Immune responses of the host Antibody

Using sensitive tests, specific serum antibody may be detected in virtually all persons infected with E. histolytica, whether they have symptoms or not, although levels are significantly higher in those with ALA. Principally immunoglobulin G (IgG), and to a lesser extent IgA, are represented; IgM declines fairly rapidly while specific IgG remains elevated for months or years, reducing the diagnostic value of serology in endemic areas. In one study levels of specific IgG4 >> IgG2 > IgG3 > IgGl were found. Coproantibodies have been detected in the feces of AD patients, and specific secretory IgA in the saliva and colostrum of those with ALA. Autoantibodies

(directed against liver, colon, neutrophils and IgG) and circulating immune complexes have been described in patients but there is no real evidence for immunopathology in human amebiasis.

Cell-mediated responses

On histological examination neither the ulcers of AD nor the hepatic abscesses of ALA show much evidence of cellular infiltration and granuloma formation; one exception to this is the ameboma, a rarely found mass of granulation tissue in the colonic lumen. In small animal models intense inflammatory changes occur early in the development of lesions but whether this occurs in human amebiasis is not known. After recovery, most ALA patients are skin-test positive but appear to be specifically unresponsive to E. histolytica antigens earlier on.

Most studies have shown that normal human leukocytes of all sorts are harmless to and are killed by E. histolytica trophozoites. ALA patients' CD8+ cells became cytotoxic after incubation with soluble amebic antigen, phytohemagglutinin or GIL. More importantly, antigenic stimulation results in the production of cytokines (interferon y (IFN7) seems to be the most important) which activate macrophages to kill trophozoites. E. histolytica is powerfully chemotactic for neutrophils, which are rapidly killed by a contact-mediated, GIL-dependent process; lytic enzymes liberated from these dead cells may be responsible for much of the tissue destruction seen in amebiasis. IFN7 and tumor necrosis factor a (TNFa)-activated neutrophils can kill trophozoites and N-formylmethionine leucyl phenylalanine (fMLP)-activated eosinophils can do so even more effectively, although, again, normal cells are killed by contact with E. histolytica.

Role of complement

It seems inevitable that E. histolytica must reach the liver via the portal circulation and therefore obvious that it must survive the journey. Reed and her colleagues showed that while all E. dispar isolates (and old, laboratory-adapted E. histolytica isolates in axenic culture) were lysed, freshly isolated strains of E. histolytica in xenic culture were apparently largely resistant to complement activated by the alternative pathway. This fact alone could have been enough to explain the noninvasiveness of E. dispar. At least two resistance mechanisms have been postulated - cleavage of C3 by the parasite's own cysteine protease and one involving yet another function for GIL - the molecule shares sequence similarities and antigenic cross-

reactivity with the complement regulatory protein CD59 and inhibits E. histolytica lysis mediated by C5b-9. However, Hamelmann and coworkers have obtained quite different results - non-pathogenic isolates (i.e. E. dispar) were nearly unaffected; freshly isolated pathogenic strains (i.e. £. histolytica) were susceptible to lysis and became more so on long-term cultivation, with or without bacteria. Complement resistance could only be acquired by hamster liver passage or by growth in media containing increasing concentrations of normal human serum. The results of the two groups are incompatible and the differences need to be resolved before the role of complement in amebiasis can be assessed.

Animal models

There are currently no realistic small animal models of human amebiasis; in all cases trophozoites must be injected directly into cecum or liver. Mice, with the exception of SCID animals, are almost completely resistant and the large literature is concerned with the in vitro effects of murine macrophages. These cells (like their human counterparts) can be activated for killing by IFN7 and TNFa; the process appears to be nitric oxide mediated and TNFa increases the expression of nitric oxide synthase. The preferred model of ALA involves intrahepatic challenge of gerbils or hamsters (see below, Vaccines) where treatments which suppress cell-mediated immunity seem to enhance abscess formation.

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