Production of immunomodulatory neuropeptides by Schistosoma mansoni.

Over the past few years it has become clear that the various immunologic characteristics of helminth infection, such as eosinophilia, elew~ted immunoglobulin E (rgE) levels and, in some cases, mastocytosis, are due to the preferential stimulation by helminths of the TH2 subset of CD4+ helper T cells d'2. TH2 cells secrete interleukins (IL) 3, 4, 5, 9 and 10, cytokines that have been shown to induce many of the cellular and humoral events described above~-3. An additional consequence of such a response is the suppression, or downregulation, of THI-cell functions, as reflected by reduced secretion of gammainterferon (IFN-y) and IL-2, two of the major cytokine products of THI cells 3, IL-10, which indirectly inhibits THI-cell activation, is implicated in this immune regulation f'4, but is suspected by many not to be the only controlling influence operating during infection. The dominance of antigen-specific TH2 over THI cell responses has been documented for mice infected with Schistosoma mansoni s. Coincidentally, infected mice exhibit a decreased ability to mount THI-cell responses against non-schistosome antigens, suggesting that infection results in a generalized inhibition of THI-cell function 6. The factors or events that lead to the induction of overt TH2-cell responses by helminths have not yet been elucidated. However, a paper published earlier this year by Odile Duvaux-Miret et al. 7, showing that S. mansani produces immunomodulatory neuropeptides, has provided a possible explanation as to how schistosome infection precipitates a helper T-cell subset imbalance. Duvaux-Miret and co-workers have reported previously that all schistosome life cycle stages contain the pro-opiomelanocortin (POMC)-derived peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone or ~-melanotropin (ac-MSH) and J3-endorphin 8, Their recent paper describes the release of two of these peptides, ACTH and I~-endorphin, by adult worms 7. ACTH is converted to o~-MSH by a neutral endopeptidase (NEP) (enkephalinase, CALLA or CDI0) on the surfaces of vertebrate polymorphonuclear leukocytes (PMN) and by a similar enzyme expressed on the surface of snail (intermediate host) immunocytes 9. AlphaMSH was shown to inhibit activation of mammalian PMN and snail immunocytes, in vitro; the former suggests that the adult worm is capable of blocking attack by phagocytic cells that it may encounter in the bloodstream. All three peptides were shown to be elevated in the hemolymph of infected snails, suggesting that they may modulate immunocyte activity during infection and thereby promote parasite survival. In light of their findings, the authors propose that the release of neuropeptides by schistosomes constitutes an adaptation of the parasite to circumvent host attack. Of particular interest to us is that it may also explain the modulation of THI-cell responses seen in infected animals, since ACTH is able to suppress IFN-y production by T cells j°. Furthermore, release of ACTH might be a contributory factor in the preferential induction of TH2-cell responses during schistosomiasis since it would be expected to stimulate the adrenal gland to produce corticosterone. Corticosterone upregulates IL-4 synthesis by TH2 cells and suppresses the synthesis of IFN-y and IL-2 (Refs 11-13). Since IL-4 is a TH2-Cell autocrine growth factor, whereas IFN-y is important in promoting T H I-cell responses ~4'15, an environment containing corticosterone would favor the induction and expansion of TH2-cell responses. Switching from THIto TH2-cell responses occurs when corticosterone is produced in response to inflammation during autoimmune disease (for review see Ref. 16). By secreting ACTH, helminth parasites may be able to induce a similar switch. The sequence of events postulated above assumes that immature schistosomes secrete negligible or pharmacologically irrelevant levels of ACTH, since a full TH2-cell response and IFN-~, downregulation in schistosome-infected mice does not occur until week 6, the time of worm maturation and the beginning of egg production s , and does not occur in mice exposed to attenuated 17 or single-sex infections (which are sub-optimal) 5, neither of which produce eggs. However, all life cycle stages have been shown to contain ACTH 8. Consequently, differences in observed immune responses occurring at different times following infection may reflect different degrees of release of ACTH by successive stages. A particularly attractive explanation to account for these discrepancies is that eggs represent a potent and prevalent (each female S. mansoni produces about 300 eggs per day) source of released ACTH, which would be consistent with the potent TH2-cell-inducing capacity of this life cycle stage tS, Each of these possibilities is readily testable. If schistosomes release ACTH primarily to divert immune attack, it is interesting to speculate that the types of immune responses inhibited by this neuropeptide, namely those mediated by THI cells, are most dangerous to the parasite ~. In such a case, development of overt TH2-cell responses during infection could be viewed as an inevitable side effect of THI-cell-suppression. Clearly, a role for parasite-derived ACTH in THI-cell down-regulation/TH2cell-induction would be strengthened by a demonstration that other helminths produce this peptide. The potential for the neuroendocrine system to influence immune and inflammatory responses has been firmly established. The production of neuropeptides by S. mansoni is an elegant addition to the growing list of examples of mimicry of host mediators by pathogens.