Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chagas' disease results from the infection of the protozoan parasite Trypanosoma cruzi and affects several million people in South America. Several alterations of the immune response have been described in this disease, such as severe immunosuppression of both cellular and humoral responses and massive polyclonal stimulation with the generation of autoantibodies crossreacting with host cells and tissues. We have obtained monoclonal antibodies (mAbs) from T. cruzi-infected mice that recognized a 50/55-kD antigen (GP50/55) on the T. cruzi membrane, but not in other parasites of the family Trypanosomatidae. One of these GP50/55-specific mAbs (C10) crossreacts with a 28-kD antigen (p28) expressed on the membrane of greater than 85% of activated mouse T and B lymphocytes, after in vitro activation with concanavalin A, Salmonella typhosa lipopolysaccharide, phorbol dibutyrate ester, or antigen, and on several murine T and B lymphocyte cell lines. Human T and B lymphocytes also express upon activation with phytohemagglutinin or Staphylococcus aureus Cowan I (SAC) a similar antigen recognized by mAb C10, although in a lower proportion of cells (30-40%). Furthermore, this mAb was able to suppress mouse and human T and B cell proliferation to any of those stimuli. In addition, sera from chagasic patients and T. cruzi-infected mice, but not from control patients or littermates, contain antibodies that recognize a similar p28 antigen on B lymphocytes. Furthermore, the immunoglobulin fractions of some chagasic sera also suppress the proliferation of human T lymphocytes. These results suggest a possible pathological role of autoantibodies as an alternative mechanism for T. cruzi-associated immunosuppression.
 ...
PMID:A Trypanosoma cruzi membrane protein shares an epitope with a lymphocyte activation antigen and induces crossreactive antibodies. 137 61

Acute Trypanosoma cruzi infection of mice results in a very marked polyclonal activation of B and T lymphocytes, accompanied by high numbers of Ig-secreting PFC and lectin-dependent effector CTL. Treatment of mice with monoclonal anti-L3T4 antibodies from the time of infection (days 0, 4, and 8) completely suppresses the polyclonal PFC response and CTL generation. Treatment of nude mice with antibody does not alter the lipopolysaccharide-induced polyclonal PFC response, and it only modulates the isotypic profile of the PFC response to T. cruzi infection, without reducing its magnitude. Furthermore, antibody-treated, T. cruzi-infected euthymic mice do not develop the typical B cell blastogenic response, but show high numbers of activated Lyt-2+ lymphoblasts in the spleen. These results indicate that effector cell generation in T. cruzi-infected mice is predominantly helper T cell-dependent.
 ...
PMID:Suppression of polyclonal antibody production in Trypanosoma cruzi-infected mice by treatment with anti-L3T4 antibodies. 295 44

The responses of spleen cells from mice infected with Trypanosoma cruzi to T and B cell-specific mitogens were monitored during the acute and chronic stages of the infection. Responses to either T (phytohemagglutinin or concanavalin A) or B (endotoxic lipopolysaccharide) cell mitogens measured on days 5, 10, 15, and 20 postinfection, i.e., at different times during the acute period, were markedly reduced. Responses measured on days 54 and 90, i.e., during the chronic stage, did not differ significantly from those of normal mouse spleen cells. Proportions of T and B lymphocytes in the spleen were reduced and unaltered, respectively, during acute T. cruzi infection but were comparable to normal values during the chronic state. These results highlight a return of normal T and B lymphocyte responses during chronic experimental Chagas' disease and suggest that transition from the acute to the chronic phase of the infection may be immunologically regulated.
 ...
PMID:Evaluation of lymphocyte responsiveness to polyclonal activators during acute and chronic experimental Trypanosoma cruzi infection. 677 31

The responses of spleen cells from mice infected with Trypanosoma cruzi to stimulation with T (concanavalin A and phytohemagglutinin) or B (lipopolysaccharide) cell-specific mitogens were monitored during the acute, transition, and chronic states of the disease. A marked reduction in the responses of infected mouse cells with respect to those of uninfected animals was observed during the acute stage, regardless of whether or not the infective dose was lethal. Reduced or absent responses were recorded with suboptimal, optimal, and supraoptimal concentrations of the mitogens. Normal levels of responsiveness to concanavalin A, phytohemagglutinin, and lipopolysaccharide were observed during the chronic stage of the disease. The trend of return to normal responses was initiated around day 40 after infection with 25 parasites. At this time, a marked decline in parasitemia levels, cessation of mortality, and disappearance of visible signs of disease began to be observed defining the transition stage that precedes establishment of chronicity. T cell levels of the spleen were markedly reduced during the acute period and returned during the chronic phase. Instead, absolute levels of B cells were significantly increased during the acute period but also normalize in the chronic phase. Immunosuppression of chronically infected mice with cyclophosphamide led to a temporary return to acute infection-type conditions, even in animals with undetectable levels of parasitemia before treatment. These results suggest that reduced T cell responses during acute experimental Chagas' disease might in part to be due to depletion of the T cell compartment. Decreased B cell responses in the presence of significant numbers of B lymphocytes implies a suppressive phenomenon, B cell alteration, or a combination of both possibilities. Recrudescence of the disease after immunosuppression with cyclophosphamide suggests that immunological mechanisms play an important role, not only in the gain of control over T. cruzi infected by the host but also in the maintenance of the chronic status.
 ...
PMID:Experimental Chagas' disease: kinetics of lymphocyte responses and immunological control of the transition from acute to chronic Trypanosoma cruzi infection. 678 38

Trypanosoma cruzi, the etiological agent of Chagas' disease, expresses a trans-sialidase at highest levels in infective trypomastigotes, where it attaches to the plasma membrane by a glycophosphoinositol linkage. Bound enzyme sheds into the extracellular milieu in a soluble form. Experiments performed in vitro suggest that the trans-sialidase participates in several parameters of T. cruzi-host interactions, like cell adhesion and complement resistance. However, the role that membrane-bound and soluble trans-sialidase plays in the infection of mammals is not understood. To begin to study the role the enzyme may play in vivo, T. cruzi trypomastigotes were inoculated subcutaneously into mice that had been sensitized for various times with the purified protein. A single dose of either endogenous or recombinant trans-sialidase injected into the connective tissues of BALB/c mice greatly enhanced parasitemia and mortality. Maximum enhancement was achieved with 1-2-h priming. Injection of the enzyme after the parasites had been established in the inoculation site had little, if any, consequence in modifying virulence. The enhancement did not seem to be through a direct effect of the enzyme on trypomastigote-host cell interactions because it occurred when the sites of trans-sialidase sensitization and parasite inoculation were physically separate. Rather, virulence enhancement seemed to depend on inflammatory cells, since priming with trans-sialidase had no significant effect in severe combined immunodeficiency mice, which lack functional T and B lymphocytes. However, antibody response to T. cruzi in the trans-sialidase-primed BALB/c mice was the same as in the control animals. Virulence enhancement was specific for the trans-sialidase because it did not occur in mice primed with Newcastle virus sialidase, which has the same substrate specificity as the T. cruzi enzyme, or with the sialidase from the bacterium Vibrio cholerae, whose substrate specificity is broader than the trypanosome sialidase. Furthermore, no enhancement of virulence occurred after sensitization with another adhesion protein (penetrin) purified from T. cruzi trypomastigotes and engineered bacteria, nor with bacterial lipopolysaccharide. The virulence-promoting activity of soluble trans-sialidase in the mouse model may be physiologically relevant because it was achieved with tiny doses, approximately 1-2 microgram/kg, raising the possibility that neutralization of the enzyme with specific probes could impair the development of Chagas' disease. In fact, a monoclonal antibody specific for the tandem repeat in the trans-sialidase COOH terminus enhanced infection of BALB/c mice, in agreement with earlier experiments in vitro, whereas antibodies against an amino acid sequence in the Cys region had the opposite effect.
 ...
PMID:Trypanosoma cruzi trans-sialidase: enhancement of virulence in a murine model of Chagas' disease. 772 48

Although a number of immunological anomalies have been shown to occur during the acute period of Trypanosoma cruzi infection, the contribution of the parasite has not been clarified. In this work, we co-cultured activated splenic mononuclear cells (SMC) from normal outbred (CD1) or inbred (CBA/J) mice with purified T. cruzi trypomastigotes and studied ensuing T- and B-lymphocyte alterations. In the presence of parasites, phytohaemagglutinin-stimulated SMC from either mouse background manifested a marked reduction in both lymphoproliferative capacity (i.e., 3H-thymidine incorporation) and cell membrane level of interleukin-2 receptors (IL-2R; determined by flow cytometry) relative to SMC from parasite-free cultures. Thus, substantial proportions of activated SMC either became unable to express detectable levels of IL-2R or expressed this receptor in significantly lower numbers than control SMC. Supernatants from T. cruzi suspensions reproduced these suppressive effects on phytohaemagglutinin-stimulated SMC from normal or chronically infected CD1 or CBA/J mice. Similar results were obtained with SMC activated with a bacterial lipopolysaccharide. Since IL-2R expression is required for activated lymphocytes to progress through the cell cycle and multiply to mount effective immune responses, impaired IL-2R expression by T. cruzi provides a plausible hypothesis for the wide-ranged immunosuppression that occurs in the infected host.
 ...
PMID:Alterations induced by Trypanosoma cruzi in activated mouse lymphocytes. 833 83

We have investigated CD4+ T-cell autoreactivity to normal syngeneic B cells in vitro in chronic experimental Chagas' disease. Resting B cells induced an intense proliferative response and lymphokine secretion by splenic CD4+ T cells from Trypanosoma cruzi-infected (8 months or more of infection) donors, compared to much lower responses by uninfected controls. On the other hand, lipopolysaccharide-activated B cells induced syngeneic CD4+ T-cell activation in both control and infected groups. The observed syngeneic T-B-cell cooperation was bidirectional. In the absence of any exogenous stimulus, CD4+ T cells from T. cruzi-infected animals induced much higher production of all tested immunoglobulin (Ig) isotypes (IgM, IgG1, IgG2a, IgG2b, IgG3) by syngeneic B cells, compared to T cells from uninfected donors. When lipopolysaccharide-treated B cells were used, CD4+ T cells from either control or infected donors enhanced IgG1 and IgG3 production, but only CD4+ T cells of infected origin induced IgG2a production in this system without addition of exogenous gamma interferon. Enhanced T-cell proliferation and Ig production were also observed with highly purified CD4+ T cells and in serum-free medium. Both proliferation and Ig production could be blocked with anti-major histocompatibility complex class II monoclonal antibodies. Enhanced reactivity and help for Ig production were seen only in response to syngeneic BALB B cells and not in response to allogeneic B10 B cells. These results indicate that chronic infection with T. cruzi results in increased CD4+ T-cell reactivity towards syngeneic B cells, which leads to spontaneous Ig production. These autoreactive T cells might play a role in polyclonal autoantibody production in chronic Chagas' disease.
 ...
PMID:Chronic experimental Chagas' disease: functional syngeneic T-B-cell cooperation in vitro in the absence of an exogenous stimulus. 869 26

Calomys callosus is a wild rodent found infected with Trypanosoma cruzi in nature. Groups of female C. callosus were subjected to ovariectomy or sham operation or served as intact controls. At 1 month after surgery, animals were inoculated intraperitoneally with 4000 blood trypomastigotes of the "Y" strain of T. cruzi. Parasitemia during the course of infection was significantly higher in ovariectomized animals as compared with sham-operated rodents and controls. On steroid hormone replacement the parasitemia of ovariectomized animals dropped to levels close to those of controls. High or low doses of progesterone, estrogen, or a combination of both exerted similar effects. Splenocyte proliferation of ovariectomized animals was unresponsive to stimuli with concanavalin A and lipopolysaccharide as compared with that of control and sham-operated groups. The results show that gonadal hormones play a fundamental role in the defense against T. cruzi infection. The influence of these procedures on the immune defense in experimental Chagas' disease is being further investigated.
 ...
PMID:Influence of female gonadal hormones on the parasitemia of female Calomys callosus infected with the "Y" strain of Trypanosoma cruzi. 949 7

Trypanosoma cruzi, the causative agent of Chagas' disease, is a protozoan parasite that infects humans and other mammals in Central and Latin America. Several alterations of the immune response after infection have been described, such as severe immunosuppression of both cellular and humoral responses and massive polyclonal B- and T-cell activation, including the expansion of self-reactive clones. We have investigated the effects of the intraperitoneal injection of a recombinant 24,000 MW T. cruzi-specific antigen (rTc24) on the immune response of normal and deficient strains of mice. We analysed the in vivo and ex vivo levels of lymphocyte activation and the proliferative responses to rTc24 by determining the expression of CD69 activation marker and the levels of thymidine incorporation by spleen cells. The numbers of antibody-producing cells were determined by ELISPOT and the levels of immunoglobulin in the sera by isotype-specific enzyme-linked immunosorbent assay. We observed an increased [3H]thymidine ([3H]TdR) incorporation by spleen cells after rTc24 stimulation in vivo and in vitro. This proliferative activity induced by rTc24 was independent of the mouse strain used in the experiments (including C3H/HeJ mice) and ruled out the possibility that rTc24 preparations were contaminated by lipopolysaccharide. The injection of rTc24 protein induced preferentially the activation of B cells, as determined by the increased expression of CD69 molecules on IgM+ spleen cells. Considerable increases of IgM-secreting B cells were determined in both athymic and euthymic BALB/c mice. Mice that are deficient in B cells (BALB.Xid) responded to rTc24 but to a lesser extent. These increases in IgM B-cell numbers were accompanied by elevated levels of IgM immunoglobulins in the sera of injected animals. Our results suggest a role for rTc24 in B-cell activation.
 ...
PMID:A 24,000 MW Trypanosoma cruzi antigen is a B-cell activator. 974 40

Trypanosoma cruzi, a parasitic protozoan, is the etiological agent of Chagas' disease. Despite the many immune system disorders recognized in this infection and the crucial role played by dendritic cells (DC) in acquired immune responses, it was not known whether these cells could be infected by T. cruzi trypomastigotes and the consequences of such an infection on their immune functions. We now provide evidence that human monocyte-derived DC can be infected by T. cruzi and can support its intracellular multiplication. Interestingly, this infection has functional consequences on immature DC and on their maturation induced by lipopolysaccharide (LPS). First, after T. cruzi infection, the basal synthesis of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) was impaired. Furthermore, the process of maturation of DC induced by LPS was drastically affected by T. cruzi infection. Indeed, secretion of cytokines such as IL-12, TNF-alpha, and IL-6, which are released normally at high levels by LPS-activated DC, as well as the up-regulation of HLA-DR and CD40 molecules, was significantly reduced after this infection. The same effects could be induced by T. cruzi-conditioned medium, indicating that at least these inhibitory effects were mediated by soluble factors released by T. cruzi. Taken together, these results provide new insights into a novel efficient mechanism, directly involving the alteration of DC function, which might be used by T. cruzi to escape the host immune responses in Chagas' disease and thus might favor persistent infection.
 ...
PMID:Trypanosoma cruzi infects human dendritic cells and prevents their maturation: inhibition of cytokines, HLA-DR, and costimulatory molecules. 1041 71


1 2 Next >>