Modulation of B-Cell Proliferative Response by a Soluble Extract ofNippostrongylus brasiliensis

Abstract

We and others have previously shown that nematodes or nematode products can stimulate or inhibit the generation of lymphocyte responses, suggesting that nematodes exert diverse effects on the developing immune responses of their host. In this study we examined the immunomodulatory effect of a soluble extract of Nippostrongylus brasiliensis (adult worm homogenate [AWH]) on B-cell responsiveness. We found that the extract inhibited the proliferation of B cells to lipopolysaccharide (LPS) stimulation in a dose-dependent manner. This effect was specific to B cells, since the extract did not inhibit T-cell proliferation to concanavalin A or anti-CD3 stimulation. The data presented here confirm that the extract is not toxic to B cells. We present evidence that the active factor is proteinaceous in nature and that the inhibitory activity is restricted to the adult stage of Nb. The extract does not appear to interfere with early activation events since it can be added up to 48 h after LPS stimulation, and it inhibited responses to phorbol myristate acetate and ionomycin. Furthermore, the proliferation of B cells to other activators was also inhibited by AWH. This observation shows that the inhibitory activity of AWH is not restricted to LPS-mediated B-cell proliferation. We present evidence that, in the absence of accessory cells, the inhibitory effect of the extract was ablated. This observation shows that the activity of AWH is not mediated directly on B cells but is mediated via the production of negative signals from accessory cells (macrophages), which affect a downstream pathway required by all B-cell activators tested. These effects on B-cell and accessory cell function are likely to have a significant effect on the outcome of infections experienced concurrently.To ensure survival and continuation of their life cycle, nematodes have evolved a unique relationship with their hosts. Part of this accommodation is the ability to modulate host immune responsiveness (25). Modulation of lymphocyte function has been widely reported among nematodes (2,3,19,21,22,28) and other parasites (6,15,27,36). For example, we have previously shown a dramatic potentiation of antibody responses to third party antigens by treatment with a body fluid extract of Ascaris suum (19). This observation is significant in that it suggests that the modulatory effect of nematodes on immune responses is far-reaching and may have profound effects on developing immune responses to unrelated antigenic challenge. We have also reported the presence of a B cell mitogen in the body fluid of A. suum, which stimulated G 0 B cells to enter the cell cycle (20). This activity of the Ascaris factor was dependent on viable accessory cells.The effect of helminth products on the developing immune response is likely to be complex. For example, in contrast to the immunostimulatory activity of the body fluid of Ascaris reported above, Ferreira and coworkers (13) and Soares and coworkers (39, 40) have reported immunomodulatory factors in secretions of A. suum, which a...

Modulation of a Heterologous Immune Response by the Products ofAscaris suum

“…The mechanisms responsible for these phenomena have not been elucidated as yet. The ability to modulate immune responsiveness is not dependent on the presence of a live infection, as antigens derived from the parasites have similar properties (5,(13)(14)(15)25).…”

“…However, the ability of ABF to modulate the DTH response was observed only if exposure occurred at the time of priming, not if it occurred at the time of challenge with heterologous antigen. This suggests that the active parasite factors act on early activation events in the developing immune response, unlike the activities of other parasite proteins in modulating ongoing responses (15,25).…”

“…Moreover, inhibition of eosinophil recruitment in vivo in response to eotaxin by hookworm excretory and secretory products is mediated by cleavage of eotaxin by a parasitederived metalloprotease, while N. brasiliensis secretes a platelet-activating factor acetylhydrolase that cleaves platelet-activating factor to an inactive form, thus preventing eosinophil and neutrophil recruitment and activation (7,12). Furthermore, N. brasiliensis products have also been shown to inhibit lipopolysaccharide-stimulated B-cell proliferation, possibly by modulation of accessory cell function (14,15). In addition, serine protease inhibitor purified from Trichuris suis potently inhibits chymotrypsin, pancreatic elastase, neutrophil elastase, and mast cell chymase (50).…”

“…As both infection and immunization result in induction of Th2 responses, it has been suggested that parasite products act to divert Th1 responses to a Th2 phenotype. For instance, products of Nippostrongylus brasiliensis induce Th2 responses to bystander antigens in uninfected mice (14,15,25). A major product of Ascaris suum, ABA-1, is a 14-kDa fatty acid-binding protein and is the target of major histocompatibility complex (MHC)-restricted IgE responses in both infected humans and animals (29).…”

Helicobacter pylori Infection in an Urban African Population

“…It has been shown in rhesus macaques that gastric pathology induced by H. pylori was related to proliferation and activation of CD4 cells through a TH1 pathway (20). Ascaris infection in humans can lead to a polarized TH2 cytokine response (5), and an extract of another nematode, Nippostrongylus brasiliensis, has been shown to act as an immunomodulator of murine B-cell responsiveness (8).…”