Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antibody response in humans naturally primed to a malaria vaccine candidate antigen (Pf155/RESA) is genetically regulated. Here, the impact of antigen presenting cells (APC) on the control of in vitro T-cell responses induced by Pf155/RESA or synthetic peptides corresponding to its major Pf155/RESA epitopes was studied. T cells and APC were from the peripheral blood of monozygotic or dizygotic twins and their age matched siblings, all living in the central highlands of Madagascar. When induced to proliferate (thymidine incorporation) in vitro by antigenic peptides, the T-cell responses varied less within the twin pairs than between them and their siblings or the entire group, implying that they were genetically regulated. Occasional MHC class II associations of some of the responses were weak and did not reflect underlying MHC class II restrictions. When T cells and APC from different but MHC class II identical donors were incubated in various combinations, antigen charged APC from homologous donors induced in vitro T-cell proliferation which differed from that induced by the T-cell donors' own APC. Pretreatment of the APC with either paraformaldehyde or anti-class II antibodies inhibited or abolished this antigen dependent T-cell proliferation. The results suggest that the observed differences in T-cell responses induced by APC from different donors reflect differences at the level of these cells. Whether they reflect differences in the proteases involved in antigen processing, in the costimulatory signals provided by the APC to the T cells or in the secretion of other regulatory factors remains to be elucidated.
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PMID:Presentation of the Plasmodium falciparum antigen Pf155/RESA to human T cells. Variations in responsiveness induced by antigen presenting cells from different but MHC class II identical donors. 773 90

T-cells have a major role both as helper cells for efficient antibody production and as inducers and effector cells in antibody-independent malaria immunity. Thus, antigens to be included into a subunit vaccine must contain T-cell epitopes to become effectively immunogenic. The P. falciparum blood stage vaccine antigen Pf155/RESA has been shown to contain T-helper epitopes inducing T-dependent anti-malarial antibodies in vitro. We have also shown that synthetic peptides representing sequences from the amino-acid repeat regions of Pf155/RESA stimulate T-cells from P. falciparum primed donors to proliferate, to release IFN-gamma and/or IL-4. In individual donors there was no correlation between these different activities. Rather, they were frequently negatively associated. However, IL-4 secretion could be induced in T-cells from donors who had elevated concentrations of serum antibodies to the same peptide as used for T-cell activation. Taken together the results support the occurrence of malaria-specific CD4+ T-cell subsets (e.g. TH1 and TH2) in humans similar to what has been found in mice and suggest the involvement of TH2-type helper cells in the induction of some important P. falciparum specific antibodies. CD4+ T-cells recognize the antigen in the context of MHC class II molecules. However, in human outbred populations no consistent MHC restrictions of anti-Pf155/RESA immune responses could be demonstrated. This is not surprising in view of the extensive polymorphism of the HLA system. Neither were there any obvious MHC class II restrictions seen when antibody- and t-cell responses were measured in naturally primed monozygotic twins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of regulatory T-cell responses in humans induced by the P. Falciparum blood stage antigen Pf155/RESA. 775 13

In reactive arthritis (ReA) a specific T cell response to the triggering bacterial antigen is present in the synovial fluid, while in paired peripheral blood T cells the response is markedly reduced. The proliferative response to ReA-associated bacteria in the peripheral blood of ReA patients was compared with that seen in the blood of healthy adults, who denied exposure to these microbes, and in the umbilical cord blood of newborns, who have clearly not been exposed to bacterial antigen. Peripheral blood mononuclear cells (PBMC) from non-exposed adults and those from umbilical cord blood proliferated to ReA-associated bacteria, whilst little response was seen in ReA PBMC. The response was MHC class II-restricted, required processing of the bacterial antigen, was seen in both CD45RO+ and CD45RA+ subsets, and was not oligoclonal. These T cell responses are similar to those previously demonstrated in non-exposed individuals to malaria, leishmania and trypanosoma antigen, and may reflect the existence of 'natural' T cell immunity to ReA-associated bacteria. The lack of such responses in ReA peripheral blood may suggest that such 'natural' responses may restrict the dissemination or progression of infection.
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PMID:Reactive arthritis-associated bacteria can stimulate lymphocyte proliferation in non-exposed individuals and newborns. 853 72

We determined the requirement for selected lymphocyte subsets and cytokines in the pathogenesis of experimental murine cerebral malaria (CM) by using gene-targeted knockout and mAb-suppressed mice. Plasmodium berghei ANKA infection induced CM in A 0/0 mice, which lack expression of surface MHC class II glycoproteins and consequently express a severe and chronic reduction in numbers of CD4+ T cells. However, when A 0/0 mice, which are on a C57BL/6 x 129 genetic background, or immune-intact C57BL/6 controls treated with anti-CD4 mAb were infected, none developed CM. The latter finding confirms an earlier report that CD4+ T cells are required for CM to occur and additionally indicates that the reduced numbers of CD4+ T cells present in A 0/0 mice are sufficient for CM development. Neither the recently described CD4+, NK1.1+ T cell subset shown to be present in A 0/0 mice nor traditional NK cells seem to be required for the induction of CM because A 0/0 and C57BL/6 mice severely depleted of both NK1.1+ populations with mAb developed CM as readily as did normal Ig-treated controls. Deficiency of Th1-associated cytokines (IFN-gamma or IL-2) in mice by gene-targeted disruptions completely inhibited CM development, whereas the lack of Th2-associated cytokines (IL-4 or IL-10) did not prevent this disease. Our observation that B cell-deficient JHD and microMT mice developed CM provides evidence that neither B cells, their products, nor B cell Ag presentation are a requisite for CM pathology. We further observed that neither beta 2m 0/0 knockout mice, which lack CD8+ alpha beta T cells, nor C57BL/6 mice depleted of CD8+ T cells with anti-CD8 mAb treatment developed CM, leading us to conclude that CD8+ T cells are also crucial for the development of CM.
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PMID:Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. 875 47

Major histocompatibility complex (MHC) molecules bind peptides bearing an appropriate 'sequence motif' for MHC binding. The use of phage display libraries exploits the ability of MHC class II molecules to exchange peptides in solution and thus select out peptide sequences with high-affinity binding from a large array of random peptides. We have analysed the peptide binding motifs of HLA-DRB1*1301 and *1302 using affinity purified HLA-DR13 molecules to purify sequentially HLA-DR13-binding peptides from a large random library of M13 phage containing nonamer inserts in the pIII coat protein. These DR13 alleles differ only at position 86 of the HLA-DR beta chain, where they contain valine and glycine residues respectively. These alleles were chosen because of their association with protection from severe malaria and chronic hepatitis B virus infection in West Africa. Analysis of the phage bound to these DR molecules suggests binding motifs. We compare the results derived from the use of the phage display library with results obtained from analysis of eluted peptides and peptide-binding studies. This analysis shows that although there is a common theme to motifs derived using different methods, there are also subtle variations between them.
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PMID:Analysis of peptide-binding motifs for two disease associated HLA-DR13 alleles using an M13 phage display library. 888 46

The hepatitis B virus (HBV) core gene codes for two partially colinear antigens: a secreted antigen (HBeAg) and the particulate core antigen (HBcAg), which assembles to form subviral particles and in virions contains the viral genome and polymerase. In this review we summarize data on the immune recognition of HBc/eA and recent progress in the use of HBcAg as a carrier moiety for heterologous epitopes. During HBV infection, HBcAg and HBeAg are important targets of antiviral immunity. HBcAg and HBeAg are serologically distinct but share all characterized T-cell epitopes. The particulate HBcAg can elicit T-cell-independent as well as T-cell-dependent antibody responses, HBeAg is a strictly T-cell-dependent antigen. Neonatal tolerance to maternally derived circulating HBeAg may facilitate chronic HBV infection after vertical transmission of HBV. In a murine transgenic model, HBc/eAg-specific Th1 cells were more readily anergized, whereas Th2 cells more easily escaped tolerization. In human HBV infection, acute adult HBV infection with subsequent virus elimination was characterized by Th1-like alpha-HBV serum IgG subtype distribution, whereas a Th2-like distribution of IgG subtypes was observed during chronic infection. During chronic infection, core gene mutants which abolish HBeAg synthesis were frequently observed. To exploit the unusual immunogenicity of particulate HBcAg as a vaccine carrier moiety, insertion sites for foreign epitopes were defined in recombinant expression systems. While fusion of epitopes to the N-terminus required a linker sequence for surface accessibility, both fusion to the N-terminus and to the C-terminus was compatible with particle assembly and preserved the native antigenicity and immunogenicity of HBcAg. Epitope insertion at an immunodominant internal site of HBcAg reduced the HBcAg immunogenicity and antigenicity and most drastically enhanced the immunogenicity of the inserted foreign epitopes. This internal site of HBcAg was used to express circumsporozoite antigen (CS) repeat epitopes of two rodent malaria parasites and of Plasmodium falciparum. Purified hybrid HBcAg-CS proteins were particulate and displayed CS antigenicity as well as reduced native HBc antigenicity. Immunization of several mouse strains with HBcAg-CS hybrid particles resulted in high-titered serum anti-CS antibodies representing all murine IgG isotypes and protected BALB/c mice against plasmodial challenge. Immunization of mice with HBcAg or HBcAg-CS particles formulated on alum, complete Freund's or incomplete Freund's adjuvant resulted in equivalent anti-CS and anti-HBc serum antibody titers. Preexisting immunity to HBcAg did not significantly alter the immunogenicity of hybrid HBcAg particles suggesting that carrier-specific immune suppression does not limit the use of hybrid HBcAg with internal insertions. Immunization with HBcAg-CS particles universally primed HBcAg-specific T cells and in addition CS-specific T cells were if the insert contained a CS-specific T-cell site for the corresponding murine MHC class II haplotype. The internal amino acid position in HBcAg is therefore permissive for the inclusion of heterologous T-helper as well as B-cell epitopes.
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PMID:Hepatitis B virus core and e antigen: immune recognition and use as a vaccine carrier moiety. 895 76

Peripheral blood gamma delta T cells from non-exposed individuals respond to antigens of the malaria parasite, Plasmodium falciparum, in vitro. This response, largely caused by T cells bearing the V gamma 9+ chain of the T-cell receptor, is stimulated by components of the parasite expressed on the schizont stage and released at schizont rupture. The response of V gamma 9+ T cells to parasite components is inhibited by antibodies to major histocompatibility complex (MHC) class I and class II. However, the inhibition by anti-MHC class II antibodies can be overcome by the addition of interleukin-2 (IL-2) to the cultures, suggesting that gamma delta T cells themselves do not recognize MHC class II molecules but require an MHC class II-dependent response taking place in the culture. In contrast, the inhibition by anti-class I antibodies cannot be reversed by addition of IL-2. Since an accompanying CD4+ T-cell response occurred in peripheral blood mononuclear cells cultured with P falciparum antigens, it was considered that these cells provide the cytokines necessary for the subsequent activation and expansion of V gamma 9+ T cells recognizing components of the parasite and MHC class I molecules. This was confirmed by reconstituting the response of enriched gamma delta T cells to P falciparum schizont extract by addition of purified CD4+ T cells.
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PMID:The response of gamma delta T cells to Plasmodium falciparum is dependent on activated CD4+ T cells and the recognition of MHC class I molecules. 895 54

The physiopathology of experimental cerebral malaria (CM), an acute neurological complication of Plasmodium berghei ANKA (PbA) infection, involves interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), two cytokines that are known to modulate major histocompatibility complex (MHC) molecule expression. The aim of this study was to evaluate whether the genetic susceptibility to CM is related to the constitutive or IFN-gamma-induced expression of MHC molecules on brain microvessels. To this end, brain microvascular endothelial cells (B-MVEC) were isolated from CM-susceptible (CM-S, CBA/J) and resistant (CM-R, BALB/c) mice. By flow cytometry, we found that less than 5% of CM-S B-MVEC constitutively expressed MHC class I molecules, in contrast to up to 90% of CM-R B-MVEC. Upon stimulation with IFN-gamma, the percentage of positive cells for MHC class I molecules in CM-S B-MVEC became comparable to CM-R B-MVEC, but a higher fluorescence intensity existed on CM-S B-MVEC compared with CM-R B-MVEC. MHC class II molecules were not constitutively expressed on B-MVEC from either strain. IFN-gamma-induced expression of MHC class II (I-A, I-E) molecules was significantly higher in CM-S than CM-R B-MVEC both in percentage of positive cells and fluorescence intensity. These data demonstrate that absent or low MHC class I and higher inducibility of MHC class II expression on B-MVEC are associated with the genetic susceptibility to CM.
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PMID:Expression of major histocompatibility complex antigens on mouse brain microvascular endothelial cells in relation to susceptibility to cerebral malaria. 937 Sep 24

The importance of immune complexes in the pathogenesis of malarial nephritis is well established. The expression was studied of major histocompatibility complex (MHC) class I and class II antigens and the infiltration of inflammatory cells, with their possible roles in cellular immune reactions in the pathogenesis of nephritis in a murine malaria model. Thirty-six kidney sections obtained on days 5, 8-10, 15, and 20 from C57BL/6J mice acutely infected with Plasmodium berghei and uninfected control mice were stained with specific antibodies for cellular immune markers by immunohistochemistry. From day 10 post-infection, markedly enhanced expression of both MHC class I and class II (Ia) antigens was observed in the kidneys. In the glomeruli, the expression was in the mesangium and along the capillaries. MHC class II was strongly expressed in the proximal tubules. Enhanced expression of MHC class I and class II was found in the endothelium of blood vessels, especially the peritubular capillaries. In addition, immune cells positive for CD4+ and CD8a+ markers, and class I and class II antigens were present around small arteries, or in focal areas of the interstitium. There were strong correlations between MHC class I expression in the glomeruli; MHC class II expression in the glomeruli/proximal tubules; and CD4+, CD8a+ infiltrates in the tubulointerstitium; with the severity of renal dysfunction (proteinuria). These findings indicate the importance of cellular immune reactions in the pathogenesis of acute murine malarial nephritis.
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PMID:Upregulation of major histocompatibility complex (MHC) antigen in nephritis associated with murine malaria infection. 971 50

The C-terminal fragment of merozoite surface protein-1 (MSP-1) of the mouse malaria parasite Plasmodium chabaudi chabaudi (AS) stimulates a weak CD4 T cell response when compared to the response to a more structurally simple region of the molecule. The tertiary structure of the C-terminal region of MSP-1 is maintained by five disulfide bonds. A peptide from this region could only be processed and loaded onto newly synthesized MHC class II molecules, whereas a peptide from the structurally simple region was available for loading onto recycling MHC class II. CD4(+) T cell hybridomas took longer to recognize an epitope derived from the disulfide-bonded region whether native parasite or recombinant MSP-1 antigen was used. Reduction of disulfide bonds in the C-terminal region subsequently allowed peptides to be loaded onto recycling MHC class II and greatly enhanced the rapidity of the T cell response. These data demonstrate that differential processing occurs intramolecularly in MSP-1, which may be responsible for the observed weak CD4 T cell responses against this region. The consequences of this in vivo may be that limited T cell help is available for protective antibody production which has important implications for designing vaccines based on MSP-1.
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PMID:Low CD4(+) T cell responses to the C-terminal region of the malaria merozoite surface protein-1 may be attributed to processing within distinct MHC class II pathways. 1116 40


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