Schistosome Egg Antigens Research Articles

C-C chemokine-induced eosinophil chemotaxis during allergic airway inflammation.

The production of eosinophil-specific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA) -mediated allergic responses to examine the role of specific C-C chemokines [macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemoattractant protein-1 (MCP-1)] in eosinophil recruitment. We have previously identified a role for MIP-1alpha in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIP-1alpha and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48-96 h after allergen (SEA) challenge. Utilizing whole-lung homogenates from allergen-challenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8-h lung homogenates and peak activity with samples from 24-h lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergen-challenged mice were preincubated in vitro with antibodies specific for MIP-1alpha, RANTES, or MCP-1, a significant reduction in eosinophil chemotaxis was observed with only MIP-1alpha and RANTES neutralization. Altogether, these studies indicate that RANTES and MIP-1alpha are major eosinophil chemotactic factors produced during allergic airway responses.

Granulomas in murine schistosomiasis mansoni have a somatostatin immunoregulatory circuit

The role of somatostatin (SRIF) in controlling the granulomatous inflammatory response to infection with the parasite Schistosoma mansoni was explored in mice. The murine granulomas contain SRIF-14. Immunoreactive SRIF and preproSRIF localize in the cytoplasmic granules of macrophages within the granulomas. The granulomas contain mRNA for preproSRIF and are not innervated. The production of SRIF by the inflammatory cells appears to be inducible. The granulomas contain mRNA for the SRIF receptors sst 2A and sst 2B, which are expressed mainly on CD4 + T lymphocytes and bind SRIF-14 with high affinity. Antigens from the schistosome eggs stimulate granuloma T lymphocytes to produce cytokines. Interferon-γ (IFN-γ) is one such cytokine made by CD4 + T lymphocytes. SRIF-14 suppresses antigen-induced IFN-γ production from granuloma cells, and this effect is blocked by anti-sst 2 antibody. SRIF was shown to inhibit IFN-γ-induced immunoglobulin G2a (IgG2a) synthesis in murine schistosomiasis. SRIF also blocks substance P (SP)-stimulated IFN-γ and IgG2a secretion. Schistosome-infected animals treated with the SRIF analog octreotide form smaller granulomas that secrete substantially less IFN-γ and IgG2a. Unpublished observations suggest that SRIF does not modulate schistosome egg antigen- or concanavalin A-stimulated granuloma lymphocyte proliferation in murine schistosomiasis. In conclusion, SRIF may be an important factor in the control of the granulomatous inflammatory response in murine schistosomiasis.

Antibody response patterns against Schistosoma mansoni in a recently exposed community in Senegal.

Acquired immune resistance is believed to be largely responsible for age-dependent infection and reinfection patterns in schistosomiasis. In a recently established but intense focus of Schistosoma mansoni in Senegal, the humoral immune response was studied in a random population sample of 289. Antibody levels of various isotypes to schistosome worm and egg antigens were determined by ELISA and related to egg counts (eggs per gram of feces [EPG]), age, and sex. Both IgG1 and IgG4 followed age-related patterns similar to egg counts and strongly correlated with EPG, even after allowing for age. Specific IgE levels increased slowly with age. The humoral immune response patterns in this recently infected population appeared to be largely similar to those in chronically infected communities. Thus far, the observations do not support the current hypothesis that age-related resistance to Schistosoma is determined by IgE-mediated protective immunity acquired during many years of exposure.

Immune response of mice infected with Schistosoma mansoni is modulated by antifibrotic treatment.

Mice infected with Schistosoma mansoni treated with beta-aminopropionitrile (BAPN), an antifibrotic agent, and the antischistosomal drug praziquantel (PZQ) were resistant to challenge for up to 5 weeks post-treatment. The combined treatment resulted in profound changes to the liver granuloma cell matrix and the composition and function of the cellular infiltrate. Although granulocytes always predominated in the infiltrate, the proportion of the cells which were macrophages was higher in mice treated with BAPN alone (39.2%) than in infected mice which were untreated (15.2%) or treated with PZQ alone (12.4%), and much higher than in mice given the combined treatment (1.8%). Two products associated with macrophage activation and cytotoxicity [tumour necrosis factor-alpha (TNF-alpha) and nitric oxide] were only detected in mice harbouring a patent infection and there was a strong positive correlation between the concentrations of each. The relatively low TNF-alpha concentrations in BAPN-treated mice seemed to be associated with the relatively small granulomas observed in these mice. BAPN treatment also led to changes in the proliferative response of the treated mice's macrophages to mitogen and soluble schistosome-egg antigen and in spleen cellularity; these changes are probably associated with the resistance to challenge infection observed in mice given BAPN with PZQ. It is clear that BAPN treatment changes the dynamics of the delayed-type hypersensitivity response within the granuloma and that this impacts on other immunological sites. How this relates to the maintenance of post-treatment resistance to a challenge infection has still to be elucidated.

Immunoregulatory potential of exogenous Schistosoma mansoni soluble egg antigen in a model of experimental schistosomiasis — I. Regulation of granuloma formation in vivo

This study was undertaken to assess the optimum conditions required to reduce the vigorous host granulomatous reaction around Schistosoma mansoni eggs. Soluble schistosomal egg antigen (SEA) at a concentration of 10 or 100 μg protein was administered i.p. or i.v. into unprimed C57BL/6 mice. SEA was injected either alone or in combination with cyclophosphamide (CY) 100 or 50 mg/kg via i.p. route. Seven or 14 days later viable eggs of S. mansoni were injected via the tail vein into treated groups and untreated normal controls. Mice were sacrificed 8, 16 and 24 days after the injection of eggs. The lungs were removed for histopathological study, measurement of granuloma diameter and phenotypic analysis of granuloma intralesional T-cell subsets. Compared to untreated controls, the lower concentration of SEA (10 μg), administered by the i.v. route 7 days before egg injection, induced a significant reduction in granuloma diameter 16 days after egg injection than that by the i.p. route or at a higher SEA concentration (100 μg). Compared to untreated controls, the higher dose of CY (100 mg/kg), given i.p. alone or in combination with 10 μg SEA by the i.v. or i.p. route, induced a significant reduction in granuloma diameter, while 50 mg/kg CY did not cause any reduction. The reduction in granuloma diameter by i.v. administration of low SEA concentration alone or in combination with CY IP, was associated with a decrease in the granuloma intralesional L3T4 +/Lyt2 + ratio. The decrease in the ratio was due to an increase in Lyt2 + cells. The results suggest that the use of low dose SEA by the i.v. route alone or combined with an immunosuppressive drug ameliorates pathological changes concurrent with S. mansoni infection.

Interferon-γ production by peripheral blood mononuclear cells from residents of an area endemic for Schistosoma mansoni

During human schistosomiasis host responses to antigens of various parasite life-cycle stages may contribute to whether the severe, hepatosplenic state develops or the patient remains relatively asymptomatic throughout infection, and may play a role in resistance. This study evaluated production of interferon γ (IFN-γ) in vitro by schistosome antigen-stimulated peripheral blood mononuclear cells (PBMCs) from asymptomatic patients, and by PBMCs from apparently uninfected, untreated persons living in areas endemic for Schistosoma mansoni (‘endemic normals’). IFN-γ production parallels PBMC proliferation in that schistosomal egg antigens stimulate patent patients' cells poorly, but strongly stimulate PBMCs from ‘endemic normals’. This is proportionally true for antigens from adult worms and cercariae. Although asymptomatic patent patients' cells produced little or no IFN-γ in response to the 3 schistosomal antigenic extracts, their PBMCs, and PBMCs from ‘endemic normals’, produced expected amounts of IFN-γ when exposed to phytohaemagglutinin. This implies that persons with patent infections have schistosome antigen-specific defects in their ability to respond to IFN-γ production that are not exhibited by putatively resistant ‘endemic normals’.

Possible role of an adrenal parasite reservoir in the pathogenesis of chronic Trypanosoma cruzi myocarditis

Mice of four inbred strains (A/J, C/57BL/6J, CBA/J, BALB/c) were compared as definitive hosts of Schistosoma mansoni. All four strains allowed the maturation of adult worms, but the percentage of recovery of mature worms varied widely according to strain (A/J, 36%, C/57BL/6J, 42%; CBA/J, 58%; BALB/c, 78%). The cell-mediated immune response of these mice to a soluble schistosomal egg antigen was determined by in vitro lymphocyte blastogenesis during the course of the infection. All strains exhibited this response by 112–2 weeks after oviposition, but the reaction was of low degree and transient in BALB/cmice. Peripheral blood eosinophil counts were determined during infection in A/J and CBA/J mice; three periods of eosinophilia (of varying intensities) were noted corresponding in time to initial cercarial penetration, development of adult worms, and production of eggs.

Substance P and somatostatin can modulate the amount of IgG2a secreted in response to schistosome egg antigens in murine schistosomiasis mansoni.

Substance P (SP) and somatostatin 1-14 (SOM) have immunoregulatory properties. Cells within the granulomas of murine schistosomiasis mansoni make both. SP enhances, whereas SOM inhibits soluble egg Ag (SEA)-induced, IFN-gamma production. IFN-gamma is important during IgG2a isotype switching. Thus, we investigated whether SP or SOM could affect IgG2a production in murine schistosomiasis. Our results show that SEA and rIFN-gamma stimulate splenic IgG2a secretion in murine schistosomiasis. Moreover, SP at > or = to 10(-10) M substantially increased both polyclonal as well as SEA-specific, IgG2a secretion from spleen cells challenged with SEA. However, cells exposed to SOM at > or = 10(-10)M showed strong inhibition. Also, both SP and SOM modulated the frequency of IgG2a-producing cells. Splenic IgG2a production in response to SEA, SP, and SOM required the presence of Thy 1.2+ cells, whereas, rIFN-gamma- induced IgG2a synthesis did not. Also, experiments using irradiation lymphocytes showed that SP, SOM, or rIFN-gamma modulation of IgG2a release was not dependent on cell proliferation. The highly specific SP receptor antagonist, CP-96,345, completely inhibited the effect of SP but not SOM on IgG2a release. This suggests that SP acted through an authentic NK-1 receptor and that SOM required a different receptor interaction. Granuloma cells secreted IgG2a constitutively. Yet, neither SEA, SP, SOM, rIFN-gamma, nor blocking anti-IFN-gamma mAb could modulate this constitutive IgG2a release during short term culture conditions. Moreover, the IgG2a secretion also continued in the absence of Thy 1.2+ lymphocytes. However, mice treated with CP-96,345 or octreotide (SOM agonist) in vivo produced granulomas that made little or no IgG2a. Spleen cell experiments showed that SEA, SP, SOM, and rIFN-gamma could only affect SEA-induced, IgG2a production during early stages of Ag stimulation. Thus, unlike the spleen, it is probable that the granulomas contain mostly activated B cells that have completed switch recombination.

The effect of zinc deficiency on granuloma formation, liver fibrosis, and antibody responses in experimental schistosomiasis.

The influence of various dietary zinc levels on the fibrotic aspects of granuloma formation and on the humoral response to schistosome egg antigens was investigated in C57Bl/6 mice by feeding groups of animals zinc-deficient diets. At six weeks of age, control and zinc-deficient mice were exposed individually to 50-60 cercariae of the Brazilian LE strain of Schistosoma mansoni. The animals were maintained on their respective diets for eight weeks postinfection, then all animals were killed and analyzed for body weight, spleen weight, collagen content of the liver, in vivo granulomatous histopathology, and antibody responses to soluble egg antigens. Zinc-deficient mice experienced stunted growth and reduced weight gain. Granulomatous hypersensitivity to schistosome eggs in the liver was measured in liver histopathologic sections using morphometric analysis and was found to be depressed in infected mice fed the moderately and the severely zinc-deficient diets. The low level of zinc in the diet also affected the humoral immune response of the host to schistosome egg antigens.

The cell‐mediated response to schistosomal antigens at the clonal level: development and characterization of a panel of egg antigen‐specific murine T cell clones

The cellular basis of the immune response underlying the granulomatous hypersensitivity in experimental murine schistosomiasis caused by Schistosoma mansoni was investigated by examining a panel of 16 egg antigen-specific T cell clones. The clones were derived from a sensitized T cell line by limiting dilution, and were selected on the basis of their strong responses against schistosomal egg antigens. By cytofluorographic analysis, it was determined that all clones were T helper cells and expressed the CD3+CD4+CD8- phenotype. Lymphokine analysis revealed that some clones secreted either interleukin (IL)-2 or IL-4, but a surprisingly large number were double producers. Southern blot analysis verified the clonality of these T cells and indicated that the clones examined included at least five independent clones by the criterion of T cell receptor beta gene rearrangements. Despite their diversity, the clones responded strongly, and virtually exclusively, to egg antigen components with isoelectric points in the limited range of 4.7 to 5.2. The relevant antigenic egg molecules were shown to require processing by accessory cells for presentation to, and stimulation of, the T cell clones.

Murine Intestinal Humoral Responses in Chronic Schistosoma mansoni Infections

Specific and non-specific production of immunoglobulins (Ig) by the intestinal mucosa was examined in mice infected with the human blood fluke Schistosoma mansoni. Ileal and colonic mucosal tissue samples were cultured for 2 days, the medium replaced and the culture continued for a further 2 days. Ig concentrations and specific antibodies to soluble schistosome egg antigens in culture supernatants were estimated by isotype-specific ELISA. Cultured mucosae from control mice produced little IgG, but significant amounts of IgA and IgM on prolonged culture. IgG concentrations were increased in infected animals, mainly in the initial culture period, indicative of systemic, rather than local origins. By contrast, significantly increased local production of IgA and IgM occurred after the start of egg deposition in the intestinal mucosae. Although specific anti-egg antibodies of the IgG and IgM class were detected, none of the local IgA response was specific for schistosome eggs. We conclude that specific intestinal immune responses to schistosome eggs reflect systemic responses, whereas locally increased IgA production is largely non-specific. This pattern of response is likely to be related to the prior systemic exposure to schistosome eggs, which results in polyclonal local B-cell activation, but fails to trigger an antigen-specific IgA mucosal response.

Immune responses during human Schistosoma mansoni. XVII. Recognition by monoclonal anti-idiotypic antibodies of several idiotopes on a monoclonal anti-soluble schistosomal egg antigen antibody and anti-soluble schistosomal egg antigen antibodies from patients with different clinical forms of infection.

A monoclonal human anti-soluble schistosomal egg Ag(SEA) antibody (E5) that stimulates anti-Id T cells and is idiotypically represented in pools of immunoaffinity-purified human anti-SEA antibodies from chronic, generally asymptomatic, intestinal (INT) patients (AM1 and AM5) was used to raise several monoclonal anti-Id: 1C2, 1C6, 4A8, 4F9, and 2A7. Cross-inhibition between these anti-Id identified distinct idiotopes on E5. Anti-SEA preparations from schistosomiasis patients (AM1, AM5, and others) were tested for their inhibition of the E5/monoclonal anti-Id reactions, in competitive ELISA. In either the E5/4A8 or E5/1C6 ELISA system, anti-SEA from INT (AM1 or AM5) or hepatointestinal (HI) (AM7) patients were able to inhibit these reactions. However, anti-SEA antibodies from acute (AM9) or hepatosplenic (HS) (AM3 or AM8) patients did not express Id that were inhibitory in these systems. These results suggest that a relatively high proportion of INT and HI anti-SEA antibodies express a dominant cross-reactive idiotope (CRI) recognized by 1C6/4A8. This CRI is also easily detected in plasmas from individual INT patients. Anti-Id 1C2 reacted strongly with an Id in AM1, AM5, or AM7, but one which also occurred, to a lesser extent, in AM3, AM8, and AM9. Monoclonal anti-Id 4F9 and 2A7 reacted weakly with idiotopes expressed by antibodies from all patients, regardless of the clinical form of their infection. These observations indicate that anti-SEA antibodies from INT and HI, but not acute or HS patients express dominant, CRI that are identified by 1C6, 4A8, or 1C2 and are also expressed on the INT-derived anti-SEA mAb E5.

The ultrastructure of the Schistosoma mansoni egg.

Helminth eggs have resisted analysis by electron microscopy because fixatives, dehydrating agents, and embedding media penetrate these eggs poorly. Slam-freezing at liquid nitrogen temperature followed by freeze-substitution and Spurr's medium embedment provides preservation of the internal structure of the Schistosoma mansoni egg shell, developing miracidium, and perimiracidial structures. The egg shell consists of the three previously described layers (outer microspinous, middle intermediately dense, and inner dense layers) with cribriform pores. A newly described layer (Reynolds' layer) develops subjacent the egg shell and is comprised of densely-packed branching filaments. A single layer of squamous cells (von Lichtenberg's envelope) closely adheres to Reynolds' layer. Between von Lichtenberg's envelope and the embryo is a space (Lehman's lacuna); this space is initially filled with electron-lucent fluid, but subsequently masses of granulofloccular material (Cheever bodies) develop; Cheever bodies are partially membrane bound. Epidermal plates differentiate from superficial cells of the embryonal cell mass, while epidermal ridges differentiate from cells just below the surface of the embryonal cell mass. The cytoplasmic layer (von Lichtenberg's envelope) interposed between the host extracellular fluid and the developing miracidia effect a barrier against a simple passive diffusion; this infers that complex macromolecules, such as schistosomal egg antigen, undergo active, and perhaps selective, transport in or out of the egg.

Anti-idiotypic T lymphocyte responsiveness in murine Schistosomiasis mansoni

Pooled sera from CBA/J mice infected for ≥ 16 weeks with the blood fluke Schistosoma mansoni were immunoaffinity purified using soluble schistosome egg antigens (SEA) coupled to Sepharose 4B. The bound and then eluted fraction was shown to contain only immunoglobulins and to have anti-SEA activity. These anti-SEA antibodies stimulated proliferation of lymph node cells from mice infected with S. mansoni for 8, 12, or ≥ 16 weeks but not from uninfected mice. The cells stimulated by anti-SEA antibodies were nylon wool adherent, Thy-1.2 +, L3T4 +, Lyt-2 − lymphocytes. Immunoglobulins without anti-SEA activity isolated from the sera of syngeneic uninfected mice were not stimulatory for cells from normal or infected animals. Thus the responding T cells appear to be stimulated by the idiotypes expressed on the syngenic anti-SEA antibodies. These data present evidence for anti-idiotypic cellular reactions in murine schistosomiasis that could play important immunoregulatory roles in this disease.

Inhibition of immediate and Arthus responses to schistosome egg antigens by T cells from Schistosoma japonicum-infected mice.

Schistosoma japonicum-infected mice develop hepatic granulomas, immediate hypersensitivity (IH), and delayed hypersensitivity (DH) to soluble egg antigens (SEA) released by parasite eggs trapped in liver sinusoids. All of these responses spontaneously regress after 7 to 9 weeks of infection. This study aimed to develop an in vivo system for the further dissection of cellular and humoral immune responses to SEA. C57BL/6 mice immunized subcutaneously with SEA in complete Freund adjuvant developed IH, an Arthus reaction, and DH to this antigen 5 to 9 days later. IH and the Arthus reaction, but not DH, were markedly inhibited if, 1 day before injection of SEA in complete Freund adjuvant, the mice were injected intravenously with purified T cells from the spleens of mice infected for at least 9 weeks. This in vivo model system can be used to study various aspects of cellular and humoral immune responses to SEA and their modulation. These results raise questions about the role of antibodies in the pathogenesis of granulomatous inflammation and about the mechanisms of its cellular regulation in infections with S. japonicum.

Immune responses during human Schistosomiasis mansoni. Evidence for antiidiotypic T lymphocyte responsiveness.

We present a method for the examination of antiidiotypic cell-mediated reactivity during chronic human infections. Pooled and individual sera from patients with schistosomiasis mansoni were purified on immunoaffinity columns of schistosomal egg antigens (SEA). The eluates contained anti-SEA antibodies, but not SEA. These antibody preparations, and their F(ab)2 fragments, stimulated dose-dependent proliferation of peripheral blood mononuclear cells (PBMN) and T lymphocytes from some, but not all active or former schistosomiasis mansoni patients, and could do so autologously. Stimulation required presentation by plastic-adherent cells. The eluates did not stimulate PBMN from persons who had never had schistosomiasis. Affinity-purified anti-SEA antibodies from former patients (cured for greater than 10 yr) did not stimulate PBMN from patients with active infections. Reabsorption on SEA columns removed stimulatory activity from the eluates. We propose that multiclonal, SEA-related idiotypes expressed by some anti-SEA antibodies stimulate proliferation of T lymphocytes that express antiidiotypic specificities.

Immune Responses During Human Schistosomiasis

Thirty-four hospitalized patients and 12 ambulatory patients, all with hepatosplenic schistosomiasis mansoni were evaluated in regard to their peripheral blood mononuclear (PBMN) cell responses to schistosomal antigenic preparations and compared with groups of 40 patients with the hepatointestinal form and 39 patients with the more common, chronic intestinal form of schistosomiasis mansoni. PBMN cell blastogenic responses were measured upon exposure to schistosomal egg antigens (SEA), adult worm antigens (SWAP) and a cercarial antigenic preparation (CERC). All groups had some individuals who did not respond to some or all of these preparations. In the hospitalized hepatosplenic group greater than 50% did not respond to SEA. Analysis of the responses in each group revealed that all responders could be subdivided into moderate and high responders. High responders to SEA had experimental minus control values of greater than 8,000 counts per minute (CPM). For SWAP and CERC, this arbitrary cut-off value was greater than 25,000 CPM and greater than 11,000 CPM, respectively. The percent of high SEA responders in the groups differed considerably. This was 23% in the chronic intestinal group, 40% in the chronic hepatointestinal group, 67% for ambulatory hepatosplenic patients and 20% for hospitalized hepatosplenic patients. Previous studies had demonstrated that 94% of patients with early (2-3 month) acute schistosomiasis mansoni were high responders to SEA and none were nonresponders. Furthermore, at the other end of the spectrum, 100% of former schistosomiasis mansoni patients (treated and cured 7-35 years previously) were high responders to SEA. None were nonresponders to any of the antigen preparations. It is proposed that during acute infection all patients express vigorous responses to SEA. Upon continued infection most patients (75%) modulate this florid response. However, continued high responders comprise 40% of the chronic hepatointestinal cases and almost 70% of the ambulatory hepatosplenic patients. These latter 2 groups may likely represent early forms of the severe clinical disease found in the hospitalized hepatosplenic patient population. Fifty percent of the hospitalized group appear anergic and no longer respond to SEA, while only 20% are high responders. Long after chemotherapy it appears that the anti-SEA regulatory mechanisms of former chronic patients have subsided, leaving strong anti-SEA responsiveness.

Studies of tolerance in schistosomiasis

We have studied the induction of immune tolerance by exogenous exposure to schistosomal egg antigen (SEA). We compared routes of administration, exposure to different forms of SEA (eggs, normal SEA, reultracentrifuged SEA), and treatment schedules. Tolerance was evaluated in comparison to SEA sensitization, after challenge with SEA or eggs. Anti-SEA responses were measured by ELISA assays, and cell-mediated responsiveness by 24-hr skin tests and pulmonary granuloma formation 8 and 16 days after intravenous egg injection. Oral administration of either SEA in PBS or NaHCO 3, or eggs in PBS did not induce tolerance or sensitization. Reultracentrifuged SEA was similar to SEA in inducing cell-mediated immune response. Intrathymic exposure to SEA either had no effect or sensitized the animal for subsequent exposure to SEA. Two intraperitoneal injections of 0.5 to 1.0 mg of SEA lead to reduced cell-mediated responses, but resulted in high levels of anti-SEA antibody, suggesting a state of split tolerance or immune deviation. Our studies suggest that with complex, poorly denned antigens such as SEA, many of the classic methods of eliciting tolerance fail. The biologic significance of the form of tolerance inducible by high doses of SEA remains to be denned.

Network interactions in Schistosoma japonicum infection. Identification and characterization of a serologically distinct immunoregulatory auto-antiidiotypic antibody population.

This study examined the role of naturally occurring anti-idiotypic antibody (anti-id), specific for epitopes on antibodies to schistosome egg antigens (SEA), in serosuppression during Schistosoma japonicum infection. Three anti-id preparations were obtained from pools of infected serum at 12, 16, and 30 wk of infection. Anti-id (12 wk) bound 36% of labeled anti-SEA antibodies, had an idiotype binding capacity (IBC) of 5 micrograms/ml, and did not suppress SEA-induced proliferation. Anti-id (16 wk) bound 17% of labeled anti-SEA antibodies, had 29 micrograms IBC/ml, and reduced 3H incorporation from 21.4 +/- 0.5 (10 micrograms/ml normal Ig) to 9.1 +/- 1.5 X 10(4) cpm (P less than 0.01). Anti-id (30 wk) bound 66% of labeled anti-SEA antibody, had 84 micrograms IBC/ml, and suppressed 3H incorporation by 88% (4.8 +/- 0.3 X 10(4) cpm, P less than 0.001). Analysis of the serologic reactivity of these three populations of anti-idiotypic antibodies revealed that anti-id (12 wk) described an idiotypic population of anti-SEA molecules containing a minor cross-reactive idiotype (SJ-CRIm). In contrast, anti-id (30 wk) described a serologically distinct, idiotypic population containing a major cross-reactive idiotype of anti-SEA molecules (SJ-CRIM). A monoclonal anti-id, which reacted with greater than 50% of the anti-SEA molecules describing SJ-CRIM, was profoundly suppressive in vitro and reduced granulomatous inflammation around parasite eggs in vivo from 113 X 10(3) micron2 to 23 X 10(3) micron2 (80% suppression, P less than 0.001). These observations suggest that immune network interactions modulate inflammation in chronic murine S. japonicum infection.

Characterization of mononuclear phagocytes in schistosomal egg granulomas of athymic mice.

Macrophages from schistosomal egg granulomas of athymic mice (nu/nu GM) and their euthymic littermates (nu/+ GM) were analyzed phenotypically for the expression of antigens encoded by the I-A subregion of the major histocompatibility complex and for their ability to perform as antigen-presenting cells. Only 11 to 15% of nu/nu GM expressed I-A antigens as compared to 61.5 to 75% of nu/+ GM. Although both populations of cells appeared to be equally effective as antigen-presenting cells appropriately sensitized lymphocytes in the presence of specific antigens--soluble schistosomal egg antigen (SEA) and human gamma-globulin (HGG)--only nu/nu GM, but not nu/+ GM, were found to stimulate I-A-restricted proliferation of schistosome-sensitized T cell populations in the absence of SEA added in vitro. Furthermore, nu/nu GM but not nu/+ GM were shown to exhibit significant proliferative capacity in vitro, but this phenomenon could not account for the observed difference in SEA-independent T cell stimulation. Finally, culture supernatants from nu/nu GM displayed significant thymocyte-stimulating activity, consistent with interleukin 1, which was not observed in nu/+ GM. These findings point to significant differences between nu/nu GM and nu/+ GM, which may be part of an adaptive mechanism of granulomatous reactivity in the absence of a competent T cell system.