Biomedical subjects
Publications and source records attributed to J Pestel.
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Rat peritoneal macrophages in serum-free cultures were triggered to release lysosomal enzymes or plasminogen activator and to incorporate glucosamine upon exposure to rat IgG that was nonspecifically aggregated after heating or by dimethylsuberimidate cross-linking or was specifically complexed by the corresponding antigen using preformed BSA-anti-BSA immune complexes. A lag period of 6 hr was observed before the increase in enzyme release or in glucosamine uptake. Although chemically prepared dimers of IgG were found sufficient to trigger the macrophages, both enzyme release and glucosamine incorporation increased with the size of the IgG aggregates. Similarly, immune complexes in IgG antibody excess (Ag/Ab ratio 1:32) were more efficient than complexes prepared at equivalence or in antigen excess, which suggests that the size of the aggregates is an important parameter of macrophage triggering. The participation of the macrophage Fc receptor for IgG in IgG-dependent macrophage triggering is suggested by similar findings using a first exposure of the cells to rat IgG then the cross-linking the cell-bound immunoglobulin by purified anti-rat IgG or the F(ab')2 fragment of it. Macrophage function in inflammatory reaction might thus be modulated by the size of IgG immune complexes.
Antibody-dependent cell-mediated cytotoxicity in reinfection immunity to schistosomes in the rat involves either IgG2a anaphylactic antibody and eosinophils or IgE antibody and macrophages. The first system requires two signals, one by the antibody through the eosinophil Fc receptor, another by mast cells through the release of mediators among which is ECF-A. IgE antibody complexed with schistosome antigen binds to an IgE-specific receptor on the macrophage and triggers the cell to release enzymes and superoxide. Immunity in rat schistosomiasis is antibody-dependent, abolished in anti-mu treated neonate rats or by passive serum transfer after selective depletion of either IgG2a or IgE. The two anaphylactic antibody-dependent cell cytotoxicity systems are in a permanent balance in immune rats, eosinophils being blocked by IgG2a immune complexes when this cell is inefficient. Anaphylactic antibodies thus play a key role in triggering and modulating effector cell function.
In earlier studies we have found that activation of the classical complement pathway (CCP) by the immature schistosomes involves the presence of IgG. By investigating the first step of this activation we have demonstrated in the present work that binding of C1q to schistosomula can occur by two different routes: 1) directly, by specific C1q receptors, and 2) indirectly through the IgG previously attached to Fc receptors present on the parasite surface. Only this second mechanism appears to be involved in CCP activation by schistosomula. Moreover, certain low m.w. schistosome antigens (less than 20,000), which activate CCP, also directly fixed C1q. In this case, IgG are not required for C activation. The presence of receptors for host protein, essentially in 2- to 3-hr-old schistosomula, i.e., the life stage of Schistosoma mansoni that are first in contact with the host, could be the first mechanism by which the schistosomes evade the immune attack.
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We studied conditions of human IgE formation in severe combined immunodeficiency (SCID) mice engrafted with peripheral blood mononuclear cells (PBMCs) from allergic patients sensitive to Dermatophagoides pteronyssinus (D.pt.). With 10 x 10(6) PBMCs injected intraperitoneally, the hu-SCID mice developed an IgE response, but only if experimental animals were immunized with the related allergen. Two routes of immunization were tested: intraperitoneal and inhalation. In these experimental conditions (allergen given at day 14 after reconstitution), a significant rise in total serum IgE but also in specific anti-D.pt. IgE was observed. No human IgE could be detected within 3-4 weeks after immunization with an unrelated allergen. Similarly, when mice were engrafted with PBMCs from nonallergic donors, even after D.pt. administration, no significant increase of serum IgE was detectable, while an IgG response was regularly found. Thus SCID mice could represent a useful model to analyze IgE production as well as the conditions of immunization required to obtain an optimal response.
We have previously established a model to study the in vivo human IgE response using humanized SCID mice. Allergic SCID mice were obtained following intraperitoneal injection with mononuclear cells from Dermatophagoides pteronyssinus (Dpt)-sensitive patients, and sensitization by Dpt allergen intraperitoneal injection (immunization) or Dpt aerosol (inhalation). Human serum IgE was measured in allergic SCID mice after administration of human recombinant IFN-gamma or the lipopeptide LP 52-71 (derived from peptide p52-71 from Der p 1, Dpt major allergen, coupled to a lipophilic moiety), during the immunization or the inhalation phase. IFN-gamma inhibited human IgE production when given at the time of immunization, but not during inhalation. This effect was long-lasting as Dpt aerosol, given one month after immunization and IFN-gamma administration, failed to increase IgE levels. Unlike Dpt or p52-71, LP 52-71 failed to induce human IgE production at day 14 and 21 after its injection, but did inhibit the development of the IgE response after a secondary Dpt-challenge. Moreover, LP 52-71 administration 14 days after Dpt inhalation decreased IgE levels, in contrast to peptide 52-71, which increased IgE levels. Thus, taken together these results indicate that the development of the human IgE response in allergic SCID mice can be modulated by modified allergen and a Th1 cytokine.
When unstimulated rat peritoneal macrophages are exposed in vitro to IC formed with BSA and specific rat anti-BSA IgG antibodies, an exocytosis of the lysosomal beta-G occurs. The maximal release of beta-G into the serum-free medium is induced, without cell lysis, by IC after a 6-h contact with the adherent cell population. This phenomenon is dose-dependent, and the percentage of beta-G in the medium is higher with IC in Ab excess than with other types of IC. In this homologous model (rat macrophages and rat antibodies) the Ag/Ab ratio of IC seems to represent an important factor of macrophage activation.
The study of antibody-dependent cellular cytoxicity mechanisms in human and experimental schistosomiasis has revealed the particular role of immune complexes in triggering phagocytic cell activation. IgE complexes or aggregates were demonstrated to bind to specific receptors on rat macrophages as well as on human or baboon macrophages, leading to the killing of the parasite target. In the eosinophil-dependent cytotoxicity mechanisms, IgE complexes have been shown to exert a regulatory effect on eosinophil activation in vitro and in vivo and on the ability of this cell population to kill parasites. The various observations reported in this review suggest that the characteristics of the Fc receptors, the composition and antigen-antibody ratio of immune complexes might be essential factors in the regulation of the immune response against parasites.