2002. Pathology and Pathogenesis of Parasitic Disease, p 293-305. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch21
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Image of Figure 2.
Figure 2.

The proinflammatory response, mediated through IFN- γ, TNF-α, and NO, is important for acute resistance to murine malaria infection, but in the absence of IL-10 or TGF-β these responses can induce severe pathology. It is postulated that an early proinflammatory cytokine response mediates protective immunity whereas a late or uncontrolled response contributes to the development of lethal pathology.

Citation: Wynn T, Kwiatkowski D. 2002. Pathology and Pathogenesis of Parasitic Disease, p 293-305. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch21
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Figure 3.

Highly polarized type 1 and type 2 cytokine responses induce distinct but equally detrimental forms of immunopathology in murine schistosomiasis. A mixed Th1-Th2-type cytokine response protects chronically -infected mice from the development of lethal egg-induced tissue pathology. Mice deficient in IL-4 and IL-10 develop highly polarized Th1-type cytokine responses following infection. Consequently, these mice suffer acute mortality, which is linked to overexpression of the proinflammatory mediators IFN-γ, TNF-α, and inducible NO and the formation of nonfibrotic granulomas. In contrast, mice deficient in IL-12 and IL-10 develop highly polarized Th2-type cytokine responses and show signs of chronic morbidity. These mice form large eosinophil-rich granulomas and develop severe hepatic fibrosis, causing portal hypertension, portal-systemic shunts, and fatal hematemesis.

Citation: Wynn T, Kwiatkowski D. 2002. Pathology and Pathogenesis of Parasitic Disease, p 293-305. In Kaufmann S, Sher A, Ahmed R (ed), Immunology of Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817978.ch21
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