Biomedical subjects

M Yazdanbakhsh

Publications and source records attributed to M Yazdanbakhsh.

At least 37 records · Page 2Linked to original sources

PubMed2000

Chronic schistosomiasis: dendritic cells generated from patients can overcome antigen-specific T cell hyporesponsiveness.

Chronic infection with helminths is associated with down-regulated antigen-specific T cell responses. In order to determine whether schistosome-specific T cells are present, yet functionally unresponsive, or absent in the periphery of chronically infected persons, autologous granulocyte-macrophage colony-stimulating factor and dendritic cells (DC) derived from interleukin (IL)-4 were used as highly efficient antigen-presenting cells (APC). Peripheral blood mononuclear cells (PBMC) from persons harboring Schistosoma haematobium infection and hyporesponsive to parasite antigen were cocultured with autologous DC in the presence of adult worm antigen (AWA). In contrast to PBMC alone, DC-supplemented cultures responded to AWA by proliferation and by IL-4 and IL-5 production and, in some patients, by production of interferon-gamma. Thus, schistosome-specific T helper cells are present in the periphery but are functionally hyporesponsive during active infection with schistosomes. Cytokine responses representing the Th1 and (more importantly) Th2 types can be restored in vitro when DC are used as APC.

Adolescent↗

PubMed2000

Clustering of Brugia malayi infection in a community in South-Sulawesi, Indonesia.

The present study was undertaken in village Karondang in South-Sulawesi, Indonesia, to investigate the influences of genetic, household and environmental factors on Brugia malayi infection. Infection status was determined by measuring both microfilariae in night blood and anti-filarial IgG4, as a marker for detection of active filarial infection. A total of 171 residents participated in the study; familial relationships between subjects were registered to construct pedigrees and distances between households were measured. The data were analysed using a test statistic for familial aggregation. For distribution of microfilariae over the study population a genetic influence on infection susceptibility was favoured over the household and environmental effects. For anti-filarial IgG4, all 3 clustering models gave significant results, suggesting that genetic, household and/or environmental factors influence specific IgG4 antibodies.

Adolescent↗

PubMed2000

The development of specific IgG4 and IgE in a paediatric population is influenced by filarial endemicity and gender.

We set out to study how anti-filarial IgG4 and IgE, which have been studied extensively in adult populations, are influenced by gender and by the degree of filarial endemicity during childhood. Development of specific IgG4 and IgE was examined in 502 children aged 3 months to 12 years, who were resident in 3 villages in South-Sulawesi with microfilaria prevalences of 6, 23 and 42 %. Specific IgG4 and IgE could be detected as early as 18 months after birth, in low amounts, and increased to levels comparable to those produced by adults at the age of 3 years. A higher prevalence of anti-filarial IgG4 in boys, indicating higher filarial infection compared to girls, became apparent after the age of 7. The specific IgG4 response was strongly influenced by the degree of filarial endemicity and production of this antibody was considerably delayed in the low transmission village. With respect to IgE, it was noted that specific IgE was consistently higher in boys from infancy onwards indicating a predisposition for high IgE production in males. The influence of filarial endemicity was less profound on IgE thaon on IgG4. In conclusion, reactivity to filarial antigens begins early in life and is differentially influenced by gender and transmission intensity.

Age Factors↗

PubMed1999

A novel serpin expressed by blood-borne microfilariae of the parasitic nematode Brugia malayi inhibits human neutrophil serine proteinases.

Serine proteinase inhibitors (serpins) play a vital regulatory role in a wide range of biological processes, and serpins from viruses have been implicated in pathogen evasion of the host defence system. For the first time, we report a functional serpin gene from nematodes that may function in this manner. This gene, named Bm-spn-2, has been isolated from the filarial nematode Brugia malayi, a causative agent of human lymphatic filariasis. Polymerase chain reaction (PCR) and Western blot experiments indicate that Bm-spn-2 is expressed only by microfilariae (Mf), which are the long-lived blood-dwelling larval stage. A survey of the greater than 14,000 expressed sequence tags (ESTs) from B malayi deposited in dbEST shows that greater than 2% of the ESTs sequenced from Mf cDNA libraries correspond to Bm-spn-2. Despite its abundance in the microfilarial stage, Bm-spn-2 has not been found in any other point in the life cycle. The predicted protein encoded by Bm-spn-2 contains 428 amino acids with a putative signal peptide. Antibodies to recombinant Bm-SPN-2 protein react specifically with a 47.5-kD native protein in Mf extract. Bm-SPN-2 is one of the largest of the 93 known serpins, due to a 22 amino acid carboxy-terminal extension, and contains the conserved serpin signature sequence. Outside these regions, levels of homology are low, and only a distant relationship can been seen to a Caenorhabditis elegans serpin. The Bm-spn-2 gene contains 6 introns, 2 of which appear to be shared by both nematode species. The B malayi introns have an extended and conserved 3' splice site and are relatively large compared with C elegans. A panel of mammalian serine proteinases were screened and Bm-SPN-2 protein was found to specifically inhibit enzymatic activity of human neutrophil cathepsin G and human neutrophil elastase, but not a range of other serine proteinases. It is possible that Bm-SPN-2 could function as a stage-specific serpin in the blood environment of the microfilarial parasite in protection from human immunity and thus may be a good candidate for protective vaccine.

Amino Acid Sequence↗

PubMed1999

T1/ST2 expression is enhanced on CD4+ T cells from schistosome egg-induced granulomas: analysis of Th cell cytokine coexpression ex vivo.

Th cells are categorized into subsets based on the cytokine production of in vitro-differentiated Th populations. For in vivo-differentiated Th subsets, little is known about the heterogeneity of cytokine production in single cells. We recently described a molecule, T1/ST2, that is preferentially expressed on the surface of Th2 cells. Here we combined high-gradient magnetic cell separation with four-color single-cell cytometry to analyze simultaneously three intracellular cytokines and T1/ST2 surface expression on CD4+ cells from lungs containing granulomas induced by Schistosoma mansoni eggs. T1/ST2 was highly up-regulated on CD4+ T cells from hepatic granulomas and granulomatous lungs. T1/ST2+ cells from granulomatous lungs preferentially produced type 2 cytokines ex vivo. In the total CD4+ population, coexpression of type 1 and type 2 cytokines occurred frequently. However, such coproduction was drastically reduced in T1/ST2+ cells compared with T1/ST2- cells. Coexpression of type 1 and type 2 cytokines was also rare in cells simultaneously producing two cytokines of one type. These findings indicate that individual CD4+ T cells in vivo have different levels of commitment to a certain Th phenotype. Coexpression of two type 2 cytokines or production of one type 2 cytokine together with surface expression of T1/ST2 indicate advanced commitment to the Th2 phenotype.

Animals↗

PubMed1999

Common features of T cell reactivity in persistent helminth infections: lymphatic filariasis and schistosomiasis.

This review highlights striking similarities in the down-regulated inflammatory responses that are observed in chronic infectious diseases. It is clear that peripheral mononuclear cells show poor antigen-specific T cell proliferation in lymphatic filariasis as well as schistosomiasis. With respect to cytokines both Th1- and Th2-type products are down-regulated during chronic infection. Drug treatment restores responsiveness in both diseases indicating a link between infection and immune suppression. Interestingly, immunological responses in subjects carrying recent infections are characterized by strong proliferation to parasite antigen and IFN-gamma production. These heightened responses are gradually down-regulated with increased length of exposure to infection.

Animals↗

PubMed1999

Reversal in microfilarial density and T cell responses in human lymphatic filariasis.

This study reports reversals in microfilarial density and the accompanying changes in cellular immune responses to filarial antigens of 39 individuals (11 microfilaria-positives, 22 microfilaria-negatives and six converters) living in an area endemic for brugian filariasis. Microfilarial counts decreased from April, the end of the rainy season to July, middle of the dry season (g.m. 88 mf/ml and 38 mf/ml, respectively; P = 0.001) and subsequently increased in November, the beginning of the rainy season (P = 0.088). Whereas the proliferative responses remained low throughout the study period in microfilaraemic individuals, in amicrofilaraemics these responses changed in the opposite direction to that of microfilarial densities. In three converters, proliferation changed in the opposite direction to the presence or absence of microfilariae. Cytokine analysis in the converters revealed that interferon-gamma was most affected by the shifts in microfilarial densities. In contrast, interleukin-4 responses showed little correlation with changes in parasite densities.

Adolescent↗

PubMed1999

Anti-filarial IgG4 in men and women living in Brugia malayi-endemic areas.

To assess whether antifilarial IgG4 can be used to study various epidemiological facets of filarial infections, we studied this isotype in 238 individuals resident in areas endemic for brugian filariasis, focusing on the differences between men and women. In the study area, the prevalence of microfilariae was 6.7% and the prevalence of antifilarial IgG4 was 49.2%. All microfilariae carriers were positive for antifilarial IgG4, whereas a proportion of the endemic normals (94/208) and clephantiasis patients (7/14) had IgG4 antibodies to filarial antigens. Data were analysed as a function of gender in distinct clinical groups and stratified for age. The prevalence of microfilariae was higher in males in all age groups, as reflected in significantly higher antifilarial IgG4 antibody levels compared to females. The prevalence of IgG4 increased to reach a plateau at the age of 30 years in both males and females. These results indicate that antifilarial IgG4 antibodies can reflect the differences in the extent of infection in males and females as measured by microfilarial counts, and that this parameter can be used for epidemiological assessments of filarial infection.

Adolescent↗

PubMed1999

Vaccination against helminth parasites--the ultimate challenge for vaccinologists?

Helminths are multicellular pathogens which infect vast numbers of human and animal hosts, causing widespread chronic disease and morbidity. Vaccination against these parasites requires more than identification of effective target antigens, because without understanding the immunology of the host-parasite relationship, ineffective immune mechanisms may be invoked, and there is a danger of amplifying immunopathogenic responses. The fundamental features of the immune response to helminths are therefore summarised in the context of vaccines to helminth parasites. The contention between type-1 and type-2 responses is a central issue in helminth infections, which bias the immune system strongly to the type-2 pathway. Evidence from both human and experimental animal infections indicates that both lineages contribute to immunity in differing circumstances, and that a balanced response leads to the most favourable outcome. A diversity of immune mechanisms can be brought to bear on various helminth species, ranging from antibody-independent macrophages, antibody-dependent granulocyte killing, and nonlymphoid actions, particularly in the gut. This diversity is highlighted by analysis of rodent infections, particularly in comparisons of cytokine-depleted and gene-targeted animals. This knowledge of protective mechanisms needs to be combined with a careful choice of parasite antigens for vaccines. Many existing candidates have been selected with host antibodies, rather than T-cell responses, and include a preponderance of highly conserved proteins with similarities to mammalian or invertebrate antigens. Advantage has yet to be taken of parasite genome projects, or of directed searches for novel, parasite-specific antigens and targets expressed only by infective stages and not mature forms which may generate immunopathology. With advances under way in parasite genomics and new vaccine delivery systems offering more rapid assessment and development, there are now excellent opportunities for new antihelminth vaccines.

Animals↗

PubMed1999

Recognition of schistosome glycolipids by immunoglobulin E: possible role in immunity.

To investigate the role of antibody responses to (glyco)lipids in immunity to schistosome infection, lipids extracted from Schistosoma mansoni eggs and adult worms were fractionated, and the antibody isotype profile reactive to the fractionated lipids in a well-characterized S. haematobium-infected population was investigated. In tests of 10 plasma samples it was found that immunoglobulin G (IgG) reactivity was highest to the fraction containing ceramidepolyhexosides, whereas IgE reactivity was most prominent to both cerebroside- and ceramidepolyhexoside-containing fractions. The fraction containing ceramidepolyhexosides was then tested for reactivity with IgG subclasses and IgE in plasma samples from 66 S. haematobium-infected patients. Considering IgG4 and IgE, isotypes of particular interest in helminth infections, we found that both isotypes recognized egg (glyco)proteins in more than 90% of the infected subjects. However, in the case of glycolipids, IgE reactivity was much more prominent than IgG4 reactivity (found in 80 and 41% of the subjects, respectively). Furthermore, worm glycolipid-specific IgE prior to treatment of the subjects with praziquantel was negatively correlated with egg counts at 2 years posttreatment, indicating that IgE directed towards glycolipids could play an important role in resistance to reinfection.

Adolescent↗

PubMed1998

Antigen-stimulated IL-4, IL-13 and IFN-gamma production by human T cells at a single-cell level.

To understand the intricate balance and the coordinate expression of the Th1 and Th2 cytokines following a natural mode of T cell triggering, antigen-stimulated IL-4, IL-13 and IFN-gamma production was studied in primary peripheral blood mononuclear cell cultures at a single-cell level. Cells from filariasis patients who respond to parasite antigen by producing not only IFN-gamma but also IL-4 and IL-13 were stimulated with Brugia malayi adult worm antigen and analyzed for co-expression of cytokines by intracellular staining. IL-4 and IL-13 were frequently co-expressed (54% of IL-4+ cells stained for IL-13 and 29% of IL-13+ cells expressed IL-4 at all time points), whereas IFN-gamma expression was totally segregated from both IL-4 and IL-13. These data indicate that in human peripheral T cells the co-expression of the dominant Th1 and Th2 cytokines within a single cell is a rare event and that IL-13 is clearly more frequently associated with a Th2 than a Th1 type response in primary T cell cultures.

Animals↗

PubMed1998

In vitro production of IgG4 by peripheral blood mononuclear cells (PBMC): the contribution of committed B cells.

IgG4 and IgE isotypes contribute marginally to the pool of circulating antibodies in healthy individuals, but are elevated during atopic diseases and particularly upon helminth infections. To examine whether the high levels of these isotypes in circulation are reflected in a higher capacity of PBMC to produce IgG4 and IgE, we examined cells from patients infected with filarial nematodes that exhibit high levels of IgG4 and IgE. Indeed, IgG4 production by PBMC correlated strongly with plasma levels of IgG4 (r=0.534, P=0.002), but such correlation was not found for IgE. The replacement of CD19+ cells from PBMC by IgD+ cells abrogated the high capacity of PBMC to make IgG4. This indicates that an altered B cell compartment accounts for the high IgG4-producing capacity of the PBMC. The high production of IgG4 in vitro was not dependent on IL-4 and IL-13, as neutralizing antibodies to these cytokines did not inhibit IgG4. However, IgE release by PBMC was dependent on IL-4 and IL-13. Antifilarial IgG4 was detected in culture supernatants from filarial patients and its production was independent of IL-4 and IL-13. These results demonstrate that in individuals with elevated IgG4. the B cell compartment in PBMC carries cells that are already committed to IgG4 production and are independent of IL-4 and IL-13.

Adult↗

PubMed1998

The effect of anti-IL-10 on proliferation and cytokine production in human schistosomiasis: fresh versus cryopreserved cells.

In this study we neutralized endogenous IL-10 in PBMC from individuals chronically infected with Schistosoma haematobium by using anti-IL-10 MoAbs, and examined the effect and adult worm antigen (AWA)-specific responses in both fresh or cryopreserved cells. Anti-IL-10 alone increased background proliferation of PBMC, but did not augment the AWA-specific responses in either fresh or frozen cells. In freshly isolated PBMC, IFN-gamma production in response to AWA was enhanced significantly in the presence of anti-IL-10. In cryopreserved cells, the augmentation of IFN-gamma in the presence of anti-IL-10 was four-fold less than in the freshly-isolated cells. Neutralization of IL-10 had no effect on IL-4 production. These data show that IL-10 plays a role in specifically down-regulating Th1-but not Th2-type responses and, in contrast to previous reports, anti-IL-10 does not augment proliferation to parasite antigen in chronic schistosomiasis.

Animals↗

PubMed1998

Antibody responses to filarial infective larvae are not dominated by the IgG4 isotype.

The humoral immune response in humans to filarial parasites is generally dominated by the IgG4 isotype, when measured by ELISA against somatic adult worm extract. In contrast, as we report here, antibodies reactive to somatic extracts of infective larvae are more equally represented by IgG1 and IgG4. Moreover, binding to surface exposed epitopes in immunofluorescence on larval stages is mediated foremost by IgG1 and IgM, secondarily by IgG2 and IgG3, and very little by IgG4. Both anti-L3 surface and somatic antibodies are strongest in elephantiasis patients, and tend to increase with age. Antibody to the L3 surface is also present in most microfilaraemic individuals who bear no detectable antibodies to the surface of the microfilarial stage. These results demonstrate that a stage- and isotype-specific response is mounted to the L3 surface which should be considered as a possible mediator of concomitant immunity in filariasis.

Age Factors↗

PubMed1998

Antigen-specific proliferation and interferon-gamma and interleukin-5 production are down-regulated during Schistosoma haematobium infection.

Antigen-specific cellular immune responses were examined in persons previously infected with Schistosoma haematobium and who were, 2 years after chemotherapy, either free from infection (n = 17) or reinfected (n = 20). Proliferation to adult worm antigen (AWA) was significantly higher in uninfected than in reinfected subjects (P = .02), whereas responses to soluble egg antigen (SEA) remained low in both groups. Interleukin (IL)-5 production in uninfected persons in response to AWA and SEA was higher than in infected subjects (P = .05 and P < .001, respectively), while IL-4 and IL-13 release was similar in the 2 groups. Levels of interferon-gamma to AWA and to SEA were inversely correlated with egg output (P = .03 and P = .02, respectively). These data indicate that the presence of schistosome infection leads to T cell proliferative hyporesponsiveness and that both typical Th1 and Th2 cytokines can be down-regulated by active infection.

Adolescent↗

PubMed1998

Advances in schistosomiasis research.

This review reports on recent developments in the areas of diagnosis, chemotherapy and pathology, where female genital schistosomiasis was recently identified as a common cause of morbidity in Schistosoma haematobium-endemic areas. As a profound understanding of processes underlying resistance and susceptibility to infection as well as pathology is central to schistosomiasis control, detailed immunological studies of immunity and granuloma formation dominate the discussion. Studies on host genetics, on T-helper cell type 1 or 2 cytokines as well as on cell types influencing immunity and granuloma formation have provided precise information that could be of relevance not only to helminth but also to microbial infections involving granulomatous reactions.

Journal Article↗

PubMed1998

Specificity of predominant IgG4 antibodies to adult and microfilarial stages of Brugia malayi.

Human infections with filarial nematodes such as Brugia malayi are accompanied by unusually high titres of parasite-specific IgG4 antibodies. We have compared the profile of antigens recognised by filarial-specific IgG1 and IgG4 isotypes by Western blotting. Serum samples were collected from 120 subjects exposed to Brugia malayi, divided into three groups of asymptomatic amicrofilaraemic (endemic normal), microfilaraemic, and elephantiasis patients. Antigen preparations were tested from both adult B. malayi parasites, and from microfilariae; 24 distinct bands were analysed from the former, and 19 from the latter. Both qualitative scoring for band reactivity, and densitometric scanning of major bands, were employed. The consistent result was one of high and preferential IgG4 reactivity to a set of low molecular weight bands, of 15, 17, 20, 31 and 33 kDa; most of the 19 other bands showed higher reactivity with IgG4. Analysis of Western blot patterns showed an overall tendency for stronger IgG4 responses in microfilaraemic cases, and higher IgG1 responses in elephantiasis patients, consistent with published studies using ELISA on unfractionated parasite extracts. This study has defined an array of filarial antigens from each stage, and relative levels of IgG4 recognition, which will be important in unravelling distinct immune responses to this complex parasite.

Animals↗

PubMed1997

HLA and elephantiasis revisited.

A recent case-control study in Indonesia suggested that the course of Brugian filariasis and in particular resistance to the development of elephantiasis was associated with certain HLA class II alleles. In order to see whether these data could be confirmed we conducted a similar study in another Indonesian population from South Sulawesi. We could not confirm our earlier results and therefore concluded that HLA-DR and -DQ alleles are at least not strongly associated with progression to elephantiasis in Brugian filariasis. The complete data are presented also for anthropological reference purposes.

Alleles↗