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Biomedical subjects

M Yazdanbakhsh

Publications and source records attributed to M Yazdanbakhsh.

At least 55 records · Page 3Linked to original sources
PubMed1997

Recognition of Schistosoma mansoni cathepsins B and L by human IgG1 and IgG4 antibodies.

Human schistosome infections are chronic in nature and elevated IgG4 levels are associated with length of exposure. To examine how structure, localization and dynamics of exposure of a protein to the immune system can affect antibody isotype expression, specific antibody levels against two Schistosoma mansoni recombinant cathepsin molecules were determined in S. mansoni-infected individuals. Cathepsin B (rCatB, secreted in the gut) and cathepsin L (rCatL, localized in the reproductive structures) were used to determine IgG1 reactivity, as a measure of the stimulation of the immune response, and the switch to IgG4 as an indicator of the dynamics and rate of presentation to the immune system. Sera from three groups of S. mansoni-infected patients were used: individuals with life-long exposure in an endemic area in Burundi, a group from a recent endemic focus in Senegal, and of acutely infected European travellers. We report for the first time the ability of rCatL to trigger an immune response and show distinct antibody isotype reactivity between rCatB versus rCatL. Patients harbouring long-term chronic infections had elevated levels of IgG4 to both antigen, whereas individuals infected for less than four years had high IgG4 to rCatB but not to rCatL. Acutely infected travellers developed IgG1 to rCatB only. Our results demonstrate that an immune response is mounted more rapidly against a cathepsin molecule secreted in the gut of the worm than against an internally localized cathepsin.

Adolescent↗
PubMed1997

Anti-schistosome IgG4 and IgE at 2 years after chemotherapy: infected versus uninfected individuals.

Specific IgG4 and IgE responses to adult worm antigen (AWA) and soluble egg antigen (SEA) were examined in 37 subjects from an area in which schistosomiasis is endemic, who were previously infected with Schistosoma haematobium and who became reinfected or remained free of infection 2 years after chemotherapy. The reinfected group was significantly younger (median age, 11 years) than the uninfected group (median age, 24 years). Posttreatment levels of IgG4 to egg antigens (IgG4-SEA) were significantly correlated with reinfection intensity (r = .74, P < .0001), and 13-fold lower levels of IgG4-SEA were observed in uninfected subjects compared with reinfected subjects. Although no correlation was observed between posttreatment IgE to AWA or to SEA, pretreatment IgE-AWA was inversely correlated with the level of reinfection (r = -.39, P = .02).

Adolescent↗
PubMed1997

Depression of antigen-specific interleukin-5 and interferon-gamma responses in human lymphatic filariasis as a function of clinical status and age.

In an area in which brugian filariasis is endemic, when cytokine levels were analyzed as a function of clinical status comparing those who were asymptomatic and amicrofilaremic with those who were microfilaremic, it was found that both interferon (IFN)-gamma and interleukin (IL)-5 were suppressed in microfilariae carriers (P < .01 and P < .001, respectively), but IL-4 was unabated. Age had a significant effect on cytokine production in both groups. In asymptomatic amicrofilaremic subjects, IL-4 production was high in young persons and decreased with age, whereas in microfilaremic subjects, IL-4 increased significantly with age. Conversely, IFN-gamma showed a tendency to increase with age in asymptomatic amicrofilaremic subjects but not in microfilaremic subjects. IL-5 decreased significantly with increasing age in both asymptomatic amicrofilaremic and microfilaremic groups. These results indicate that the length of exposure to and infection with filarial parasites can each exert a substantial effect on the cytokine response profiles of host T cell populations.

Adolescent↗
PubMed1997

Selective usage of defined TCRBV genes in response to filarial antigens.

The characterization of T cell reactivities that are prone to down-modulation by filarial parasites is central to understanding how these nematodes can survive for long periods of time within their human host and to design appropriate immunoprophylactic measures. In the present study, TCRBV gene usage was analyzed in response to filarial antigens by PCR using a panel of TCRBV gene segment family-specific oligonucleotide primers. Analysis of individuals highly responsive to Brugia malayi adult worm antigen (BmA) (n = 4) indicated that following stimulation with BmA a maximum of four TCRBV gene families were over-represented in each subject. Those were TCRBV2, 9, 19 and 23 in subject 1; TCRBV8, 9 and 16 in subject 2; TCRBV2, 8, 9 and 11 in subject 3; and TCRBV13 and 23 in subject 4. The analysis of one subject who was unresponsive to BmA before but regained responsiveness after diethylcarbamazine treatment revealed that there was no overexpression of a particular TCRBV gene family before chemotherapy, whereas after chemotherapy three TCRBV gene families (TCRBV8, 16 and 19) were found to be overexpressed. Complementarity determining region 3 size analysis of a selection of the overexpressed TCRBV genes displayed oligoclonality in some of the observed expansions. Together these observations show that limited T cell subpopulations are clonally amplified in BmA-stimulated peripheral blood mononuclear cells of filarial responder subjects, possibly driven by a restricted number of antigens.

Adolescent↗
PubMed1997

Interleukin-12 suppresses immunoglobulin E production but enhances immunoglobulin G4 production by human peripheral blood mononuclear cells.

The effect of interleukin-12 (IL-12) on human immunoglobulin G4 (IgG4) and IgE production was examined with cells derived from filarial patients and European controls. IL-12 inhibited IgE release but enhanced IgG4 production in cultures of peripheral blood mononuclear cells stimulated with anti-CD2 plus IL-2. When purified T- and B-cell cocultures were examined, IL-12 again markedly enhanced IgG4, whereas IgE production was no longer inhibited.

Animals↗
PubMed1996

Schistosoma mansoni excretory circulating cathodic antigen shares Lewis-x epitopes with a human granulocyte surface antigen and evokes host antibodies mediating complement-dependent lysis of granulocytes.

Parasitic worms of the genus Schistosoma excrete relatively large amounts of immunogenic glycoproteins (circulating cathodic antigen [CCA]) that contain polysaccharide side chains with the trisaccharide Lewis-x (L(ex)) as a repeating unit. These carbohydrates evoke high titers of specific IgM antibodies that cross-react with the repeating L(ex) units on the surface of granulocytes. Consequently this might lead, in the presence of complement, to lysis of the granulocytes. In the present study, this hypothesis was investigated using anti-CCA mouse monoclonal antibodies (MoAbs) and polyclonal antibodies purified from sera of infected humans. By flow cytometry, it was demonstrated that the mouse MoAbs directed against CCA strongly recognized the granulocytes. It could also be shown that these MoAbs, as well as anti-CCA IgM antibodies purified from infected human sera, caused lysis of granulocytes in a complement-dependent cytotoxicity assay. Sera from healthy controls or from patients with other helminth infections resulted in negligible granulocytotoxicity. These in vitro observed phenomena may explain the mild to moderate neutropenia that occurs in schistosomiasis patients.

Animals↗
PubMed1996

CD30 expression does not discriminate between human Th1- and Th2-type T cells.

CD30 is a member of the TNF receptor superfamily that is commonly used as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease. More recently, it has been proposed that CD30 is preferentially up-regulated on Th2-type human T cells. We analyzed regulation of CD30 expression on both peripheral blood T cells and T cell clones. In short-term culture, CD30 expression could be induced on T cells by Ags that elicit Th2-type responses (Schistosoma haematobium, adult worm Ag, and Toxocaria canis, excretory/secretory Ag) and Th0-type responses (tetanus toxoid), as well as Th1-type responses (tuberculin purified protein derivative). Moreover, simultaneous measurement of membrane phenotype and cytokine production showed that CD30-expressing cells can produce IFN-gamma. Finally, within panels of randomly generated as well as Ag-specific T cell clones, CD30 expression was found on Th0-, Th2-, and Th1-type clones. We conclude that induction of CD30 on activated T cells is not related to differentiation in Th0-, Th1-, or Th2-type cells.

Cell Differentiation↗
PubMed1996

In Th2-biased lymphatic filarial patients, responses to purified protein derivative of Mycobacterium tuberculosis remain Th1.

Natural infection with filarial nematode parasites results in immune responses skewed towards T helper (Th)2, while infection with mycobacteria shows many characteristics of a Th1-dominated response. Cytokines typifying Th1, interferon (IFN)-gamma, and Th2, interleukin (IL)-4, were measured following stimulation of peripheral blood mononuclear cells from filarial patients with Brugia malayi adult worm antigen (BmA) and purified protein derivative of Mycobacterium tuberculosis (PPD). In response to PPD, only 1 out of 81 patients produced IL-4, and this at an amount (4.4 pg/ml) just above the detection limit, whereas 59% of patients responded to BmA by releasing IL-4. Conversely, substantial quantities of IFN-gamma were released in response to PPD (geometric mean 37.43 U/ml) compared to low BmA-stimulated IFN-gamma production in the same patients (geometric mean 5.02 U/ml). These results demonstrate that the strong skewing of the cytokine environment towards Th2 in filarial patients in vivo does not influence the predominance of a Th1 type immune response to PPD.

Animals↗
PubMed1996

Elevated proliferation and interleukin-4 release from CD4+ cells after chemotherapy in human Schistosoma haematobium infection.

Cellular immune responses to schistosomal antigens were examined in 110 Schistosoma haematobium-infected individuals before and 5 weeks after treatment with praziquantel. Chemotherapy resulted in significant decrease in worm load as measured by egg output and circulating antigens. The proliferative responses to adult worm antigen (AWA) increased significantly after treatment (p < 0.001) whereas purified protein derivative of tuberculin or phytohemagglutinin responsiveness was unaffected. Interleukin (IL)-4 production in response to both AWA and soluble egg antigen (SEA) increased markedly after treatment (p < 0.001), but IL-5 remained unchanged. None of the studied subjects released any measurable IL-2 and only 21% produced interferon (IFN)-gamma in response to parasite antigens. The deficiency in either IFN-gamma or IL-2 release was not restored by chemotherapy. Thus chronic infection with S. haematobium is associated with the reversible down-regulation of T cell proliferative responses and IL-4 release. Results from cell depletion experiments indicated that CD4+ T cells were the target of this down-modulation.

Adolescent↗
PubMed1996

Antischistosome IgG4 and IgE responses are affected differentially by chemotherapy in children versus adults.

Specific IgG4 and IgE responses and polyclonal cytokine profiles were studied in 110 Schistosoma haematobium-infected persons before and 5 weeks after chemotherapy. Pretreatment IgG4 responses to soluble egg antigen (SEA) correlated with intensity of infection. After chemotherapy, a significant decrease in egg output and circulating anodic antigen was associated with a substantial drop in the IgG4 response to SEA (IgG4-SEA) in adults and children, suggesting that egg laying is a major stimulus for IgG4-SEA. After chemotherapy, IgG4 and IgE to adult worm antigen and IgE to SEA increased in children but remained unchanged in adults. This indicates that the immunoregulatory mechanisms operative in S. haematobium-infected adults differ from those in infected children. The effect of treatment on cytokine profiles was determined following stimulation of whole blood with anti-CD3 antibodies. A significant decrease in interleukin-4 production after treatment indicated that reduction in helminth load may lead to a reduced number of Th2-type cells.

Adolescent↗
PubMed1995

T-cell activation and the balance of antibody isotypes in human lymphatic filariasis.

Human filarial infection presents a spectrum of clinical states with two major poles: asymptomatic microfilaraemia and amicrofilaraemic chronic disease. Microfilaremia is associated with a Th1-type tolerance, and maximal IgG4 antibodies, while elephantiasis patients react across a broad range of immune parameters. In this review, Rick Maizels and his colleagues discuss recent advances in the immunology of human filariasis and present a summary of their latest studies in an endemic area of Indonesia.

Journal Article↗
PubMed1995

HLA and elephantiasis in lymphatic filariasis.

Lymphatic filariasis presents a spectrum of manifestations with infection-free asymptomatics at one end and elephantiasis at the other. In order to determine if any HLA antigens are associated with the development of elephantiasis, we compared the HLA frequencies in 55 elephantiasis patients with those in 40 controls consisting of individuals older than 45 years of age without any signs of elephantiasis. The only significant difference in class I antigen frequencies was observed for B27, which was present in 11% of the patients and absent in the controls. More differences were observed in HLA class II antigen frequencies. Both DR3 and the 2B3 epitope (on DQ6, DQ8, and DQ9 molecules) were significantly decreased in patients with elephantiasis whereas the DQ5 frequency was significantly higher in patients than in controls. Analysis of specific antibody isotype profiles revealed that DQ5-positive individuals had increased levels of antifilarial IgG3, an isotype known to be involved in tissue damage. These data suggest that HLA class II genes may control the course of Brugian filariasis by influencing the T-cell-dependent antibody repertoire.

Animals↗
PubMed1995

Elevated cellular immune responses and interferon-gamma release after long-term diethylcarbamazine treatment of patients with human lymphatic filariasis.

Cellular immune responses to filarial antigens were examined in persons before and 1 year after beginning treatment with diethylcarbamazine (DEC). The subjects (17 microfilaremics, 13 asymptomatic amicrofilaremics, and 13 with elephantiasis) had not responded to Brgia malayi adult worm antigen (BmA) before chemotherapy. T cell proliferative responses to BmA improved significantly after therapy in the 3 clinical groups (P < .05) but was highest in the elephantiasis patients and asymptomatic amicrofilareimics. Cytokine release profiles after stimulation with parasite antigen were analyzed. Production of interferon (IFN)-gamma by BmA-stimulated mononuclear cells increased significantly after DEC treatment (geometric mean, 39.6-55.7 U/mL; P < .05), largely due to improved responses in elephantiasis patients and asymptomatic amicrofilaremics. In contrast, BmA-induced interleukin (IL)-4 release did not change significantly in these same patients after treatment. Thus, both microfilaremic and amicrofilaremic infections with B. malayi are associated with similar down-regulation of proliferative T cell function and IFN-gamma release.

Adolescent↗
PubMed1995

Differential decline in filaria-specific IgG1, IgG4, and IgE antibodies in Brugia malayi-infected patients after diethylcarbamazine chemotherapy.

In human filariasis, the predominant serum antibody is IgG4, accompanied by significant IgE production. The ratio of IgG4 to IgE is highest in asymptomatic microfilaremic carriers, while chronic disease is associated with elevated IgG1-3. The changes in isotypes following chemotherapy with diethylcarbamazine (DEC) were studied in 2 groups of Brugia malayi-infected patients from Sumatra and South Kalimantan, Indonesia. Similar results were obtained from each group. IgG4 levels decreased sharply (65%-78%) within 12 months. IgG1 levels declined in a less consistent and extreme manner, and levels of IgG2 and IgG3 declined only in patients with elephantiasis, who also had the highest initial levels of these antibodies. IgE responses were relatively stable to therapy in microfilaremic patients (7%-28% reduction) and showed only moderate decline (56% over 2 years) in elephantiasis patients. Active filarial infection is thus associated with specific IgG4 antibodies, but there is independent expression of the IgE and IgG4 isotypes in filariasis.

Adult↗
PubMed1995

Specific T cell unresponsiveness in human filariasis: diversity in underlying mechanisms.

In an attempt to overcome T cell unresponsiveness to filarial antigens, 65 individuals belonging to the three clinical groups of elephantiasis patients, microfilaraemics, and asymptomatic amicrofilaraemics who exhibited unresponsiveness to Brugia malayi adult worm antigen (BmA) were studied. Peripheral blood mononuclear cells were cocultured with antigen and one of the following reagents that have been reported to be effective in reconstituting T cell proliferation: interleukin-2 (IL-2), interleukin-7 (IL-7), anti-interleukin-4, anti-interleukin-10, anti-CD2, anti-CD27, anti-CD28, indomethacin, phorbol myristate acetate (PMA), or calcium ionophore (A23187). We were able to overcome antigen-specific unresponsiveness in only a minority of the individuals studied. Co-culture with IL-2, IL-7, indomethacin and PMA were the only conditions which resulted in enhanced proliferation to BmA in these individuals. In general, unresponsiveness in elephantiasis patients was easier to reverse than in other clinical groups: in 50% of elephantiasis patients, in 12.5% of microfilaraemics and in 20% of asymptomatic amicrofilaraemics. The results indicate that more than one distinct immunological mechanism may account for the antigen-specific unresponsiveness in individuals exposed to and infected with brugian filariasis.

Animals↗
PubMed1995

Differential antibody isotype reactivity to specific antigens in human lymphatic filariasis: gp15/400 preferentially induces immunoglobulin E (IgE), IgG4, and IgG2.

Lymphatic filarial infection in humans is associated with a strong skewing of the immune response towards the TH2 arm, with prominent interleukin 4-producing cells and elevated levels of immunoglobulin G4 (IgG4) and IgE antibodies in peripheral blood. To determine how such a generalized TH2 imbalance governs responses to individual parasite antigens, the profiles of isotypes of antibodies to two recombinant proteins of Brugia spp. were studied. One molecule was the C-terminal portion of the filarial heat shock protein 70 (Bpa-26), representative of a cytoplasmic protein, and the second antigen was a single unit of the tandem repeats of a Brugia polypeptide (BpL-4), a secreted product which is prominently exposed to the immune system. Serum samples from 146 individuals resident in areas in which brugian filariasis is endemic were used, and it was found that whereas the levels of IgG1 and IgG3 responses to both Bpa-26 and BpL-4 were high, IgG4 and IgE antibodies to only BpL-4, not to Bpa-26, were prominent. Thus, an antigen which is chronically exposed to the immune system elicited a TH2-dependent isotype switch, as manifested by increased IgG4 and IgE responses. Moreover, IgG4 and IgE responses to BpL-4 showed a strong negative association, suggesting that mediators other than interleukin 4 must be responsible for such differential regulation of these two isotypes. When the data were analyzed as a function of clinical status, a striking association between elevated levels of IgG3 antibodies to Bpa-26 and manifestation of chronic obstructive disease was found; elephantiasis patients showed significantly higher levels of IgG3 antibodies to Bpa-26 than microfilaremics and asymptomatic amicrofilaremics. This indicates that an imbalance of isotypes of antibodies to particular filarial antigens might play a role in the pathogenesis of chronic disease.

Adolescent↗
PubMed1993

Differential expression of IgE and IgG4 specific antibody responses in asymptomatic and chronic human filariasis.

A population of 164 adult individuals resident in an area endemic for Brugia malayi lymphatic filariasis has been studied for humoral immune responses to filarial parasites. Antibody levels to Ag extracted from adult worms were determined for each of the IgG subclasses, for IgM and for IgE. The dominant isotype of antifilarial antibody was IgG4, which represented 88% of total IgG in asymptomatic microfilaremics, most of whom possessed 100 to 1000 micrograms/ml of specific antibody of this subclass (geometric mean 762 micrograms/ml). Patients with chronic disease (elephantiasis), who were generally amicrofilaremic, had substantially higher levels of IgG1, IgG2, and IgG3, but a 3.4-fold lower geometric mean level of specific IgG4 (222 micrograms/ml) than asymptomatics with or without microfilaremia. In contrast, specific IgE antibody levels in cases of elephantiasis were on average 4.5 times higher than those found in the asymptomatic carrier state. The majority of microfilaremics were therefore typified by extremely high specific IgG4 concentrations and relatively low IgE reactivities, whereas clinical cases tended to show the reverse relationship. The possible roles of these isotypes and the implications of changing IgG4/IgE balances in disease are discussed.

Adolescent↗