Angiosarcoma of the eyelid: yellow plaques causing ptosis.
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Aged↗
Biomedical subjects
M J Stadecker
Publications and source records attributed to M J Stadecker.
In situ analysis of B7-2 costimulatory, major histocompatibility complex class II, and adhesion molecule expression in schistosomal egg granulomas.
Immunopathological damage in schistosomiasis consist of egg granuloma formation, which is a hypersensitivity reaction mediated by antigen-specific CD4+ T helper (Th) lymphocytes. Th cells are dependent on accessory cell-bound co-stimulatory signals for activation. The B7 molecules provide critical costimulation, as in their absence T cells are rendered unresponsive. We investigated the kinetics of B7-2 molecule expression in schistosomal egg granulomas by immunocytochemical analysis in situ. We also monitored major histocompatibility complex (MHC) class II, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression, as well as the presence of macrophages, T cells, and B cells. B7-2 expression was elevated in cells of the large granulomas of the acute (6-1/2 week) infection, and sharply declined thereafter. MHC class II expression was similarly elevated in the acute granulomas, but in contrast to B7-2, remained relatively constant throughout 12 1/2 weeks of infection. Moreover, ICAM-1 and VCAM-1 were expressed in acute and chronic granulomas. However, whereas ICAM-1 was constitutively expressed in normal liver, VCAM-1 was dramatically induced in the livers upon onset of disease. The findings suggest that the acute granulomas are rich in accessory cells with overall phenotypic configurations that support Th-cell activation, although at subsequent times, granulomas contain increasing numbers of B7-poor accessory cells capable of inducing Th-cell unresponsiveness. Thus, cellular interactions in early granulomas may be able to amplify egg-induced immunopathology, whereas interactions taking place in succeeding granulomas appear to precipitate its down-regulation.
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T cells expressing the gamma delta T cell receptor are not required for egg granuloma formation in schistosomiasis.
Immunopathology in schistosomiasis consists of a granulomatous response around parasite eggs. It has been established that granuloma formation is mediated by CD4+ T helper cells. However, the role of T cells bearing the gamma delta T cell receptor (TCR) has not been determined. In this study we utilized mutant mice that lack either alpha beta or gamma delta T cells as a result of gene targeting to investigate the relative roles of alpha beta and gamma delta T cells in the induction of immunopathology related to schistosomiasis. Mutant and control mice were infected with Schistosoma mansoni and granuloma formation as well as lymph node cell proliferative responses to egg antigens were analyzed after 8 weeks. TCR delta mutant mice (lacking gamma delta T cells) displayed vigorous formation of egg granulomas that were not significantly different from those observed in normal controls, both in terms of granuloma size and cellular composition. In contrast, TCR alpha and TCR beta mutant mice (lacking alpha beta T cells) were unable to form granulomas. Moreover, mesenteric lymph node cells from TCR delta mutant and control mice responded strongly to egg antigens in vitro, while TCR alpha and beta mutant mice did not. Our studies show that in schistosomiasis granuloma formation and proliferative responses to egg antigens are strictly dependent on alpha beta T cells. They also suggest that gamma delta T cells by themselves can neither mediate a granulomatous inflammation, nor significantly modify one mediated by alpha beta T cells.
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In situ analysis of cytokine responses in experimental murine schistosomiasis.
BACKGROUND: Infection with schistosomiasis results in CD4+ T helper (Th) cell-dependent granulomatous inflammation around parasite eggs. T cell-derived cytokines play a critical role in the induction and subsequent down-modulation of the granulomas. These cytokine responses have been previously examined in lymphoid cell supernatants or in tissue homogenates but have not been examined directly in the local microenvironment of the lesions or in the reacting lymphoid tissues. EXPERIMENTAL DESIGN: With the use of specific mAb, the cytokines IL-2, IFN gamma, IL-4, and IL-10 were investigated by direct immunocytochemical analysis in situ in hepatic egg granulomas and lymphoid organs from acutely and chronically infected mice. Cytokine expression in situ was compared with cytokine production during a secondary response in vitro. RESULTS: All cytokines examined were detected in various amounts in both the hepatic egg granulomas as well as in mesenteric lymph nodes and spleen. The majority of cells expressing the cytokines was found in lymph nodes, and very few were found in granulomas. Relatively small numbers of granulomas contained most of the cytokine-expressing cells, which tended to localize in their periphery. Granulomas and lymphoid organs in the acute disease contained significantly more cytokine-expressing cells in comparison with those from the chronic disease. This observation correlated well with cytokine production in vitro. CONCLUSIONS: Direct immunocytochemical examination in situ was used to detect and measure cytokine-producing cells in hepatic egg granulomas and reacting lymphoid organs of acute and chronic experimental murine schistosomiasis. Observed cytokine patterns suggest that granulomas contain T lymphocytes of both the Th-1 and Th-2 types and that cytokine production occurs during a limited time in the early granuloma. The immunocytochemical technique affords a direct appraisal of amount, dynamics, and localization of cytokine-producing cells in the unperturbed local environment.
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Regulation of T helper cell responses in experimental murine schistosomiasis by IL-10. Effect on expression of B7 and B7-2 costimulatory molecules by macrophages.
Granulomatous inflammation in schistosomiasis is a manifestation of cell-mediated hypersensitivity to parasite egg Ags that is predictably reduced in size over the course of the disease. This down-regulation may reflect a state of anergy in the T cells mediating granuloma formation after interaction with accessory cells incapable of providing full stimulation. The present studies were conducted to investigate this mechanism at the molecular level. We found that granuloma macrophages (GM) strongly inhibit the ability of splenic APC to stimulate egg Ag-specific Th1 responses. This property was shown to be dependent on their secretion of IL-10. Moreover, activated GM in culture were found to express little or no costimulatory Ags B7 or B7-2. However, when their autocrine secretion of IL-10 was neutralized with specific mAb, GM displayed an up-regulation of costimulatory molecules as well as of MHC class II Ags. Most importantly, GM cultured in the presence of anti-IL-10 mAb, acquired the ability to stimulate egg Ag-specific T cells. By independently blocking each of the induced costimulatory Ags, it appeared that B7-2 molecules provided stronger costimulation than B7. In separate experiments, culture supernatants from GM exerted a powerful inhibition of costimulatory Ag expression on Con-A-stimulated peritoneal exudate cells in vivo, which could similarly be attributed to IL-10. Our results demonstrate that IL-10 can play a critical role in the generation of accessory cells that, by virtue of down-regulation of costimulatory molecules, may be capable of inducing anergy in T cells mediating the vigorous granulomatous response of acute stage schistosomiasis. Our studies lend support to the contention that a state of unresponsiveness in pathogenic T cells may precipitate the down-regulation of granuloma formation and provide a molecular basis for the underlying mechanisms.
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Macrophages from schistosomal egg granulomas induce unresponsiveness in specific cloned Th-1 lymphocytes in vitro and down-regulate schistosomal granulomatous disease in vivo.
We previously have proposed that accessory cells from individuals infected with schistosomiasis induce unresponsiveness in specific Th-1 lymphocytes resulting in the immunologic down-regulation of egg-induced granulomatous inflammation characteristically seen in this disease. We now show that macrophages isolated from schistosomal egg granulomas (GM) fail to serve as stimulatory APC for cloned, murine schistosomal egg Ag (SEA)-specific, CD4+, Th-1-type lymphocytes, while being able to stimulate Th-2-type responses. Instead, GM render Th-1 cells unresponsive to restimulation. Based on these findings, we tested two approaches to down-regulate the granulomatous inflammation associated with a schistosomal challenge infection. First, active ectopic granuloma induction in response to Schistosoma mansoni eggs, but not to Ascaris lumbricoides eggs, resulted in a significant reduction of granulomatous disease in vivo, as well as in the inhibition of specific proliferation of mesenteric lymph node cells in vitro. Second, passive administration of purified GM, but not of normal peritoneal cells (PC), resulted, similarly, in significant reduction of granuloma size in vivo and specific lympho-proliferation in vitro. Moreover, cytokine analysis of supernatants from stimulated lymph node cells disclosed that the Th-1-derived cytokine IL-2 decreased to undetectable levels, at the same time as the Th-2-derived cytokines IL-4 and IL-10 increased, in animals receiving GM, in contrast to those receiving PC or no cells. These findings are consistent with the interpretation that accessory cells such as GM induce unresponsiveness in specific Th-1 cells that, in turn, results in the down-regulation of granulomatous schistosomal disease and its in vitro correlates.
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The shrinking schistosomal egg granuloma: how accessory cells control T cell-mediated pathology.
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Animals↗
Accessory cell signals regulate Th-cell responses: from basic immunology to a model of helminthic disease.
Schistosome helminths inflict serious tissue damage by eliciting T helper (Th)-cell-mediated granulomatous inflammation around parasite eggs. The egg granulomas are large in acute disease and smaller in chronic disease. To explain this downregulation in chronic disease, Miguel Stadecker and Pedro Flores Villanueva describe a mechanism whereby CD4+ Th1-type lymphocytes, which are associated with the initial vigorous granuloma formation, are rendered anergic to subsequent antigenic stimulation. This results in the reduction of granuloma size and in the dominance of Th2-type lymphocyte responses.
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Role of IL-10 on antigen-presenting cell function for schistosomal egg-specific monoclonal T helper cell responses in vitro and in vivo.
Egg Ag-stimulated lymphoid cell culture supernatants from schistosome-infected mice significantly inhibited Ag-specific, MHC-restricted proliferative responses of cloned schistosomal egg Ag-specific CD4+, Th-1-type lymphocytes. The inhibitory molecule in the supernatants was found to be the cytokine IL-10. Maximal IL-10 was produced by cells from mice carrying 8-wk schistosome infections, and none by cells from normal mice. IL-10 exerted its biologic activity on APC, and not directly on the cloned lymphocytes, resulting in the inhibition of Th-1 lymphocyte proliferation, whereas Th-2 responses were not affected. Most significantly, IL-10 also affected Th-1 clone activity in vivo, as measured by the inhibition of schistosomal egg Ag-specific local delayed-type hypersensitivity reactions. IL-10 produced in schistosome-infected individuals may play a role in the generation of APC, such as macrophages in schistosomal egg granulomas, unable to efficiently stimulate, but capable of inducing a state of anergy/unresponsiveness in Th-1 lymphocytes. We believe that this state of Th-1 cell anergy translates into the down-regulation of granulomatous hypersensitivity (immunomodulation) characteristically observed in the evolving schistosomal disease.
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The cell-mediated response to schistosomal antigens at the clonal level. III. Identification of soluble egg antigens recognized by cloned specific granulomagenic murine CD4+ Th1-type lymphocytes.
Granulomatous inflammation in schistosomiasis is a consequence of T cell-mediated hypersensitivity to parasite egg Ag. In the present study we used three consecutive independent chromatographic procedures to fractionate and identify the soluble egg Ag recognized by schistosome-specific, cloned, murine, CD4+ Th1-type lymphocytes, which had been shown previously to be capable of mediating granuloma formation in vivo when adoptively transferred to normal syngeneic hosts challenged with an i.v. injection of eggs. The stimulatory activity resided in two acidic egg molecules, with apparent molecular masses of 64 to 68 kDa and 38 to 42 kDa, each of which ran as a single band on SDS-PAGE after purification. Fast performance liquid chromatography and SDS-PAGE performed under reducing conditions suggested that the two molecules are related and that the 38- to 42-kDa molecule is a subunit of the 64- to 68-kDa molecule. Polyclonal lymphoid cells from schistosome-infected mice were similarly stimulated by the purified 64- to 68-kDa and 38- to 42-kDa molecules, implying that these are sensitizing Ag in the natural disease.
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Arginine-dependent generation of reactive nitrogen intermediates is instrumental in the in vitro killing of protoscoleces of Echinococcus multilocularis by activated macrophages.
The interaction between protoscoleces of Echinococcus multilocularis and activated murine macrophages was examined in this study. Marked protoscolicidal activity was displayed by peritoneal macrophages (PM) activated with interferon-gamma (IFN-gamma), or IFN-gamma plus lipopolysaccharide. Pretreatment of the parasites with heat-inactivated specific murine infection serum, but not with normal serum rendered them more susceptible to PM killing. NG-monomethyl-L-arginine, a competitive inhibitor of L-arginine completely inhibited the killing activity of activated PM, while reconstitution of arginine-free medium with L-arginine restored the killing properties of the activated PM. The results show that activated PM have the ability to kill E. multilocularis protoscoleces in vitro and suggest that reactive nitrogen intermediates (RNI) play an important role in the mechanism. An oxygen-mediated mechanism did not appear to play a role because scavengers of reactive oxygen species did not reduce the killing activity. The arginine-dependent killing mechanism was enhanced by superoxide dismutase (SOD), probably because SOD might prolong the effect of nitric oxide. Secretion of RNI by activated macrophages may be capable of a significant role in preventing of the dissemination of E. multilocularis infection in vivo.
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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.
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The role of T-cell anergy in the immunomodulation of schistosomiasis.
Schistosomes are capable of causing severe tissue damage, which results from the granulomatous inflammation that develops around the parasite eggs. Characteristic of this inflammatory process is its gradual, spontaneous down-regulation (immunomodulation) as the disease progresses. There has been general agreement that the granulomatous inflammation is a consequence of T(H)-cell-mediated delayed-type hypersensitivity to egg antigens. However, the basis of immunomodulation is less clear and has been attributed to various causes. In this review, Miguel Stadecker proposes a novel mechanism of immunomodulation based on the observation that accessory cells from schistosome-infected individuals are capable of inducing a state of unresponsiveness or energy in a subpopulation of antigen-specific CD4(+) T(H)-cell clones identified with delayed-type hypersensitivity reactions.
Journal Article↗
Larvicidal properties of macrophages induced by cloned murine schistosomal egg antigen-specific CD4 positive T-helper lymphocytes.
The role of T-helper (TH) lymphocytes in activating peritoneal macrophages (PM) to kill larvae of the helminth Schistosoma mansoni (schistosomula) was investigated with the use of egg antigen-specific CD4 positive TH clones of both the TH1 and TH2 types. Results showed that stimulated TH1 clones, in exceedingly small numbers, or supernatants thereof, conferred on PM the ability to kill schistosomula. The molecule responsible for PM activation was found to be interferon-gamma (IFN-gamma). IFN-gamma-induced PM larvicidal activity was dependent on live cells, energy, as well as protein synthesis, and appeared to be mediated by toxic nitrogen metabolites. In contrast, egg antigen-specific TH2 clones, or their supernants, failed to induce PM larval killing, as they did not secrete IFN-gamma, or any equivalent macrophage activating factor. We postulate a mechanism by which egg antigen-specific TH1 clones may be capable of playing a critical role in the resistance to schistosomal reinfection through IFN-gamma-mediated activation of macrophage helminthotoxicity.
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Fibroepithelioma-like changes associated with anogenital epidermotropic mucinous carcinoma. Fibroepitheliomatous Paget phenomenon.
We describe two patients with crusted perineal plaques that were biopsied and diagnosed as Paget's disease. Resection specimens of each contained a dermal mucinous carcinoma with extensive epidermotropism and coexistent epidermal basaloid proliferations closely resembling fibroepithelioma (Pinkus). The presence of the Paget phenomenon was supported by histochemical, immunohistochemical, and ultrastructural evidence. No other primary neoplasms were found in either patient. Followup at 2 1/2 and 3 1/2 years, respectively, has been negative. We conclude that either the fibroepitheliomatous changes may be induced by or may represent a collison (unlikely) with the epidermotropic mucinous carcinoma. It is proposed that the concept fibroepitheliomatous Paget phenomenon be used to stand for the histologic changes common to our cases as well as those previously reported.
Adenocarcinoma, Mucinous↗
The cell-mediated response to schistosomal antigens at the clonal level. In vivo functions of cloned murine egg antigen-specific CD4+ T helper type 1 lymphocytes.
It is now well established that the granulomatous inflammation surrounding the eggs of Schistosoma mansoni is mediated by Th lymphocytes. Our laboratory has recently cloned murine CD4+ Th cells specific for schistosomal egg Ag (SEA). In the current study, SEA-specific IL-2-producing Th1 clones were tested for their ability to mediate local delayed-type hypersensitivity (DTH) reactions, as well as granuloma formation in vivo. Marked delayed-onset erythema and induration developed in footpads of normal syngeneic hosts injected with SEA together with SEA-specific Th1 clones. Histologic examination of these lesions revealed typical, predominantly mononuclear, cell infiltrates characteristic of DTH reactions. Conversely, no reactions were observed in allogeneic hosts, in the absence of SEA, or with the use of a control Th1 clone. Moreover, adoptive transfer of cloned SEA-specific Th1 cells to normal syngeneic mice mediated, in 4 days, the formation of vigorous granulomas around schistosomal eggs embolized in the lungs. Such granulomas, which were quantitated by computer-assisted morphometric analysis, were comparable in size to those elicited by lung-embolized eggs in SEA/CFA-immunized mice. In contrast, significantly smaller granulomas were observed in normal recipients of eggs plus a control Th1 clone or of eggs alone. Our data indicate that Ag-specific, MHC-restricted, local DTH reactions, as well as egg granuloma formation in vivo, can be mediated by monoclonal SEA-specific Th1 cells. They suggest that T cell sensitization to only small numbers of SEA determinants may be sufficient to elicit the hepatointestinal granulomatous inflammation associated with schistosomiasis.
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Differential sensitivity of virgin and memory T lymphocytes to calcium ionophores suggests a buoyant density separation method and a model for memory cell hyporesponsiveness to Con A.
Previous work from this laboratory has indicated that murine memory T cells differ from virgin T cells in that the former are more resistant to agents that alter intracellular [Ca]i. We have used this difference to devise a method for separating virgin from memory T cells by centrifugation over an ionomycin-containing Percoll step gradient after brief exposure to 2 microM ionomycin. Under these conditions, those T cells that are most sensitive to ionomycin-induced changes in [Ca]i become more dense and therefore travel further into the Percoll/ionomycin gradient than cells that are more resistant to ionomycin. We show that the ionomycin-resistant cell population is enriched for cells that express high levels of Pgp-1 (CD44), and low levels of CD45RB, and thus appears to consist largely of memory T cells. Both CD4 and CD8 cells can be divided into Pgp-1hi and Pgp-1lo subsets in this way. Cells recovered from such a gradient and washed to remove the ionomycin appear normally functional, i.e., neither more nor less responsive to mitogens and costimuli than untreated cells. Limiting dilution methods show that the ionomycin-sensitive (virgin) subset contains most of the Con A-responsive precursors for cytotoxicity, and most of the cells able to produce IL-2 in responses to Con A or staphylococcal enterotoxin B. Ag-specific helper memory cells are, however, found predominantly in the ionomycin-resistant fraction of the spleen and draining lymph nodes of mice infected with Schistosoma mansoni. Changes in resistance to calcium signal development may represent a fundamental distinction between virgin and memory T cells, and could contribute to differences in activation requirements between these two cell subsets.
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Induction and maintenance of anergy in mature T cells.
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