RESUMEN
Malaria is associated with complicated immunopathogenesis. In this study, we provide evidence for an unexpected role of TLR3 in promoting the establishment of Plasmodium yoelii infection through delayed clearance of parasitemia in wild type C57BL/6jRj (B6) compared with TLR3 knockout mice. In this study, we confirmed an increased expression of Tlr3, Trif, Tbk1, and Irf7/Irf3 in the liver 42 h postinfection and the initiation of an early burst of proinflammatory response such as Ifng, NF-kB, and Tnfa in B6 mice that may promote parasite fitness. Interestingly, in the absence of TLR3, we showed the involvement of high IFN-γ and lower type I IFN response in the early clearance of parasitemia. In parallel, we observed an increase in splenic NK and NKT cells expressing TLR3 in infected B6 mice, suggesting a role for TLR sensing in the innate immune response. Finally, we find evidence that the increase in the frequency of CD19+TLR3+ B cells along with reduced levels of total IgG in B6 mice possibly suggests the initiation of TLR3-dependent pathway early during P. yoelii infection. Our results thus reveal a new mechanism in which a parasite-activated TLR3 pathway promotes blood stage infection along with quantitative and qualitative differences in Ab responses.
Asunto(s)
Malaria/inmunología , Mamíferos/inmunología , Mamíferos/parasitología , Plasmodium yoelii/inmunología , Receptor Toll-Like 3/inmunología , Animales , Linfocitos B/inmunología , Inmunidad Innata/inmunología , Inmunoglobulina G/inmunología , Inflamación/inmunología , Inflamación/parasitología , Interferón Tipo I/inmunología , Interferón gamma/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/parasitología , Malaria/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/parasitología , Parasitemia/inmunología , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Genetic mapping and genome-wide studies provide evidence for the association of several genetic polymorphisms with malaria, a complex pathological disease with multiple severity degrees. We have previously described Berr1and Berr2 as candidate genes identified in the WLA/Pas inbreed mouse strain predisposing to resistance to cerebral malaria (CM) induced by P. berghei ANKA. We report in this study the phenotypic and functional characteristics of a congenic strain we have derived for Berr2WLA allele on the C57BL/6JR (B6) background. B6.WLA-Berr2 was found highly resistant to CM compared to C57BL/6JR susceptible mice. The mechanisms associated with CM resistance were analyzed by combining genotype, transcriptomic and immune response studies. We found that B6.WLA-Berr2 mice showed a reduced parasite sequestration and blood-brain barrier disruption with low CXCR3+ T cell infiltration in the brain along with altered glial cell response upon P. berghei ANKA infection compared to B6. In addition, we have identified the CD300f, belonging to a family of Ig-like encoding genes, as a potential candidate associated with CM resistance. Microglia cells isolated from the brain of infected B6.WLA-Berr2 mice significantly expressed higher level of CD300f compared to CMS mice and were associated with inhibition of inflammatory response.
Asunto(s)
Malaria Cerebral/genética , Microglía/metabolismo , Receptores Inmunológicos/metabolismo , Alelos , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/patología , Mapeo Cromosómico , Modelos Animales de Enfermedad , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Femenino , Genotipo , Malaria Cerebral/metabolismo , Malaria Cerebral/parasitología , Ratones , Ratones Endogámicos C57BL , Microglía/fisiología , Receptores Inmunológicos/genéticaRESUMEN
Astrocytes and microglia are activated during cerebral malaria (CM) and contribute to the production and release of several mediators during neuroinflammatory processes. Whether these changes are the consequence of a direct crosstalk between glial cells and the malarial parasite and how these cells participate in the pathogenesis of CM is not yet clear. We therefore examined the interaction of astrocytes and microglia with Plasmodium berghei ANKA-infected red blood cells using primary cell cultures derived from newborn C57BL/6 mice. We observed a dynamic transfer of vesicles from the parasite to astrocytes within minutes of contact, and the phagocytosis of infected red blood cells by microglia. Differential gene expression studies using the Affymetrix GeneChip® microarray, and quantitative PCR analyses showed the increase in expression of the set of genes belonging to the immune response network in parasite activated astrocytes and microglia. Interestingly, expression of these genes was also significantly upregulated in brains of mice dying from CM compared with uninfected mice or infected mice that did not develop the neuropathology. Accumulation of parasite-derived vesicles within astrocytes, and the phagocytosis of infected red blood cells by microglia induced a subsequent increase in interferon gamma inducible protein 10 (IP10) in both the brain and plasma of infected mice at the onset of CM, confirming a role for this molecule in CM pathogenesis. Altogether, these observations point to a possible role for glial cells in the neuropathological processes leading to CM. GLIA 2016 GLIA 2017;65:75-92.
Asunto(s)
Astrocitos/parasitología , Eritrocitos/parasitología , Malaria Cerebral/parasitología , Microglía/parasitología , Fagocitosis/fisiología , Animales , Astrocitos/metabolismo , Encéfalo/parasitología , Encéfalo/patología , Células Cultivadas , Citocinas/metabolismo , Femenino , Malaria Cerebral/patología , Ratones Endogámicos C57BL , Microglía/metabolismoRESUMEN
The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4(+) T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4(+) T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4(+) T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4(-/-)) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.
Asunto(s)
Encéfalo/inmunología , Malaria Cerebral/inmunología , Plasmodium berghei/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Encéfalo/citología , Encéfalo/parasitología , Antígenos CD4/genética , Antígenos CD4/metabolismo , Movimiento Celular/inmunología , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Malaria Cerebral/parasitología , Malaria Cerebral/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Bazo/citología , Bazo/inmunología , Linfocitos T Reguladores/trasplanteRESUMEN
Cerebral malaria is the deadliest complication of Plasmodium falciparum infection. Its pathophysiology is associated with a strong pro-inflammatory reaction and the activation of glial cells. Among modulators released during the infection, heme seems to play a controversial role in the pathophysiology of malaria. Herein, we first investigated the phenotype of glial cells during cerebral malaria in C57BL/6 mice infected with P. berghei ANKA. Given the fact that high levels of heme were associated with cerebral malaria, we then investigated its impact on microglial, astrocyte, and T cell responses to further clarify its contribution in the neuropathophysiology. Surprisingly, we found that administration of heme twice a day from day three of infection induced the expression of the Heme oxygenase-1 (Hmox1) gene and prevented brain damages. More specifically, heme inhibited the M1 phenotype of microglia, hampered the activation of astrocytes, and decreased the cerebral expression of Ifng, Tnfa and Ip10. Heme might that way alter the migration of pathogenic CD4 and CD8 T lymphocytes within the brain observed during cerebral malaria. Taking into account that cerebral malaria results from a complex interplay between host- and parasite-derived factors, it is possible that genetic polymorphisms of Hmox1, which could be associated with the control of systemic levels of heme during P. falciparum infection, might explain its dual role and its contribution to the resistance to cerebral malaria.
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Astrocitos/inmunología , Encéfalo/inmunología , Encéfalo/parasitología , Hemo/metabolismo , Malaria Cerebral/inmunología , Microglía/inmunología , Linfocitos T/metabolismo , Animales , Femenino , Hemo/administración & dosificación , Hemo-Oxigenasa 1/metabolismo , Encefalitis Infecciosa/complicaciones , Malaria Cerebral/complicaciones , Malaria Cerebral/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Plasmodium berghei/patogenicidad , BazoRESUMEN
Several immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.
Asunto(s)
Hemo/metabolismo , Malaria Falciparum/sangre , Plasmodium falciparum/fisiología , Adulto , Quimiocina CCL2/sangre , Progresión de la Enfermedad , Femenino , Hemopexina/metabolismo , Humanos , India , Interleucina-10/sangre , Malaria Falciparum/parasitología , Malaria Falciparum/patología , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
BACKGROUND: Plasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)-mainly associated with acute renal failure (ARF)-and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha. METHODS: P. falciparum malaria patients from the SCB Medical College Cuttack in the Odisha state in India were enrolled along with three sets of controls: healthy individuals, patients with sepsis and encephalitis (n = 222). We determined plasma concentrations of pro- and anti-inflammatory cytokines and chemokines for all individuals using a multiplex assay. We then used an ensemble of statistical analytical methods to ascertain whether particular sets of cytokines/chemokines were predictors of severity or signatures of a disease category. RESULTS: Of the 26 cytokines/chemokines tested, 19 increased significantly during malaria and clearly distinguished malaria patients from controls, as well as sepsis and encephalitis patients. High amounts of IL-17, IP-10, and IL-10 predicted MOD, decreased IL-17 and MIP-1α segregated CM-MOD from MOD, and increased IL-12p40 differentiated CM from CM-MOD. Most severe malaria patients with ARF exhibited high levels of IL-17. CONCLUSION: We report distinct differences in cytokine production correlating with malarial disease severity in Odisha and Maharashtra populations in India. We show that CM, CM-MOD and MOD are clearly distinct malaria-associated pathologies. High amounts of IL-17, IP-10, and IL-10 were predictors of MOD; decreased IL-17 and MIP-1α separated CM-MOD from MOD; and increased IL-12p40 differentiated CM from CM-MOD. Data also suggest that the IL-17 pathway may contribute to malaria pathogenesis via different regulatory mechanisms and may represent an interesting target to mitigate the pathological processes in malaria-associated ARF.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Quimiocina CXCL10/fisiología , Interleucina-10/fisiología , Interleucina-17/fisiología , Malaria Falciparum/fisiopatología , Insuficiencia Multiorgánica/fisiopatología , Lesión Renal Aguda/patología , Quimiocina CXCL10/sangre , Humanos , Interleucina-10/sangre , Interleucina-17/sangre , Malaria Falciparum/patología , Insuficiencia Multiorgánica/patologíaRESUMEN
BACKGROUND: Mechanisms of acquired protection to malaria in asymptomatic Plasmodium falciparum carriers are only partially understood. Among them, the role plays by the self-reactive antibodies has not been clarified yet. In this study, the relationship between repertoires of circulating self-reactive and parasite-specific immunoglobulin G (IgG), their correlation with cytokine levels, and their association with protection against malaria was investigated in asymptomatic Plasmodium falciparum-infected Gabonese children. METHODS: The diversity of P. falciparum-specific antibody repertoire was analysed using a protein micro-array immunoassay, the total auto-antibody repertoire by quantitative immunoblotting and circulating cytokine levels were measured by ELISA in endemic controls (EC) and P. falciparum-infected children from Gabon with asymptomatic (AM) or mild malaria (MM). The association of self- and parasite-specific antibody repertoires with circulating cytokines was evaluated using single linkage hierarchical clustering, Kruskal-Wallis tests and Spearman's rank correlation. RESULTS: Children with AM exhibited an IgG response to merozoite surface protein 3 (MSP3) but not to MSP1-19, although their levels of total P. falciparum-specific IgG were similar to those in the MM group. Moreover, the asymptomatic children had increased levels of autoantibodies recognising brain antigens. In addition, a correlation between IL-10 levels and parasite load was found in AM and MM children. These two groups also exhibited significant correlations between plasma levels of IL-10 and IFN-γ with age and with total plasma IgG levels. IL-10 and IFN-γ levels were also associated with auto-antibody responses in AM. CONCLUSIONS: Altogether, these results indicate that a self-reactive polyclonal response associated with increased IgG to MSP3 and high plasma levels of IL-10 and IFN-γ may contribute to protective immune mechanisms triggered in asymptomatic P. falciparum infection in Gabonese children.
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Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Autoanticuerpos/sangre , Interleucina-10/sangre , Malaria Falciparum/inmunología , Plasmodium falciparum/fisiología , Proteínas Protozoarias/inmunología , Infecciones Asintomáticas , Autoanticuerpos/biosíntesis , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Gabón , Humanos , Lactante , Malaria Falciparum/parasitología , MasculinoRESUMEN
Plasmodium falciparum infection generally induces elevated total plasma levels of immunoglobulins, some of which recognize self- or parasite-specific antigens. To our knowledge, we are the first to report high levels of functional immunoglobulin E (IgE) autoantibodies recognizing brain 14-3-3 protein ε in asymptomatic P. falciparum malaria. 14-3-3 ε protein belongs to a family of proteins that binds to CD81, a member of the tetraspanin superfamily elicited in hepatocyte invasion by sporozoites. Levels of expression of 14-3-3 ε protein were found to be increased in vivo and in vitro during Plasmodium yoelii and P. falciparum intrahepatic development. Collectively, these results indicate that self-reactive IgE is produced during malaria. In addition, the negative correlation between levels of self-reactive IgE to 14-3-3 ε protein and parasitemia in asymptomatic malaria due to P. falciparum supports a role for these IgE molecules in defense mechanisms, probably by interfering with development of liver-stage parasites through the CD81 pathway.
Asunto(s)
Proteínas 14-3-3/inmunología , Autoanticuerpos/sangre , Inmunoglobulina E/sangre , Malaria Falciparum/inmunología , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Animales , Anopheles/parasitología , Autoantígenos , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica , Humanos , Lactante , Hígado/parasitología , Malaria Falciparum/patología , Plasmodium falciparum/inmunología , Plasmodium falciparum/fisiología , Plasmodium yoelii/inmunología , Plasmodium yoelii/fisiologíaRESUMEN
Cutaneous leishmaniasis (CL) caused by infection with the parasite Leishmania exhibits a large spectrum of clinical manifestations ranging from single healing to severe chronic lesions with the manifestation of resistance or not to treatment. Depending on the specie and multiple environmental parameters, the evolution of lesions is determined by a complex interaction between parasite factors and the early immune responses triggered, including innate and adaptive mechanisms. Moreover, lesion resolution requires parasite control as well as modulation of the pathologic local inflammation responses and the initiation of wound healing responses. Here, we have summarized recent advances in understanding the in situ immune response to cutaneous leishmaniasis: i) in North Africa caused by Leishmania (L.) major, L. tropica, and L. infantum, which caused in most cases localized autoresolutives forms, and ii) in French Guiana resulting from L. guyanensis and L. braziliensis, two of the most prevalent strains that may induce potentially mucosal forms of the disease. This review will allow a better understanding of local immune parameters, including cellular and cytokines release in the lesion, that controls infection and/or protect against the pathogenesis in new world compared to old world CL.
Asunto(s)
Leishmania , Leishmaniasis Cutánea , Humanos , Guyana Francesa/epidemiología , África del Norte , CitocinasRESUMEN
Malaria, caused by Plasmodium species (spp.), is a deadly parasitic disease that results in approximately 400,000 deaths per year globally. Autophagy pathways play a fundamental role in the developmental stages of the parasite within the mammalian host. They are also involved in the production of Plasmodium-derived extracellular vesicles (EVs), which play an important role in the infection process, either by providing nutrients for parasite growth or by contributing to the immunopathophysiology of the disease. For example, during the hepatic stage, Plasmodium-derived EVs contribute to parasite virulence by modulating the host immune response. EVs help in evading the different autophagy mechanisms deployed by the host for parasite clearance. During cerebral malaria, on the other hand, parasite-derived EVs promote an astrocyte-mediated inflammatory response, through the induction of a non-conventional host autophagy pathway. In this review, we will discuss the cross-talk between Plasmodium-derived microvesicles and autophagy, and how it influences the outcome of infection.
RESUMEN
The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56(lck), actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the gammadeltaTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR- but not gammadeltaTCR-expressing cells. A role of c-Cbl-mediated ubiquitination in pre-TCR degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl-deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function.
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Endocitosis , Receptores de Antígenos de Linfocitos T/metabolismo , Actinas/metabolismo , Animales , Biopolímeros/metabolismo , Membrana Celular/metabolismo , Cisteína Endopeptidasas/metabolismo , Dinaminas , GTP Fosfohidrolasas/metabolismo , Hidrólisis , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Lisosomas/metabolismo , Ratones , Ratones SCID , Complejos Multienzimáticos/metabolismo , Complejo de la Endopetidasa Proteasomal , Transducción de SeñalRESUMEN
In the present report, we revisited the B cell responsiveness of 7 wild-derived mouse strains to various toll-like receptor ligands (TLR-L). We found that 2 of them, namely PWK and STF presented profound defects in B cell proliferative responses to most of the TLR-L. Yet, their macrophage responses were largely unaffected, suggesting that regulation of TLR pathways are distinct in B cells and macrophages. We also showed that, anti-CD40 mAbs rescued the low proliferative responses to CpG in both PWK and STF B cells. In the other hand, CpG synergized with LPS to induce high levels of proliferation in STF B cells, which did not respond to LPS alone. Cytokine or immunoglobulin (Ig) productions, in vitro, were less impaired than the proliferative responses to LPS or CpG alone. In STF B cells, both ERK, P38 and JNK pathways were affected following in vitro TLR4 or TLR9 signaling. Moreover, while the basal levels of Ig secreting cells and of serum Igs were similar to that of control mice, antibody responses to both TI and TD antigens were severely affected, mainly in STF mice. Our findings therefore highlight the relevance of wild-derived mouse strains and TLR-L to study B cell physiology.
Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Macrófagos Peritoneales/inmunología , Proteínas Quinasas/metabolismo , Receptores Toll-Like/inmunología , Animales , Formación de Anticuerpos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/efectos de los fármacos , Citocinas/inmunología , Ligandos , Lipopéptidos/farmacología , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Modelos Animales , Oligodesoxirribonucleótidos/farmacología , Polimorfismo Genético , Proteínas Quinasas/efectos de los fármacos , Proteínas Quinasas/inmunología , Receptores Toll-Like/efectos de los fármacos , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: In murine models of malaria, an early proinflammatory response has been associated with the resolution of blood-stage infection. To dissect the protective immune mechanism that allow the control of parasitaemia, the early immune response of C57BL/6 mice induced during a non-lethal plasmodial infection was analysed. METHODS: Mice were infected with Plasmodium yoelii 265BY sporozoites, the natural invasive form of the parasite, in order to complete its full life cycle. The concentrations of three proinflammatory cytokines in the sera of mice were determined by ELISA at different time points of infection. The contribution of the liver and the spleen to this cytokinic response was evaluated and the cytokine-producing lymphocytes were identified by flow cytometry. The physiological relevance of these results was tested by monitoring parasitaemia in genetically deficient C57BL/6 mice or wild-type mice treated with anti-cytokine neutralizing antibody. Finally, the cytokinic response in sera of mice infected with parasitized-RBCs was analysed. RESULTS: The early immune response of C57BL/6 mice to sporozoite-induced malaria is characterized by a peak of IFN-gamma in the serum at day 5 of infection and splenic CD4 T lymphocytes are the major producer of this cytokine at this time point. Somewhat unexpected, the parasitaemia is significantly lower in P. yoelii-infected mice in the absence of IFN-gamma. More precisely, at early time points of infection, IFN-gamma favours parasitaemia, whereas helping to clear efficiently the blood-stage parasites at later time points. Interestingly, the early IFN-gamma burst is induced by the pre-erythrocytic stage. CONCLUSION: These results challenge the current view regarding the role of IFN-gamma on the control of parasite growth since they show that IFN-gamma is not an essential mediator of protection in P. yoelii-infected C57BL/6 mice. Moreover, the mice parasitaemia is more efficiently controlled in the absence of an early IFN-gamma production, suggesting that this cytokine promotes parasite's growth. Finally, this early burst of IFN-gamma is induced by the pre-erythrocytic stage, showing the impact of this stage on the immune response taking place during the subsequent erythrocytic stage.
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Interferón gamma/inmunología , Parasitemia/inmunología , Plasmodium yoelii/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Interferón gamma/sangre , Hígado/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Bazo/inmunologíaRESUMEN
Mouse T-cell development is unfinished at birth and continues during the first month of life, when T cells exit from the thymus and colonize secondary hematopoietic organs to build up a peripheral T-cell repertoire. T-cell responses against beta-cell-derived autoantigens are initiated in the pancreatic lymph nodes (PLN) of non-obese diabetic (NOD) mice during the same time period. We hypothesized that the combined effect of T-cell development and T-cell activation against tissue-specific antigens would create unique TCR repertoires in two different lymph node stations in NOD mice. To test this hypothesis, we determined the length distribution of the third complementarity-determining region (CDR3) of the TCR in the PLN and the inguinal lymph nodes (ILN) of 10, 14, 18 and 22-day-old NOD females. The analysis of all the BV genes revealed significant perturbations of the repertoire between days 10 and 22 but with no statistical differences between the PLN and ILN repertoires. In contrast, when a set of BV chains were amplified using BJ-specific primers, several unique TCR perturbations were observed in the PLN compared to the ILN. We propose that the TCR repertoire in peripheral lymph nodes of NOD mice develops dynamically between 10 and 22 days of age as a result of a developmental process. On top of that development, the local environment may fine-tune that repertoire, possibly by means of stimulation of T cells by tissue-specific antigens presented by local APC.
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Ganglios Linfáticos/inmunología , Páncreas/inmunología , Estado Prediabético/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Animales Recién Nacidos , Regiones Determinantes de Complementariedad/inmunología , Femenino , Ratones , Ratones Endogámicos NOD , Factores de TiempoRESUMEN
In vertebrates, the world of antigenic motifs is matched to large populations of lymphocytes through specific recognition of an epitope by a given receptor unique to a lymphocyte clone. The concept of immune repertoire was proposed to describe this diversity of lymphocyte receptors - Ig and TCR - required by the network of interactions. The immune repertoires became useful tools to describe lymphocyte and receptor populations through the development of the immune system and in pathological situations. Recently, the development of mass technologies made possible a comprehensive survey of immune repertoires at the genome, transcript and protein levels, and some of these techniques have been already adapted to TCR and Ig repertoire analyses. Such approaches generate very big datasets, which necessitates complex and multi-parametric annotations in dedicated databases. They also require new analysis methods, leading to the integration of structure and dynamics of the immune repertoires, at different time scales (immune response, development of the individual, evolution of the species). Such methods may be extended to the analysis of new classes of adaptive-like receptors, which were recently discovered in different invertebrates and in agnathans. Ultimately, they may allow a parallel monitoring of pathogen and immune repertoires addressing the reciprocal influences that decide for the host survival or death. In this review, we first study the characteristics of Ig and TCR repertoires, and we examine several systematic approaches developed for the analysis of these "classical" immune repertoires at different levels. We then consider examples of the recent developments of modeling and statistical analysis, and we discuss their relevance and their importance for the study of the immune diversity. An extended view of immune repertoires is proposed, integrating the diversity of other receptors involved in immune recognition. Also, we discuss how repertoire studies could link pathogen variation and immune diversity to reveal regulatory patterns and rules driving their co-diversification race.
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Subgrupos de Linfocitos B/inmunología , Reordenamiento Génico de Linfocito T , Receptores de Antígenos de Linfocitos T , Receptores Inmunológicos , Subgrupos de Linfocitos T/inmunología , Receptores Toll-Like , Animales , Genómica/métodos , Humanos , Inmunoglobulinas , Receptores de Antígenos de Linfocitos T/genética , Receptores Inmunológicos/genética , Receptores Toll-Like/genéticaRESUMEN
Pathogenic CD8+ T cells are implicated in the physiopathological mechanisms leading to experimental cerebral malaria (CM) in Plasmodium berghei ANKA (PbA) infected mice. Therefore, we hypothesised that in CM susceptible mice the neuropathology could be, at least in part, the result of an inefficient control of pathogenic effector T cells by CD4+ CD25+ Treg cells. Remarkably, the number of CD4+ CD25high T cells expressing Foxp3 increased in the spleen during the course of infection. These cells displayed an activated phenotype and consistent with that, CD4+ CD25high Treg cells isolated from PbA-infected mice showed an enhanced regulatory activity in vitro. Surprisingly, these cells do not migrate to the brain at the time of neurological symptoms as the conventional CD4+ T cells do. CM was not exacerbated in anti-CD25 treated mice when infected with PbA one month after treatment, even if splenic CD8+ T cells expressing CD69 increased in these mice. Taken together, these results show that P. berghei infection leads to an increase of the number of splenic CD4+ CD25high Treg cells exhibiting in vitro suppressive function, but they do not seem to be involved in vivo in the protection against CM.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Malaria Cerebral/inmunología , Plasmodium berghei/fisiología , Animales , Malaria Cerebral/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/citologíaRESUMEN
BACKGROUND: There is an increase of serum levels of IgE during Plasmodium falciparum infections in individuals living in endemic areas. These IgEs either protect against malaria or increase malaria pathogenesis. To get an insight into the exact role played by IgE in the outcome of P. falciparum infection, total IgE levels and functional anti-parasite IgE response were studied in children and adults, from two different endemic areas Gabon and India, exhibiting either uncomplicated malaria, severe non cerebral malaria or cerebral malaria, in comparison with control individuals. METHODOLOGY AND RESULTS: Blood samples were collected from controls and P. falciparum-infected patients before treatment on the day of hospitalization (day 0) in India and, in addition, on days 7 and 30 after treatment in Gabon. Total IgE levels were determined by ELISA and functional P. falciparum-specific IgE were estimated using a mast cell line RBL-2H3 transfected with a human Fcepsilon RI alpha-chain that triggers degranulation upon human IgE cross-linking. Mann Whitney and Kruskall Wallis tests were used to compare groups and the Spearman test was used for correlations. Total IgE levels were confirmed to increase upon infection and differ with level of transmission and age but were not directly related to the disease phenotype. All studied groups exhibited functional parasite-specific IgEs able to induce mast cell degranulation in vitro in the presence of P. falciparum antigens. Plasma IgE levels correlated with those of IL-10 in uncomplicated malaria patients from Gabon. In Indian patients, plasma IFN-gamma , TNF and IL-10 levels were significantly correlated with IgE concentrations in all groups. CONCLUSION: Circulating levels of total IgE do not appear to correlate with protection or pathology, or with anti-inflammatory cytokine pattern bias during malaria. On the contrary, the P. falciparum-specific IgE response seems to contribute to the control of parasites, since functional activity was higher in asymptomatic and uncomplicated malaria patients than in severe or cerebral malaria groups.
Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Especificidad de Anticuerpos , Inmunoglobulina E/sangre , Malaria Cerebral/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Adolescente , Adulto , Anciano , Animales , Línea Celular , Niño , Preescolar , Femenino , Gabón , Humanos , India , Lactante , Malaria Cerebral/parasitología , Malaria Cerebral/fisiopatología , Malaria Falciparum/parasitología , Malaria Falciparum/fisiopatología , Masculino , Mastocitos , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
Cerebral malaria (CM) caused by Plasmodium falciparum parasites often leads to the death of infected patients or to persisting neurological sequelae despite anti-parasitic treatments. Erythropoietin (EPO) was recently suggested as a potential adjunctive treatment for CM. However diverging results were obtained in patients from Sub-Saharan countries infected with P. falciparum. In this study, we measured EPO levels in the plasma of well-defined groups of P. falciparum-infected patients, from the state of Odisha in India, with mild malaria (MM), CM, or severe non-CM (NCM). EPO levels were then correlated with biological parameters, including parasite biomass, heme, tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon gamma-induced protein (IP)-10, and monocyte chemoattractant protein (MCP)-1 plasma concentrations by Spearman's rank and multiple correlation analyses. We found a significant increase in EPO levels with malaria severity degree, and more specifically during fatal CM. In addition, EPO levels were also found correlated positively with heme, TNF-α, IL-10, IP-10 and MCP-1 during CM. We also found a significant multivariate correlation between EPO, TNF-α, IL-10, IP-10 MCP-1 and heme, suggesting an association of EPO with a network of immune factors in CM patients. The contradictory levels of circulating EPO reported in CM patients in India when compared to Africa highlights the need for the optimization of adjunctive treatments according to the targeted population.