Papers by Lucia Jamli Abel
Mediators of Inflammation, 2014
Chagas disease, caused by the protozoan parasiteTrypanosoma cruzi(T. cruzi), is characterized by ... more Chagas disease, caused by the protozoan parasiteTrypanosoma cruzi(T. cruzi), is characterized by immunopathology driven by IFN-γsecreting Th1-like T cells.T. cruzihas a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described thatT. cruzior its products—like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)—are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-γprimed murine macrophages. However, little is known about whetherT. cruzior GPI-mucins exert a similar action in human cells. We therefore decided to further investigate thein vitrocytokine production profile from human mononuclear cells from uninfected donors exposed toT. cruzias well as tGPI-mucins. We observed that both livingT. cruzitrypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood mo...
Memórias do Instituto Oswaldo Cruz, 2003
We compared plasma tumor necrosis factor-α (TNF-α) levels among asymptomatic/"indeterminate" Chag... more We compared plasma tumor necrosis factor-α (TNF-α) levels among asymptomatic/"indeterminate" Chagas disease patients (ASY) and patients across the clinical spectrum of chronic Chagas disease cardiomyopathy (CCC). Idiopathic dilated cardiomyopathy (DCM) patients and normal controls (NC) were included as controls. ASY Chagas disease patients had significantly higher plasma TNF-α levels than NC. TNF-α levels among severe CCC patients with significant left ventricular (LV) dysfunction were similar to those of DCM patients, showing average 2-fold higher levels than CCC patients without LV dysfunction and ASY patients, and 8-fold higher levels than NC. In Chagas disease, chronic TNF-α production prior to heart failure may play a role in CCC progression.
Journal of Autoimmunity, 2001
One-third of all Trypanosoma cruzi-infected patients eventually develop chronic Chagas' disease c... more One-third of all Trypanosoma cruzi-infected patients eventually develop chronic Chagas' disease cardiomyopathy (CCC), a particularly lethal inflammatory dilated cardiomyopathy, where parasites are scarce and heart-infiltrating mononuclear cells seem to be the effectors of tissue damage. Since T. cruzi is a major inducer of interleukin-12 production, the role of inflammatory cytokines in the pathogenesis of CCC was investigated. We assayed cytokine production by peripheral blood mononuclear cells (PBMC) from CCC and asymptomatic T. cruzi-infected (ASY) individuals, as well as by T cell lines from endomyocardial biopsies from CCC patients. PBMC from CCC and ASY patients produced higher IFN-levels than normal (N) individuals in response to B13 protein and phytohaemagglutinin PHA; IFN-high responders (≥1 ng/ml) were 2-3 fold more frequent among CCC patients than ASY individuals. Conversely, IL-4 production in response to the same stimuli was suppressed among T. cruzi-infected patients. The frequency of PHA-induced IFNproducing cells on PBMC was significantly higher among CCC than ASY and N individuals. IFN-and TNF-were produced by ten out of ten PHAstimulated T cell lines from CCC patients; IL-2 and IL-10 were produced by four out of ten and one out of ten lines, respectively; IL-4, IL-1 , IL-1 , IL-6 and IL-12 were undetectable. Our results suggest that CCC and ASY patients may respond differentially to the IFN-inducing stimulus provided by T. cruzi infection. Given the T 1-type cytokine profile of heart-infiltrating T cell lines from CCC patients, the ability to mount a vigorous IFN-response may play a role on the differential susceptibility to CCC development.
Brazilian Journal of Medical and Biological Research, 1998
The hallmark of chronic Chagas disease cardiomyopathy (CCC) is the finding of a T cell-rich infla... more The hallmark of chronic Chagas disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens (Cunha-Neto et al. (1996) Journal of Clinical Investigation, 98: 1709-1712). Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas cardiomyopathy. The bulk of evidence points to a significant production of IFN-γ and TNF-α which may be linked to T. cruziinduced IL-12 production.
Brazilian Journal of Medical and Biological Research, 1998
Six hundred million people are at risk of infection by Schistosoma mansoni. MHC haplotypes have b... more Six hundred million people are at risk of infection by Schistosoma mansoni. MHC haplotypes have been reported to segregate with susceptibility to schistosomiasis in murine models. In humans, a major gene related to susceptibility/resistance to infection by S. mansoni (SM1) and displaying the mean fecal egg count as phenotype was detected by segregation analysis. This gene displayed a codominant mode of inheritance with an estimated frequency of 0.20-0.25 for the deleterious allele and accounted for more than 50% of the variance of infection levels. To determine if the SM1 gene segregates with the human MHC chromosomal region, we performed a linkage study by the lod score method. We typed for HLA-A, B, C, DR and DQ antigens in 11 informative families from an endemic area for schistosomiasis in Bahia, Brazil, by the microlymphocytotoxicity technique. HLA-DR typing by the polymerase chain reaction with sequence-specific primers (PCR-SSP) and HLA-DQ were confirmed by PCR-sequencespecific oligonucleotide probes (PCR-SSOP). The lod scores for the different q values obtained clearly indicate that there is no physical linkage between HLA and SM1 genes. Thus, susceptibility or resistance to schistosomiasis, as defined by mean fecal egg count, is not primarily dependent on the hosts HLA profile. However, if the HLA molecule plays an important role in specific immune responses to S. mansoni, this may involve the development of the different clinical aspects of the disease such as granuloma formation and development of hepatosplenomegaly.
Brazilian Journal of Medical and Biological Research, 1997
Previous reports from our group have demonstrated the association of molecular mimicry between ca... more Previous reports from our group have demonstrated the association of molecular mimicry between cardiac myosin and the immunodominant Trypanosoma cruzi protein B13 with chronic Chagas' disease cardiomyopathy at both the antibody and heart-infiltrating T cell level. At the peripheral blood level, we observed no difference in primary proliferative responses to T. cruzi B13 protein between chronic Chagas' cardiopathy patients, asymptomatic chagasics and normal individuals. In the present study, we investigated whether T cells sensitized by T. cruzi B13 protein respond to cardiac myosin. T cell clones generated from a B13-stimulated T cell line obtained from peripheral blood of a B13-responsive normal donor were tested for proliferation against B13 protein and human cardiac myosin. The results showed that one clone responded to B13 protein alone and the clone FA46, displaying the highest stimulation index to B13 protein (SI = 25.7), also recognized cardiac myosin. These data show that B13 and cardiac myosin share epitopes at the T cell level and that sensitization of a T cell with B13 protein results in response to cardiac myosin. It can be hypothesized that this also occurs in vivo during T. cruzi infection which results in heart tissue damage in chronic Chagas' disease cardiomyopathy.
The American Journal of Pathology, 2004
Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize hear... more Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize heart proteins and streptococcal M peptides. To functionally characterize heart-infiltrating T lymphocytes, we evaluated their cytokine profile, both directly in situ and in T-cell lines derived from the heart (HIL). Interferon (IFN)-␥, tumor necrosis factor (TNF)-␣, interleukin (IL)-4, and IL-10 expressions were characterized in 20 heart tissue infiltrates from 14 RHD patients by immunohistochemistry. IFN-␥-, TNF-␣-, and IL-10-positive cells were consistently predominant, whereas IL-4 was scarce in the valves. In agreement with these data, the in vitro experiments, in which 13 HILs derived from heart samples of eight patients were stimulated with M5 protein and the immunodominant M5 (81-96) peptide, IL-4 was detected in HIL derived from the atrium (three of six) but not from the valve (zero of seven). IFN-␥ and IL-10 production were detected in culture supernatants in 11 of 13 and 6 of 12 HILs, respectively. The predominant IFN-␥ and TNF-␣ expression in the heart suggests that Th1-type cytokines could mediate RHD. Unlike in reversible myocardium inflammation , the significantly lower IL-4 expression in the valvular tissue (P ؍ 0.02) may contribute to the progression of the RHD leading to permanent valvular damage (relative risk, 4.3; odds ratio, 15.8). The lack of IL-4 in vitro production by valve-derived HIL also emphasizes the more severe tissue destruction in valves observed in RHD.
Journal of Water and Health, 2017
Desalination of seawater is becoming an important means to address the increasing scarcity of fre... more Desalination of seawater is becoming an important means to address the increasing scarcity of freshwater resources in the world. Seawater has been used as drinking water in the health, food, and medical fields and various beneficial effects have been suggested, although not confirmed. Given the presence of 63 minerals and trace elements in drinking desalinated seawater (63 DSW), we evaluated their effects on the behavior of tumorigenic and nontumorigenic cells through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and annexin-V-fluorescein isothiocyanate/propidium iodide staining. Our results showed that cell viability and proliferation in the presence of 63 DSW were significantly greater than in mineral water and in the presence of fetal bovine serum in a dose-dependent manner. Furthermore, 63 DSW showed no toxic effect on murine embryonic fibroblast (NIH-3T3) and murine melanoma (B16-F10) cells. In another assay, we also showed that pre-treatment of non-ad...
Ciência Rural, 2012
Este estudo teve como objetivo verificar a eficiência do uso de imunoestimulante associado a anti... more Este estudo teve como objetivo verificar a eficiência do uso de imunoestimulante associado a anti-helmíntico no tratamento das helmintoses de ovinos. Os animais do grupo I (n=29) receberam o anti-helmíntico albendazole (11mg kg-1) em administração única e o imunoestimulante composto de Propionibacterium granulosum (16ug kg-1) e lipopolissacarídeo (LPS) de Escherichia coli (1,2ug kg-1) em duas doses com intervalo de 48 horas e os animais do grupo II (n=29) receberam o anti-helmíntico albendazole (11mg kg-1). Amostras foram colhidas semanalmente durante 28 dias para a realização da contagem total e diferencial de leucócitos, hematócrito e contagem de ovos por grama de fezes (OPG). Os animais que receberam imunoestimulante associado a anti-helmíntico apresentaram aumento significativo dos valores de eosinófilos e linfócitos (P<0,05) em relação aos animais que receberam somente anti-helmíntico. Na contagem de ovos por grama de fezes (OPG), não foram observadas diferenças significativ...
Microbes and Infection, 2005
Proteins containing tandemly repetitive sequences are present in several immunodominant protein a... more Proteins containing tandemly repetitive sequences are present in several immunodominant protein antigens in pathogenic protozoan parasites. The tandemly repetitive Trypanosoma cruzi B13 protein is recognized by IgG antibodies from 98% of Chagas&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; disease patients. Little is known about the molecular mechanisms that lead to the immunodominance of the repeated sequences, and there is limited information on T cell epitopes in such repetitive antigens. We finely characterized the T cell recognition of the tandemly repetitive, degenerate B13 protein by T cell lines, clones and PBMC from Chagas&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; disease cardiomyopathy (CCC), asymptomatic T. cruzi infected (ASY) and non-infected individuals (N). PBMC proliferative responses to recombinant B13 protein were restricted to individuals bearing HLA-DQA1*0501(DQ7), -DR1, and -DR2; B13 peptides bound to the same HLA molecules in binding assays. The HLA-DQ7-restricted minimal T cell epitope [FGQAAAG(D/E)KP] was identified with an overlapping combinatorial peptide library including all B13 sequence variants in T. cruzi Y strain B13 protein; the underlined small residues GQA were the major HLA contact residues. Among natural B13 15-mer variant peptides, molecular modeling showed that several variant positions were solvent (TCR)-exposed, and substitutions at exposed positions abolished recognition. While natural B13 variant peptide S15.9 seems to be the immunodominant epitope for Chagas&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; disease patients, S15.4 was preferentially recognized by CCC rather than ASY patients, which may be pathogenically relevant. This is the first thorough characterization of T cell epitopes of a tandemly repetitive protozoan antigen and may suggest a role for T cell help in the immunodominance of protozoan repetitive antigens.
Journal of Autoimmunity, 2001
One-third of all Trypanosoma cruzi-infected patients eventually develop chronic Chagas' disease c... more One-third of all Trypanosoma cruzi-infected patients eventually develop chronic Chagas' disease cardiomyopathy (CCC), a particularly lethal inflammatory dilated cardiomyopathy, where parasites are scarce and heart-infiltrating mononuclear cells seem to be the effectors of tissue damage. Since T. cruzi is a major inducer of interleukin-12 production, the role of inflammatory cytokines in the pathogenesis of CCC was investigated. We assayed cytokine production by peripheral blood mononuclear cells (PBMC) from CCC and asymptomatic T. cruzi-infected (ASY) individuals, as well as by T cell lines from endomyocardial biopsies from CCC patients. PBMC from CCC and ASY patients produced higher IFN-levels than normal (N) individuals in response to B13 protein and phytohaemagglutinin PHA; IFN-high responders (≥1 ng/ml) were 2-3 fold more frequent among CCC patients than ASY individuals. Conversely, IL-4 production in response to the same stimuli was suppressed among T. cruzi-infected patients. The frequency of PHA-induced IFNproducing cells on PBMC was significantly higher among CCC than ASY and N individuals. IFN-and TNF-were produced by ten out of ten PHAstimulated T cell lines from CCC patients; IL-2 and IL-10 were produced by four out of ten and one out of ten lines, respectively; IL-4, IL-1 , IL-1 , IL-6 and IL-12 were undetectable. Our results suggest that CCC and ASY patients may respond differentially to the IFN--inducing stimulus provided by T. cruzi infection. Given the T 1 -type cytokine profile of heart-infiltrating T cell lines from CCC patients, the ability to mount a vigorous IFN-response may play a role on the differential susceptibility to CCC development.
The American Journal of Pathology, 2004
Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize hear... more Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize heart proteins and streptococcal M peptides. To functionally characterize heart-infiltrating T lymphocytes, we evaluated their cytokine profile, both directly in situ and in T-cell lines derived from the heart (HIL). Interferon (IFN)-␥, tumor necrosis factor (TNF)-␣, interleukin (IL)-4, and IL-10 expressions were characterized in 20 heart tissue infiltrates from 14 RHD patients by immunohistochemistry. IFN-␥-, TNF-␣-, and IL-10-positive cells were consistently predominant, whereas IL-4 was scarce in the valves. In agreement with these data, the in vitro experiments, in which 13 HILs derived from heart samples of eight patients were stimulated with M5 protein and the immunodominant M5 (81-96) peptide, IL-4 was detected in HIL derived from the atrium (three of six) but not from the valve (zero of seven). IFN-␥ and IL-10 production were detected in culture supernatants in 11 of 13 and 6 of 12 HILs, respectively. The predominant IFN-␥ and TNF-␣ expression in the heart suggests that Th1-type cytokines could mediate RHD. Unlike in reversible myocardium inflammation , the significantly lower IL-4 expression in the valvular tissue (P ؍ 0.02) may contribute to the progression of the RHD leading to permanent valvular damage (relative risk, 4.3; odds ratio, 15.8). The lack of IL-4 in vitro production by valve-derived HIL also emphasizes the more severe tissue destruction in valves observed in RHD.
Journal of Autoimmunity, 2001
One-third of all Trypanosoma cruzi-infected patients eventually develop chronic Chagas' disease c... more One-third of all Trypanosoma cruzi-infected patients eventually develop chronic Chagas' disease cardiomyopathy (CCC), a particularly lethal inflammatory dilated cardiomyopathy, where parasites are scarce and heart-infiltrating mononuclear cells seem to be the effectors of tissue damage. Since T. cruzi is a major inducer of interleukin-12 production, the role of inflammatory cytokines in the pathogenesis of CCC was investigated. We assayed cytokine production by peripheral blood mononuclear cells (PBMC) from CCC and asymptomatic T. cruzi-infected (ASY) individuals, as well as by T cell lines from endomyocardial biopsies from CCC patients. PBMC from CCC and ASY patients produced higher IFN-levels than normal (N) individuals in response to B13 protein and phytohaemagglutinin PHA; IFN-high responders (≥1 ng/ml) were 2-3 fold more frequent among CCC patients than ASY individuals. Conversely, IL-4 production in response to the same stimuli was suppressed among T. cruzi-infected patients. The frequency of PHA-induced IFNproducing cells on PBMC was significantly higher among CCC than ASY and N individuals. IFN-and TNF-were produced by ten out of ten PHAstimulated T cell lines from CCC patients; IL-2 and IL-10 were produced by four out of ten and one out of ten lines, respectively; IL-4, IL-1 , IL-1 , IL-6 and IL-12 were undetectable. Our results suggest that CCC and ASY patients may respond differentially to the IFN--inducing stimulus provided by T. cruzi infection. Given the T 1 -type cytokine profile of heart-infiltrating T cell lines from CCC patients, the ability to mount a vigorous IFN-response may play a role on the differential susceptibility to CCC development.
Brazilian Journal of Medical and Biological Research, 1998
The hallmark of chronic Chagas disease cardiomyopathy (CCC) is the finding of a T cell-rich infla... more The hallmark of chronic Chagas disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens ) Journal of Clinical Investigation, 98: 1709-1712. Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas cardiomyopathy. The bulk of evidence points to a significant production of IFN-γ and TNF-α which may be linked to T.
Microbes and …, 2005
Proteins containing tandemly repetitive sequences are present in several immunodominant protein a... more Proteins containing tandemly repetitive sequences are present in several immunodominant protein antigens in pathogenic protozoan parasites. The tandemly repetitive Trypanosoma cruzi B13 protein is recognized by IgG antibodies from 98% of Chagas' disease patients. Little is ...
Clinical Immunology, 2008
Mycobacterium tuberculosis being an intracellular pathogen with its fast mutant activity has prob... more Mycobacterium tuberculosis being an intracellular pathogen with its fast mutant activity has probably developed immune escape strategies. Migration of highly polarized T cells to pathologic site of TB is facilitated by chemokines and their receptors and important in determining the local immunity. To define the molecular basis of T cells homing in TB, we studied the expression of three homing receptors CXCR3, CCR5 and CD11a at single cell level on T cells obtained from peripheral blood and local compartment (pleural effusion fluid & BAL of miliary and pulmonary tuberculosis) in 42 patients with various forms of tuberculosis. Using three color flow cytometry, we observed enrichment of CXCR3, CCR5 dual positive and single positive T cells at local disease site over the peripheral blood. Our data suggest the active recruitment of these dual positive T cells to the pathologic site of TB. In addition, in 70% of the cases, all CCR5+ cells were invariably positive for CXCR3 but all CXCR3+ cells didn't co-express CCR5. In vitro chemokines (RANTES & ITAC) driven cell migration study confirmed the above findings. This provides molecular basis of previously observed hierarchy of CXCR3 in T cell recruitment in tuberculosis. Our data highlights the important role of CXCR3 and CCR5 in selective recruitment of highly polarized Th1 cells at the tubercular pathological site.
Mediators of Inflammation, 2014
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized b... more Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products-like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)-are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins.
Microbes and Infection, 2005
Proteins containing tandemly repetitive sequences are present in several immunodominant protein a... more Proteins containing tandemly repetitive sequences are present in several immunodominant protein antigens in pathogenic protozoan parasites. The tandemly repetitive Trypanosoma cruzi B13 protein is recognized by IgG antibodies from 98% of Chagas' disease patients. Little is known about the molecular mechanisms that lead to the immunodominance of the repeated sequences, and there is limited information on T cell epitopes in such repetitive antigens. We finely characterized the T cell recognition of the tandemly repetitive, degenerate B13 protein by T cell lines, clones and PBMC from Chagas' disease cardiomyopathy (CCC), asymptomatic T. cruzi infected (ASY) and non-infected individuals (N). PBMC proliferative responses to recombinant B13 protein were restricted to individuals bearing HLA-DQA1*0501(DQ7), -DR1, and -DR2; B13 peptides bound to the same HLA molecules in binding assays. The HLA-DQ7-restricted minimal T cell epitope [FGQAAAG(D/E)KP] was identified with an overlapping combinatorial peptide library including all B13 sequence variants in T. cruzi Y strain B13 protein; the underlined small residues GQA were the major HLA contact residues. Among natural B13 15-mer variant peptides, molecular modeling showed that several variant positions were solvent (TCR)-exposed, and substitutions at exposed positions abolished recognition. While natural B13 variant peptide S15.9 seems to be the immunodominant epitope for Chagas' disease patients, S15.4 was preferentially recognized by CCC rather than ASY patients, which may be pathogenically relevant. This is the first thorough characterization of T cell epitopes of a tandemly repetitive protozoan antigen and may suggest a role for T cell help in the immunodominance of protozoan repetitive antigens.
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Papers by Lucia Jamli Abel