Biomedical subjects

M Troye-Blomberg

Publications and source records attributed to M Troye-Blomberg.

At least 55 records · Page 3Linked to original sources

PubMed1999

Immune regulation of protection and pathogenesis in Plasmodium falciparum malaria.

The immune mechanisms whereby malaria parasites are eliminated by the human host or how they may avoid the immune response are poorly understood. Individuals living in malaria-endemic areas gradually acquire immunity. It is well established that this immunity involves both cell-mediated and humoral mechanisms and that T cells are the major regulators in both these events. The existence of functionally distinct P. falciparum-specific CD4+ T-cell subsets in humans has been shown in several studies. However, in contrast to what is the case in murine models there is no definitive link between the activation of various T cells and the course of human P. falciparum blood-stage infection. In the present paper we will review recent findings which illustrate how the balance between functionally different T-cell subsets affects the development of malaria immunity but also may contribute to its pathogenicity. An example of the latter is the deposition of IgE-containing immune complexes in small vessels, probably leading to local overproduction of tumor-necrosis factor (TNF), a pathogenic factor in malaria.

Animals↗

PubMed1998

Expansion of IL-3-responsive IL-4-producing non-B non-T cells correlates with anemia and IL-3 production in mice infected with blood-stage Plasmodium chabaudi malaria.

A prominent switch of CD4+ T cells from Th1 to Th2 type response occurs in mice infected with the non-lethal malaria parasite Plasmodium chabaudi chabaudi AS around the time of peak parasitemia. This is reflected by a decrease in IFN-gamma- and an increase in IL-4-producing cells. The peak occurs approximately 9-10 days after infection and is accompanied by anemia. The mechanism behind the switch in Th cell response is poorly understood. We here report on the production of IL-4 from a non-T cell source during P. chabaudi infection in BALB/c mice. Flow cytometric analysis of spleen and peripheral blood leukocytes (PBL) showed a dramatic increase in the percentage of non-B non-T (NBNT) cells 9-23 days after P. chabaudi infection with peak values by day 15 (approximately 30 % of splenocytes and approximately 55 % of PBL being NBNT cells). The expansion of NBNT cells correlated closely with the appearance of a cell type secreting IL-4 and IL-6 following stimulation with IL-3 and/or cross-linking of FcgammaR. Compared to cells from uninfected animals, NBNT cells from P. chabaudi-infected mice were shown to be hyper-responsive to IL-3. The levels of the hematopoietic cytokine IL-3 were elevated in supernatants from unstimulated spleen cell cultures as well as in serum at the same time points at which NBNT cell-derived IL-4 and IL-6 were detected from spleen cultures and PBL. Thus, IL-3-responsive IL-4-producing NBNT cells may provide cytokines supporting the switch from Th1 to a Th2 response which is important for the final clearance of the parasite in P. chabaudi malaria.

Anemia↗

PubMed1998

Abnormal T cell receptor V gene usage in myasthenia gravis: prevalence and characterization of expanded T cell populations.

The usage of T cell receptor (TCR) Valpha/Vbeta chains on cells from 38 patients with myasthenia gravis (MG) was determined by flow cytometry. There was a decreased number of cells expressing Vbeta2 in CD8+ and Vbeta3 in CD4+ cells in patients compared with healthy individuals. Abnormal expansions of T cells using particular TCR Valpha/Vbeta gene products were found in 18/38 patients. A significantly higher usage of Vbeta13 was observed but there was no restriction with regard to other TCR Valpha/Vbeta. Expanded cells belonging to both CD4+ and CD8+ were present in MG patients while restricted to the CD8+ population in healthy individuals. To elucidate the role of the expanded populations, we studied characteristics of the expanded and non-expanded T cells from MG patients who had persistent T cell expansions over more than 2 years. The cells were analysed with regard to phenotype, cytokine secretion, cytokine mRNA expression and reactivity with the autoantigen, the acetylcholine receptor. The characteristics of the expanded populations in MG clearly differed from those found in healthy individuals. More cells in the CD4+ expanded populations expressed HLA-DR and there was also a tendency for higher expression of CD25, CD28 and CD57. The number of cells spontaneously secreting cytokines was higher in the expanded populations. A dominant Th1-type cytokine secretion and mRNA expression was noted. Autoantigen-reactive CD4+ T cells were largely restricted to the expanded populations.

Adult↗

PubMed1998

Increased frequencies of allergen-induced interleukin-13-producing cells in atopic individuals during the pollen season.

We have reported previously that allergen-specific serum IgE levels were correlated with allergen-induced interleukin (IL)-4 in type I allergic individuals. Here, we wanted to investigate whether IL-13, another switch factor for IgE, was induced by allergen in vitro and if so, whether this was correlated with the elevated serum IgE-levels seen in atopic individuals, and whether the cytokine profile changed during pollen season. Peripheral blood mononuclear cells from 14 atopic and 14 healthy individuals collected out of the pollen season were incubated in vitro with allergens (birch or timothy) and the number of IL-4, IL-13, IL-10 and IFN-gamma producing cells was determined by ELISPOT. In response to the specific allergen, IL-13-producing cells were seen in allergic but not in healthy individuals. The number of IL-13-producing cells was significantly correlated with the allergen-specific serum IgE levels. When the allergic individuals were tested during the pollen season, the number of allergen-specific IL-4- and IL-13-producing cells, as well as serum levels of specific IgE, increased. The IL-13 increase seen in ELISPOT was confirmed by a RT-PCR assay. No seasonal changes were seen in response to purified protein derivative (PPD) or the mitogen PHA. During the pollen season, the IL-4 and IL-13 responses were highly correlated. Taken together, our results support the roles of both IL-13 and IL-4 in the regulation of allergen-specific IgE levels in atopic individuals.

Aged↗

PubMed1998

Altered immune responses in mice with concomitant Schistosoma mansoni and Plasmodium chabaudi infections.

Mixed parasitic infections are common in many parts of the world. However, little is known about how concurrent infections affect the immunity to and/or pathogenesis of each other. Protection and elimination of blood-stage Plasmodium chabaudi chabaudi AS in resistant mice are characterized by a sequential activation of CD4(+) Th1 and Th2 cells. The patent egg-laying stage of the murine model of Schistosoma mansoni is associated with a strong Th2 response to both Schistosoma and unrelated antigens. In this study, we investigated how infection of mice with S. mansoni would affect the immune response to and pathogenesis of a P. chabaudi infection. C57BL/6 mice infected with S. mansoni for 8 weeks were infected with blood-stage P. chabaudi. Malaria parasitemias were significantly higher in these mice than in mice infected with P. chabaudi only. In doubly infected mice, both spleen cell proliferative and Th2 responses to S. mansoni soluble egg antigen (SEA) or anti-CD3 were suppressed up to 1 month after the malaria infection. Findings for SEA-specific immunoglobulin M (IgM) and IgG serum antibody levels were similar. No significant effects were seen on P. chabaudi-induced gamma interferon responses. However, tumor necrosis factor alpha (TNF-alpha) production was significantly lower in double-infected mice. Thus, a defect in TNF-alpha production might contribute to the increased malaria parasitemias seen in S. mansoni-P. chabaudi-infected mice. Taken together, our data show that schistosoma and malaria infections profoundly affect each other, findings which might have implications for the development of vaccines.

Animals↗

PubMed1998

Selected problems of malaria blood stage immunity.

Both antibody dependent and cell mediated mechanisms contribute to immunity in malaria. The parasites vary in sensitivity to antibody mediated inhibition due to underlying antigenic variation. When Plasmodium falciparum isolates are tested with antibodies from the donor originally harbouring the parasites or with those from other donors, growth inhibition is usually lowest in the autologous combinations. Parasites with decreased sensitivity are also generated in vitro by culturing them for prolonged periods in the presence of certain anti-plasmodial antibodies. When the antibodies are removed, a successive return of sensitivity develops. The decrease in sensitivity to inhibition may either be due to down-regulation of synthesis of the antigen or a selection of parasites with low antigen expression from the heterogeneous original populations. Both T lymphocytes carrying alpha/beta and gamma/delta antigen-receptors play a role in malaria immunity. However, although gamma/delta T cells may expand 40-fold or more in the peripheral immune system in acutely infected humans and also inhibit parasite growth in vitro and in vivo, their relative importance for protection or pathogenicity is presently unclear. Of the two major T cell subsets (CD4+, CD8+) carrying alpha/beta T cell receptors, the role of CD8+ T cells in blood stage infections appears to be limited. Instead, CD4+ T cells are of major importance. These cells comprise at least two functionally different subsets (Th1, Th2), distinguished on the basis of lymphokine secretion. In some rodent malaria models, Th1 cells producing primarily IL2 and IFN gamma give rise to protection in early infection while Th2 cells producing IL4 are essential for parasite clearance in late infection. In other mouse strains, the same parasites induce a strong Th2 response in early infection, resulting in a lethal course. CD4+ T cells of either Th1 or Th2 type also have regulatory functions in human P. falciparum malaria. Most humans living in areas of high endemicity have significantly elevated blood levels of IgE, reflecting a skewing of the underlying T helper cell ratio in favour of Th2, responsible for the switch in immunoglobulin isotypes. Less than 5% of the IgE in malaria represents antibodies to P. falciparum. IgE elevation is highest in patients with severe and particularly cerebral malaria and is frequently associated with an elevation of tumour necrosis factor alpha (TNF). The release of this cytokine from monocytes/macrophages may reflect crosslinking of their low affinity receptors for IgE (CD23) by IgE containing immune complexes from malarial sera. Local overproduction of TNF is considered a major pathogenic mechanism, responsible for fever and tissue lesions in severe malaria. Although TNF overproduction in malaria is generally assumed to be due to direct stimulation of effector cells by certain parasite derived toxins, the present results suggest that IgE elevation constitutes yet another mechanism contributing to the pathogenicity of P. falciparum in human malaria.

Animals↗

PubMed1997

T- and B-cell responses of malaria immune individuals to synthetic peptides corresponding to non-repeat sequences in the N-terminal region of the Plasmodium falciparum antigen Pf155/RESA.

While the C-terminal repeat region of Pf155/RESA, a Plasmodium falciparum vaccine candidate has been extensively studied for B- and T-cell reactivities, little is so far known about the non-repeat region in this respect. The present study aimed at investigating the non-repeat sequence 171-227 of Pf155/RESA for T- and B-cell epitopes. Eight overlapping peptides were synthesised and assayed for their ability to stimulate peripheral blood mononuclear cells obtained from P. falciparum-immune donors to proliferate and to induce secretion of interferon-gamma (IFN-gamma) and/or interleukin 4 (IL-4) using the ELISPOT assay. The plasmas of the corresponding donors were tested for antibody reactivity with the same peptides in ELISA. The individual cellular responses to the different peptides varied and in general they were not correlated, emphasising the importance of including several parameters for T-cell activation. The most frequent T-cell responses (proliferation, IFN-gamma and/or IL-4) were seen with two partially overlapping peptides corresponding to the sequences 171-185 and 181-195 that induced responses in 71 and 62% of the donors, respectively. Although, the frequency of responders was high, the magnitude of the responses was generally low. Two overlapping peptides corresponding to the sequence 186-206 bound antibodies from a large number of plasma samples. IL-4 producing cells were frequently found in donors whose sera contained antibodies to the corresponding peptide. However, there was no absolute correlation and many donors having anti-peptide antibodies could also be induced to produce IFN-gamma. In conclusion, the non-repeat region of Pf155/RESA contains several epitopes inducing functionally distinct T-cell responses. The sequence 171-206 was found to contain both B- and T-cell epitopes recognised by almost all individuals naturally primed to malaria. Thus, this sequence should be a useful tool in future immuno-epidemiological studies and/or for inclusion into a subunit vaccine against the asexual blood stages of the P. falciparum parasite.

Adolescent↗

PubMed1997

Allergen induced cytokine profiles in type I allergic individuals before and after immunotherapy.

Allergen immunotherapy (IT) involves subcutaneous injections of increasing doses of specific allergen over a period of time. It is recognised as highly effective in the treatment of patients with allergic rhinitis. However, the specific immunological mechanisms by which IT achieves its effect have not been fully elucidated. Recent studies, have shown that the clinical effects following IT of allergic individuals is concomitant with a reduced production of IL-4 by allergen specific CD4+ T-cells. The aim of the present study was to gain better knowledge about the immunological mechanisms by which IT exerts its beneficial effects. For this purpose, peripheral blood mononuclear cells (PBMC) from ten individuals receiving birch allergen or placebo in an IT-study performed in a double-blind manner, were analysed for IL-4, IFN-gamma, IL-5 and IL-10 mRNA expression at the onset of the study and during the pollen season, during treatment. Both spontaneous and in vitro allergen-induced cytokine mRNA expression was analysed using reverse transcriptase-polymerase chain reaction (RT-PCR). Spontaneous expression of IL-4 mRNA could be detected in most of the allergic patients, but not in healthy donors. The IT-treated patients showed a decrease in the spontaneous expression of IL-4 mRNA during the pollen season as compared to at the onset of the study, while in patients receiving placebo the IL-4 mRNA expression increased or remained unchanged. Similar results were obtained after in vitro stimulation with allergen. This was in contrast to the results for IFN-gamma, which was readily detected in both patient groups with no significant differences between the groups at either timepoint. IL-5 was shown to be increased during the pollen season in both groups and thereby presumably not affected by allergen IT. Taken together, these observations suggest that the cytokine profiles in circulating T lymphocytes change as a consequence of allergen IT.

Allergens↗

PubMed1997

A malariometric survey in a rural community in the Muheza district, Tanzania: age profiles in the development of humoral immune responses.

A malariometric survey was carried out in a rural community situated in a malaria holoendemic endemic area of Tanzania. A random sample (n = 228) of different age groups was taken to elucidate the association between anti-Pf155/RESA and anti-Pf332 antibody responses and classical malaria indices. Parasitaemia, fever, splenomegaly, haematocrit and antimalarial consumption were assessed. Antibody responses against Pf155/RESA and Pf332 peptides were determined by ELISA. The age profiles of parasite density, splenomegaly, fever, haematocrit values and prevalence of antibody responses indicated intensive malaria exposure and the highest impact of malaria in small children. Forty-five percent of the study population had detectable chloroquine and desethyl-chloroquine blood levels, and the highest frequency and concentrations were recorded in the 12-23 months old. There was no significant association between the presence of drug and parasite density in the different age groups, although in the < 15 years old there was lower parasite prevalence among the children positive for drug in their blood (P < 0.05). High prevalence of antibody responses to all antigens was observed already at an early age, but the mean anti-Pf155/RESA and anti-Pf332 antibody levels increased significantly only in the adult group (P < 0.01). Significantly lower mean parasite densities were observed in high responders to Pf155/RESA and Pf332 peptides for the > or = 10 years old. For the 1-9 years, a similar difference was only observed in the high responders to Pf332. For the whole material, anti-Pf155/RESA and anti-Pf332 antibody levels correlated positively with age. When the effect of age was allowed for in analysing the relationship between parasite density and antibody level against the different antigens, a significant negative correlation was found only with regard to Pf332 in the > = 10 years age group. These results suggest that anti-Pf332 antibodies appear to be a better indicator for antiparasitic immunity, but both antigens are important for immune protection.

Adolescent↗

PubMed1997

Specific induction of interleukin-4-producing cells in response to in vitro allergen stimulation in atopic individuals.

BACKGROUND AND OBJECTIVE: CD4+ T cells can be divided into two major subsets, T helper (TH)1 and TH2 cells. Interleukin-4 (IL-4) is produced by TH2 cells and induces switching of immunoglobulin (Ig) M/IgG to IgE. Interferon-gamma (IFNgamma) produced by TH1 cells counteracts the IgE-promoting effects of IL-4. In this study we wanted to investigate whether the number of IL-4-producing cells could be a direct measurement of allergen exposure in vitro, and whether this was correlated to the elevated serum IgE-levels seen in atopic persons. METHODS: We compared the number of IL-4- and IFNgamma-producing cells using an enzyme-linked immunospot assay (ELISPOT) in response to allergens from birch and cat in peripheral mononuclear cells from atopic and healthy individuals. RESULTS: In the two sensitized groups there was an increase in the number of IL-4-producing cells in response to the specific allergen which was not seen in the healthy group (1/20000 cells and 1/200000 cells, respectively, P < 0.001 for birch). In criss-cross experiments where birch-sensitized individuals were stimulated with cat allergen, no IL-4-producing cells were seen, indicating a high degree of specificity. In individual subjects, the elevated numbers of IL-4-producing cells were significantly correlated with their allergen-specific serum IgE levels. When allergen was combined with a suboptimal dose of PHA, there was a synergistic increase in the number of allergen-induced IL-4-producing cells (1/4000 cells) in the atopic donors, which was not seen with the number of IFNgamma-producing cells. CONCLUSIONS: Allergen-specific IL-4 producing cells in a peripheral blood mononuclear cell (PBMC) culture can be detected by ELISPOT and the response can synergistically be enhanced by suboptimal concentrations of PHA.

Adult↗

PubMed1997

Elevated plasma levels of IgE in Plasmodium falciparum-primed individuals reflect an increased ratio of IL-4 to interferon-gamma (IFN-gamma)-producing cells.

People living in Plasmodium falciparum-endemic areas frequently have elevated levels of total as well as P. falciparum-specific serum IgE. This study aimed at investigating whether the elevated serum IgE levels reflect a shift in the balance between CD4+ T helper 1 (Th1) and T helper 2 (Th2) cells in individuals naturally exposed to the P. falciparum parasite. To investigate the role of Th1 and Th2 cells in the human P. falciparum system we used the ELISPOT assay to determine the ratio of IFN-gamma- and IL-4-producing cells after specific antigen or mitogen activation in vitro. The donors were individuals who had acquired immunity through natural exposure to the parasite. In response to the specific malaria antigens, very few IL-4-producing cells were seen. However, in the response of individual donors to the polyclonal T cell activator, leucoagglutinin (La), the anti-malarial IgE levels in plasma were correlated with an increased ratio of IL-4/IFN-gamma producing cells. Thus, donors with ratios of IL-4/IFN-gamma > 1 exhibited mean plasma anti-malarial IgE levels significantly greater than those with ratios < 1. In individuals not living in P. falciparum-endemic areas the ratio of IL-4/IFN-gamma was always < 1. Taken together, our data suggest a shift in the balance between Th1 and Th2 cells in naturally P. falciparum-primed individuals, associated with elevated anti-P. falciparum plasma IgE levels. The role and biological significance of IgE (Th2-type immune response) for protection against P. falciparum and/or pathogenesis of malaria require further study.

Adolescent↗

PubMed1997

Lymphocyte activation and subset redistribution in the peripheral blood in acute malaria illness: distinct gammadelta+ T cell patterns in Plasmodium falciparum and P. vivax infections.

Lymphocyte subset distributions and activation in the peripheral blood were studied in 39 patients with acute malaria and 16 healthy controls from Addis Ababa and Nazareth, Ethiopia. As confirmed by polymerase chain reaction (PCR), 15 patients were infected with Plasmodium falciparum (Pf), 17 with P. vivax (Pv) and seven were double-infected (Di) with both Pf and Pv. Three-colour flow cytometry was used for phenotyping. Total leucocyte and lymphocyte counts were lower in malaria patients than in controls. The T cell count was reduced in Pf patients, while in the Pv and Di patients there was a reduction in the natural killer (NK) cell count. The CD4/CD8 ratio remained unchanged. gammadelta+ T cells were significantly elevated in Pf and Di patients, but not in Pv patients. The increase in gammadelta+ T cells was mostly due to an increase in Vdelta1+ cells. Analyses of cellular activation indicated by the expressions of CD25 and HLA-DR revealed significantly higher numbers of activated CD3+ cells, including gammadelta+ T cells, in all patient groups compared with controls. Our results thus indicate that in acute malaria illness there is a complex pattern of change in lymphocyte subset distribution and activation, including gammadelta+ T cells. These patterns in Pf infection seem to be distinct from those in Pv infection.

Acute Disease↗

PubMed1997

Analysis of the T-cell receptor V beta usage in monozygotic and dizygotic twins living in a Plasmodium falciparum endemic area in west Africa.

To investigate the influence of genetic and/or environmental factors in the development and shaping of the human peripheral T cell repertoire the authors studied the T-cell receptor (TCR) V beta usage in 10 adult monozygous (Mz) and nine dizygous (Dz) twin pairs living in a Plasmodium falciparum endemic area in West Africa. The TCR repertoire was determined using a small panel of anti-V beta specific monoclonal antibodies (MoAbs) using conventional immunofluorescence assays. The results revealed that the V beta repertoire was similar to that recently described for a Caucasian population using a similar panel of antibodies. The frequencies of particular V beta genes tested were influenced neither by anti-malarial antibody titres nor by parasite densities, indicating that the P. falciparum parasite is not a dominating factor in determining the peripheral T cell repertoire. All donors were human leucocyte antigen (HLA) class I and II typed; no association was found between the expression of any V beta genes and MHC haplotype. The V beta usage was more concordant within the Mz than within the Dz pairs. For a group comprising four HLA class II identical individuals, the average within-pair difference was significantly greater than for the whole Mz group, but similar to that seen for the total Dz group. Thus, the data suggest that genetic, rather than environmental, factors have a profound effect on the shaping of the human circulating T cell repertoire and that the major genetic factors are encoded by non-HLA class II genes.

Adolescent↗

PubMed1997

Circulating T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human epidermal keratins.

Psoriasis is a T-cell mediated inflammatory skin disease which has been associated with group A, beta-haemolytic streptococcal infections. Four 20 a.a. long M6-peptides sharing 5-6 a.a. sequences with human epidermal keratins were identified. To investigate the role of potentially cross-reactive T cells in the pathogenesis of psoriasis, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) responses of circulating T cells to these peptides were analysed by ELISPOT and RT-PCR in 14 psoriatic patients, 12 healthy individuals and six patients with atopic dermatitis (AD). Untreated psoriatic patients' responses were significantly higher to these peptides than healthy and AD controls, while responses to a control M6-peptide, not sharing sequences with keratin, were negligible in all groups. No difference was found in response to streptokinase/streptodornase (SK/SD). M6-protein and peptides exclusively elicited IFN-gamma production, with little IL-4 production, even in AD patients. Interferon-gamma responses to all the M6-peptides were abolished after successful treatment of psoriatic patients, but responses to SK/SD were unaffected. The results indicate that active psoriasis is associated with Th1-like cells responding to streptococcal M6-peptides sharing sequences with human epidermal keratin. This is consistent with the hypothesis that psoriasis may be induced and exacerbated in susceptible individuals by M-protein specific Th1-like cells that cross-react with human epidermal keratin.

Adult↗

PubMed1997

Increased allergen-specific Th2 responses in vitro in atopic subjects receiving subclinical allergen challenge.

The study aimed to determine whether inhalation of subclinical allergen doses-leads to a shift in the balance between T helper (Th) 1 and Th2 cells in asthmatic patients. Elevated IgE requires allergen-specific T cells producing cytokines such as interleukin (IL)-4 or IL-13. Interferon-gamma (IFN-gamma) produced by Th1 cells counteracts the effects of IL-4. In nature, allergic persons are often exposed to low levels of allergen, leading to hyperreactivity, but not to acute allergic reactions. In this study, nine allergic persons inhaled low doses of allergen or placebo in a double-blind manner over seven consecutive weekdays. During the study, the bronchial responsiveness to histamine challenge increased, but no subject exhibited asthmatic symptoms. Blood was drawn on days 0, 1, 4, and 9, and the number of IL-4- and IFN-gamma-producing cells was measured by enzyme-linked immunospot (ELISPOT) assay after in vitro stimulation with a low-dose phytohemagglutinin (PHA) mixed with the relevant allergen or with PHA alone. In three of the four subjects receiving allergen, the IL-4/IFN-gamma ratio increased during the time of the study. No increase was seen in the placebo group. No increase was seen in serum IgE levels in any of the groups. We conclude that a shift in the balance between Th1 and Th2 cells can be detected in subjects exposed to subclinical allergen doses.

Allergens↗

PubMed1997

Selective compartmentalization of gammadelta-T lymphocytes in human breastmilk.

In human breastmilk, T lymphocytes with gammadelta-receptor (TCR) are more frequent than those with alphabeta-TCR, in comparison with peripheral blood. Differential representation has also been demonstrated for subpopulations of gammadelta-T cells. Reactivity was visualized with three monoclonal antibodies against Vdelta1, Vdelta2 and Vgamma2 on T cells from the breastmilk and peripheral blood of 12 women who had recently given birth. Confirming the results with Vdelta1, it was found that Vdelta1 (p < 0.01) and Vgamma2 (p < 0.05) but not Vdelta2 were overrepresented on T cells in milk as compared with blood. This selective compartmentalization seems to reflect the homing of certain cells to the mammary gland.

Antibodies, Monoclonal↗

PubMed1997

Immunoglobulin E, a pathogenic factor in Plasmodium falciparum malaria.

Most children and adults living in areas where the endemicity of Plasmodium falciparum malaria is high have significantly elevated levels of both total immunoglobulin E (IgE) and IgE antimalarial antibodies in blood. This elevation is highest in patients with cerebral malaria, suggesting a pathogenic role for this immunoglobulin isotype. In this study, we show that IgE elevation may also be seen in severe malaria without cerebral involvement and parallels an elevation of tumor necrosis factor alpha (TNF). IgE-containing serum from malaria immune donors was added to tissue culture plates coated with rabbit anti-human IgE antibodies or with P. falciparum antigen. IgE-anti-IgE complexes as well as antigen-binding IgE antibodies induced TNF release from peripheral blood mononuclear cells (PBMC). Nonmalaria control sera with no IgE elevation induced significantly less of this cytokine, and the TNF-inducing capacity of malaria sera was also strongly reduced by passing them over anti-IgE Sepharose columns. The cells giving rise to TNF were adherent PBMC. The release of this cytokine probably reflects cross-linking of their low-affinity receptors for IgE (CD23) by IgE-containing immune complexes known to give rise to monocyte activation via the NO transduction pathway. In line with this, adherent monocytic cells exposed to IgE complexes displayed increased expression of CD23. As the malaria sera contained IgG anti-IgE antibodies, such complexes probably also play a role in the induction of TNF in vivo. Overproduction of TNF is considered a major pathogenic mechanism responsible for fever and tissue lesions in P. falciparum malaria. This overproduction is generally assumed to reflect a direct stimulation of effector cells by certain parasite-derived toxins. Our results suggest that IgE elevation constitutes yet another important mechanism involved in excessive TNF induction in this disease.

Adult↗

PubMed1996

T cell-derived IL-3 induces the production of IL-4 by non-B, non-T cells to amplify the Th2-cytokine response to a non-parasite antigen in Schistosoma mansoni-infected mice.

We describe a novel amplification mechanism underlying the increased early IL-4 production observed in Schistosoma mansoni-infected mice in response to a non-parasite Ag, sperm whale myoglobin (SwMb). Earlier studies have shown that splenic Fc epsilon R+ non-B, non-T (NBNT) cells from schistosome-infected mice secrete IL-4 after stimulation with parasite Ag. We now demonstrate that purified NBNT cells from SwMb-immunized S. mansoni-infected mice do not respond directly to SwMb, but produce IL-4 in response to IL-3. Accordingly, we show that the early SwMb-specific IL-4 response of spleen cells (SC) from immunized infected mice is dependent on IL-3 and on CD4+ T cells. Thus, most of the early SwMb-induced IL-4 from SC of infected mice appears to be produced by NBNT cells triggered by IL-3 synthesized by SwMb-specific CD4+ T cells. IL-3-induced IL-4 production was also observed in purified NBNT cells from immunized uninfected mice, but the frequency and/or IL-4-producing capacity of splenic IL-3-responsive cells was found to be 8 to 16 times higher in immunized infected animals. IL-4 production by purified CD4+ cells from immunized infected mice was also seen after SwMb stimulation, but this response showed slower kinetics than those of total SC, was IL-3-independent, and on average threefold greater than that by CD4+ cells from immunized uninfected controls. Thus, increased SwMb-induced IL-4 production in immunized S. mansoni-infected mice results from direct synthesis by CD4+ T cells, as well as their stimulation via IL-3 of an expanded population of NBNT cells. The latter pathway may serve as an amplification loop for Th2-cytokine responses.

Animals↗