RESUMO
A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group. Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-ß and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.
Assuntos
COVID-19 , Eritropoese , Síndrome de Fadiga Crônica , SARS-CoV-2 , Humanos , Síndrome de Fadiga Crônica/imunologia , Síndrome de Fadiga Crônica/sangue , COVID-19/imunologia , COVID-19/sangue , COVID-19/complicações , Feminino , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Adulto , Eritropoese/imunologia , Galectinas/sangue , Galectinas/imunologia , Citocinas/sangue , Citocinas/metabolismo , Síndrome de COVID-19 Pós-Aguda , Inflamação/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/sangueRESUMO
BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) attributable to anti-M is rare, although case reports implicate anti-M in varying severities of HDFN, including fetal hydrops and intrauterine death. CASE DESCRIPTION: We describe the case of a newborn with HDFN associated with an atypical immunoglobulin (Ig) G anti-M that reacted best at cold temperatures. The maternal antibody detected in pregnancy was not reactive at 37°C, and a direct antiglobulin test (DAT) on red blood cells (RBCs) from the newborn was negative, suggesting an anti-M that should not have been clinically relevant. However, the infant developed hyperbilirubinemia (bilirubin level, 17.6 mg/dL), hemolytic anemia (hemoglobin nadir, 5.5 g/dL), and reticulocytopenia. Laboratory testing demonstrated the presence of an IgG anti-M in maternal and neonatal samples reacting best at 4°C. This passively acquired IgG anti-M provoked hemolytic anemia in the infant and likely suppressed erythropoiesis, resulting in reticulocytopenia with prolonged anemia. He was treated for IgG anti-M HDFN with 10 intravenous Ig infusions and 10 days of oral prednisone followed by a taper. He required seven transfusions with M- RBCs. His hemoglobin level normalized at 3 months of age. Follow-up at 2 years revealed no hematologic or neuro-developmental concerns. CONCLUSION: To our knowledge, this is the second report of HDFN attributable to an IgG anti-M reacting preferentially at cold temperature with no 37°C reactivity. Clinically relevant IgG anti-M may elude standard testing. Early recognition and testing for cold-reacting IgG anti-M should be considered for newborns with hemolysis, a negative DAT, and prolonged anemia.
Assuntos
Anemia Hemolítica/imunologia , Eritroblastose Fetal/diagnóstico , Eritroblastose Fetal/imunologia , Imunoglobulina G/sangue , Anemia Hemolítica/complicações , Anemia Hemolítica/tratamento farmacológico , Anemia Hemolítica/etiologia , Transfusão de Sangue , Temperatura Baixa , Teste de Coombs , Eritroblastose Fetal/tratamento farmacológico , Eritroblastose Fetal/etiologia , Eritrócitos/imunologia , Eritropoese/imunologia , Feminino , Hemoglobinas/metabolismo , Humanos , Recém-Nascido , Masculino , GravidezRESUMO
Biological treatments such as enzyme-replacement therapies (ERT) can generate anti-drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low-dose methotrexate (TLD-MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long-lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD-MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high-risk, cross-reactive immunological material (CRIM)-negative infantile-onset Pompe disease (IOPD) patients. More recently, evaluation of TLD-MTX demonstrated benefit in CRIM-positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD-MTX, non-targeted transcriptional and proteomic screens were conducted and revealed up-regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter-119+ CD71+ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD-MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Eritroblastos/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Metotrexato/administração & dosagem , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Relação Dose-Resposta a Droga , Eritroblastos/citologia , Eritroblastos/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/imunologia , Eritrócitos/metabolismo , Eritropoese/efeitos dos fármacos , Eritropoese/genética , Eritropoese/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Metotrexato/imunologia , Camundongos Endogâmicos C57BL , Proteômica/métodos , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , alfa-Glucosidases/administração & dosagemRESUMO
Paired Box (Pax) gene family, a group of transcription regulators have been implicated in diverse physiological processes. However, their role during hematopoiesis which generate a plethora of blood cells remains largely unknown. Using a previously reported single cell transcriptomics data, we analyzed the expression of individual Pax family members in hematopoietic cells in zebrafish. We have identified that Pax9, which is an essential regulator for odontogenesis and palatogenesis, is selectively localized within a single cluster of the hematopoietic lineage. To further analyze the function of Pax9 in hematopoiesis, we generated two independent pax9 knock-out mutants using the CRISPR-Cas9 technique. We found that Pax9 appears to be an essential regulator for granulopoiesis but dispensable for erythropoiesis during development, as lack of pax9 selectively decreased the number of neutrophils with a concomitant decrease in the expression level of neutrophil markers. In addition, embryos, where pax9 was functionally disrupted by injecting morpholinos, failed to increase the number of neutrophils in response to pathogenic bacteria, suggesting that Pax9 is not only essential for developmental granulopoiesis but also emergency granulopoiesis. Due to the inability to initiate emergency granulopoiesis, innate immune responses were severely compromised in pax9 morpholino-mediated embryos, increasing their susceptibility and mortality. Taken together, our data indicate that Pax9 is essential for granulopoiesis and promotes innate immunity in zebrafish larvae.
Assuntos
Eritropoese/imunologia , Mielopoese/imunologia , Fator de Transcrição PAX9/imunologia , Proteínas de Peixe-Zebra/imunologia , Peixe-Zebra/imunologia , Animais , Animais Geneticamente Modificados , Infecções Bacterianas/imunologia , Sistemas CRISPR-Cas , Eritropoese/genética , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Granulócitos/imunologia , Imunidade Inata/genética , Imunidade Inata/fisiologia , Mielopoese/genética , Fator de Transcrição PAX9/deficiência , Fator de Transcrição PAX9/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genéticaRESUMO
Anemia of inflammation (AI) is the second most prevalent anemia after iron deficiency anemia and results in persistent low blood erythrocytes and hemoglobin, fatigue, weakness, and early death. Anemia of inflammation is common in people with chronic inflammation, chronic infections, or sepsis. Although several studies have reported the effect of inflammation on stress erythropoiesis and iron homeostasis, the mechanisms by which inflammation suppresses erythropoiesis in the bone marrow (BM), where differentiation and maturation of erythroid cells from hematopoietic stem cells (HSCs) occurs, have not been extensively studied. Here we show that in a mouse model of acute sepsis, bacterial lipopolysaccharides (LPS) suppress medullary erythroblastic islands (EBIs) and erythropoiesis in a TLR-4- and MyD88-dependent manner with concomitant mobilization of HSCs. LPS suppressive effect on erythropoiesis is indirect as erythroid progenitors and erythroblasts do not express TLR-4 whereas EBI macrophages do. Using cytokine receptor gene knock-out mice LPS-induced mobilization of HSCs is G-CSF-dependent whereas LPS-induced suppression of medullary erythropoiesis does not require G- CSF-, IL- 1-, or TNF-mediated signaling. Therefore suppression of medullary erythropoiesis and mobilization of HSCs in response to LPS are mechanistically distinct. Our findings also suggest that EBI macrophages in the BM may sense innate immune stimuli in response to acute inflammation or infections to rapidly convert to a pro-inflammatory function at the expense of their erythropoietic function.
Assuntos
Anemia/imunologia , Medula Óssea/imunologia , Eritropoese/imunologia , Macrófagos/imunologia , Sepse/complicações , Animais , Fator Estimulador de Colônias de Granulócitos , Interleucina-1 , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Sepse/imunologia , Fator de Necrose Tumoral alfaRESUMO
Steady-state erythropoiesis generates new erythrocytes at a constant rate, and it has enormous productive capacity. This production is balanced by the removal of senescent erythrocytes by macrophages in the spleen and liver. Erythroid homeostasis is highly regulated to maintain sufficient erythrocytes for efficient oxygen delivery to the tissues, while avoiding viscosity problems associated with overproduction. However, there are times when this constant production of erythrocytes is inhibited or is inadequate; at these times, erythroid output is increased to compensate for the loss of production. In some cases, increased steady-state erythropoiesis can offset the loss of erythrocytes but, in response to inflammation caused by infection or tissue damage, steady-state erythropoiesis is inhibited. To maintain homeostasis under these conditions, an alternative stress erythropoiesis pathway is activated. Emerging data suggest that the bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis pathway is integrated into the inflammatory response and generates a bolus of new erythrocytes that maintain homeostasis until steady-state erythropoiesis can resume. In this perspective, we define the mechanisms that generate new erythrocytes when steady-state erythropoiesis is impaired and discuss experimental models to study human stress erythropoiesis.
Assuntos
Proteína Morfogenética Óssea 4/genética , Eritrócitos/citologia , Células Precursoras Eritroides/citologia , Eritropoese/genética , Macrófagos/citologia , Estresse Fisiológico/genética , Animais , Proteína Morfogenética Óssea 4/imunologia , Senescência Celular/imunologia , Citocinas/genética , Citocinas/imunologia , Eritrócitos/imunologia , Células Precursoras Eritroides/imunologia , Eritropoese/imunologia , Regulação da Expressão Gênica , Humanos , Inflamação , Fígado/citologia , Fígado/imunologia , Macrófagos/imunologia , Camundongos , Modelos Biológicos , Fagocitose , Baço/citologia , Baço/imunologia , Estresse Fisiológico/imunologiaRESUMO
Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrow-resident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1-reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes.
Assuntos
Células Precursoras Eritroides/imunologia , Eritropoese/imunologia , Mastócitos/imunologia , Mastocitose/imunologia , Trichinella spiralis/imunologia , Triquinelose/imunologia , Animais , Anidrase Carbônica I/genética , Anidrase Carbônica I/imunologia , Células Precursoras Eritroides/parasitologia , Células Precursoras Eritroides/patologia , Feminino , Mastócitos/parasitologia , Mastócitos/patologia , Mastocitose/genética , Mastocitose/patologia , Camundongos , Camundongos Transgênicos , Triquinelose/genética , Triquinelose/patologiaRESUMO
Bone marrow medullary erythropoiesis is primarily homeostatic. It produces new erythrocytes at a constant rate, which is balanced by the turnover of senescent erythrocytes by macrophages in the spleen. Despite the enormous capacity of the bone marrow to produce erythrocytes, there are times when it is unable to keep pace with erythroid demand. At these times stress erythropoiesis predominates. Stress erythropoiesis generates a large bolus of new erythrocytes to maintain homeostasis until steady state erythropoiesis can resume. In this review, we outline the mechanistic differences between stress erythropoiesis and steady state erythropoiesis and show that their responses to inflammation are complementary. We propose a new hypothesis that stress erythropoiesis is induced by inflammation and plays a key role in maintaining erythroid homeostasis during inflammatory responses.
Assuntos
Eritropoese/imunologia , Inflamação/imunologia , Estresse Fisiológico/imunologia , Animais , Humanos , CamundongosRESUMO
BACKGROUND: Vaccination induces survival of otherwise lethal blood-stage infections of the experimental malaria Plasmodium chabaudi. Blood-stage malaria induces extramedullary erythropoiesis in the liver. This study investigates how vaccination affects the course of malaria-induced expression of erythrocytic genes in the liver. METHODS: Female Balb/c mice were vaccinated at week 3 and week 1 before challenging with 106 P. chabaudi-parasitized erythrocytes. The non-infectious vaccine consisted of erythrocyte ghosts isolated from P. chabaudi-infected erythrocytes. Gene expression microarrays and quantitative real-time PCR were used to compare mRNA expression of different erythrocytic genes in the liver of vaccination-protected and non-protected mice during infections on days 0, 1, 4, 8, and 11 p.i. RESULTS: Global transcriptomics analyses reveal vaccination-induced modifications of malaria-induced increases in hepatic gene expression on days 4 and 11 p.i. On these days, vaccination also alters hepatic expression of the erythropoiesis-involved genes Ermap, Kel, Rhd, Rhag, Slc4a1, Gypa, Add2, Ank1, Epb4.1, Epb4.2, Epb4.9, Spta1, Sptb, Tmod1, Ahsp, Acyp1, Gata1, Gfi1b, Tal1, Klf1, Epor, and Cldn13. In vaccination-protected mice, expression of these genes, except Epb4.1, is significantly higher on day 4 p.i. than in un-protected non-vaccinated mice, reaches maximal expression at peak parasitaemia on day 8 p.i., and is slowed down or even decreased towards the end of crisis phase on day 11 p.i.. After day 1 p.i., Epor expression takes about the same course as that of the other erythroid genes. Hepatic expression of Epo, however, is delayed in both vaccinated and non-vaccinated mice for the first 4 days p.i. and is maximal at significantly higher levels in vaccinated mice on day 8 p.i., before declining towards the end of crisis phase on day 11 p.i. CONCLUSION: The present data indicate that vaccination accelerates malaria-induced erythroblastosis in the liver for 1-2 days. This may contribute to earlier replenishment of peripheral red blood cells by liver-derived reticulocytes, which may favour final survival of otherwise lethal blood-stage malaria, since reticulocytes are not preferred as host cells by P. chabaudi.
Assuntos
Eritropoese/imunologia , Fígado/patologia , Malária/sangue , Plasmodium chabaudi/imunologia , Vacinação/efeitos adversos , Animais , Membrana Eritrocítica/imunologia , Eritropoese/genética , Feminino , Fígado/parasitologia , Malária/patologia , Vacinas Antimaláricas/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Análise de Componente Principal , Reação em Cadeia da Polimerase em Tempo Real , Organismos Livres de Patógenos Específicos , TranscriptomaRESUMO
Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1ß promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.
Assuntos
Proteínas de Ligação a DNA/imunologia , Eritropoese/imunologia , Heme/imunologia , Inflamação/imunologia , Estresse Fisiológico/imunologia , Animais , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/imunologia , Proteína Morfogenética Óssea 4/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Eritrócitos/imunologia , Eritrócitos/metabolismo , Células Precursoras Eritroides/imunologia , Células Precursoras Eritroides/metabolismo , Eritropoese/genética , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/imunologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Heme/metabolismo , Inflamação/genética , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/genética , Fagocitose/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Baço/imunologia , Baço/metabolismo , Estresse Fisiológico/genéticaRESUMO
PURPOSE: Anaemia and resistance to erythropoiesis-stimulating agents (ESAs) are common complications in haemodialysis (HD) patients. We investigated the role of hepcidin in the development of anaemia and ESA resistance/hyporesponsiveness and its relation to the plasma levels of the inflammatory markers interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP). METHODS: This study included 60 maintenance HD patients attending Ain Shams University Hospital and 30 age- and sex-matched healthy subjects as a control group. Serum hepcidin, IL-6, hsCRP and haemoglobin (Hb) levels were measured in all subjects. The erythropoietin resistance index (ERI) was calculated in the patient group only. RESULTS: There was a significant difference between the patients and controls; the patients had higher hepcidin, IL-6, and hsCRP levels and a lower Hb level. Patients were classified according to their response to ESAs into responder and non-responder groups. Those in the non-responder group had higher hepcidin, IL-6, and hsCRP levels, a higher ERI, and a lower Hb level. Hepcidin showed a positive correlation with IL-6 and hsCRP but a negative correlation with Hb. Upon performing a ROC curve analysis, a cut-off of ≥ 280 ng/ml for hepcidin and ≥ 7.5 for ERI was able to discriminate the responder and non-responder groups with a prognostic accuracy of 83% and 77.3%, respectively. In addition, upon classifying the patients into tertiles according to the ERI, hepcidin significantly increased with increasing ERI. CONCLUSION: Our findings demonstrate an association between the hepcidin level, anaemia and ESA resistance/hyporesponsiveness in HD patients, suggesting its possible role as a candidate marker for ESA resistance.
Assuntos
Anemia , Proteína C-Reativa/análise , Eritropoese , Hematínicos , Hepcidinas/sangue , Interleucina-6/sangue , Falência Renal Crônica , Diálise Renal/efeitos adversos , Idoso , Anemia/diagnóstico , Anemia/tratamento farmacológico , Anemia/etiologia , Biomarcadores/sangue , Correlação de Dados , Resistência a Medicamentos/imunologia , Eritropoese/efeitos dos fármacos , Eritropoese/imunologia , Feminino , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Humanos , Ferro/metabolismo , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-IdadeRESUMO
Macrophages are represented in all tissues by phenotypically distinct resident populations that show great functional diversity. Macrophages generally play a protumoral role, and they are attractive targets for cancer therapy. In this study, we found that CD169+ macrophages depletion inhibited the growth of established Lewis lung carcinoma tumors in mice. Benefits must be weighed against potential adverse effects in cancer therapy. Here, we investigated the adverse effects of CD169+ macrophages depletion on bone and bone marrow in mice bearing Lewis lung carcinoma tumors. Our studies showed that depletion of CD169+ macrophages in LLC tumor-bearing mice disrupted bone homeostasis, including bone weight loss and bone mineral density decrease. Further studies revealed that bone marrow erythropoiesis was severely impaired after depletion of CD169+ macrophages in LLC tumor-bearing mice. Our findings suggest that depletion of macrophages for cancer therapy may be associated with potential adverse effects that need to be recognized, prevented, and optimally managed.
Assuntos
Medula Óssea/imunologia , Osso e Ossos/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Eritropoese/imunologia , Homeostase/imunologia , Macrófagos/imunologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/imunologia , Medula Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/genética , Linhagem Celular Tumoral , Células Cultivadas , Toxina Diftérica/administração & dosagem , Toxina Diftérica/farmacologia , Eritropoese/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Homeostase/efeitos dos fármacos , Homeostase/genética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismoRESUMO
African trypanosomosis (AT) is a chronically debilitating parasitic disease of medical and economic importance for the development of sub-Saharan Africa. The trypanosomes that cause this disease are extracellular protozoan parasites that have developed efficient immune escape mechanisms to manipulate the entire host immune response to allow parasite survival and transmission. During the early stage of infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS), involving classically activated macrophages (i.e., M1), is required for initial parasite control. Yet, the persistence of this M1-type MPS activation in trypanosusceptible animals causes immunopathology with anemia as the most prominent pathological feature. By contrast, in trypanotolerant animals, there is an induction of IL-10 that promotes the induction of alternatively activated macrophages (M2) and collectively dampens tissue damage. A comparative gene expression analysis between M1 and M2 cells identified galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF) as novel M1-promoting factors, possibly acting synergistically and in concert with TNF-α during anemia development. While Gal-3 enhances erythrophagocytosis, MIF promotes both myeloid cell recruitment and iron retention within the MPS, thereby depriving iron for erythropoiesis. Hence, the enhanced erythrophagocytosis and suppressed erythropoiesis lead to anemia. Moreover, a thorough investigation using MIF-deficient mice revealed that the underlying mechanisms in AT-associated anemia development in trypanosusceptible and tolerant animals are quite distinct. In trypanosusceptible animals, anemia resembles anemia of inflammation, while in trypanotolerant animals' hemodilution, mainly caused by hepatosplenomegaly, is an additional factor contributing to anemia. In this review, we give an overview of how trypanosome- and host-derived factors can contribute to trypanosomosis-associated anemia development with a focus on the MPS system. Finally, we will discuss potential intervention strategies to alleviate AT-associated anemia that might also have therapeutic potential.
Assuntos
Anemia/imunologia , Interações Hospedeiro-Parasita/imunologia , Sistema Fagocitário Mononuclear/imunologia , Trypanosoma brucei gambiense/imunologia , Tripanossomíase Africana/imunologia , Anemia/sangue , Anemia/parasitologia , Animais , Modelos Animais de Doenças , Eritropoese/imunologia , Galectina 3/imunologia , Galectina 3/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Fatores Inibidores da Migração de Macrófagos/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos , Sistema Fagocitário Mononuclear/metabolismo , Trypanosoma brucei gambiense/patogenicidade , Tripanossomíase Africana/sangue , Tripanossomíase Africana/parasitologiaRESUMO
Human visceral leishmaniasis, a parasitic disease of major public health importance in developing countries, is characterized by variable degrees of severity of anemia, but the mechanisms underlying this change in peripheral blood have not been thoroughly explored. Here, we used an experimental model of visceral leishmaniasis in C57BL/6 mice to explore the basis of anemia following infection with Leishmania donovani. 28 days post-infection, mice showed bone marrow dyserythropoiesis by myelogram, with a reduction of TER119+ CD71-/+ erythroblasts. Reduction of medullary erythropoiesis coincided with loss of CD169high bone marrow stromal macrophages and a reduction of CXCL12-expressing stromal cells. Although the spleen is a site of extramedullary erythropoiesis and erythrophagocytosis, splenectomy did not impact the extent of anemia or affect the repression of medullary hematopoiesis that was observed in infected mice. In contrast, these changes in bone marrow erythropoiesis were not evident in B6.Rag2-/- mice, but could be fully reconstituted by adoptive transfer of IFNγ-producing but not IFNγ-deficient CD4+ T cells, mimicking the expansion of IFNγ-producing CD4+ T cells that occurs during infection in wild type mice. Collectively, these data indicate that anemia during experimental murine visceral leishmaniasis can be driven by defects associated with the bone marrow erythropoietic niche, and that this represents a further example of CD4+ T cell-mediated immunopathology affecting hematopoietic competence.
Assuntos
Anemia/etiologia , Linfócitos T CD4-Positivos/imunologia , Eritropoese/imunologia , Leishmania donovani/imunologia , Leishmaniose Visceral/imunologia , Transferência Adotiva , Animais , Medula Óssea/fisiologia , Linfócitos T CD4-Positivos/transplante , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Leishmaniose Visceral/complicações , Leishmaniose Visceral/parasitologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Estromais/fisiologiaRESUMO
Altitude training is associated with changes in blood markers, which can confound results of the Athlete?s Biological Passport (ABP). This meta-analysis aims to describe the fluctuations during- and post-altitude in key ABP variables; hemoglobin concentration ([Hb]), square-root transformed reticulocyte percentage (sqrt(retic%)) and the OFF-score. Individual de-identified raw data were provided from 17 studies. Separate linear mixed effects analyses were performed for delta values from baseline for [Hb], sqrt(retic%) and OFF-score, by altitude phase (during and post). Mixed models were fitted with the hierarchical structure: study and subject within study as random effects. Delta values as response variables and altitude dose (in kilometer hours; km.hr = altitude (m) / 1000 x hours), sex, age, protocol and baseline values as fixed effects. Allowances were made for potential autocorrelation. Within two days at natural altitude [Hb] rapidly increased. Subsequent delta [Hb] values increased with altitude dose, reaching a plateau of 0.94 g/dL [95%CI (0.69, 1.20)] at ~1000 km.hr. Delta sqrt(retic%) and OFF-score were the first to identify an erythrocyte response, with respective increases and decreases observed within 100 to 200 km.hr. Post-altitude, [Hb] remained elevated for two weeks. Delta sqrt(retic%) declined below baseline, the magnitude of change was dependent on altitude dose. Baseline values were a significant covariate (p<0.05). The response to altitude is complex resulting in a wide range of individual responses, influenced primarily by altitude dose and baseline values. Improved knowledge of the plausible hematological variations during- and post-altitude provides fundamental information for both the ABP expert and sports physician.
Assuntos
Atletas , Biomarcadores/sangue , Hipóxia Celular/imunologia , Eritropoese/imunologia , Altitude , Feminino , Humanos , MasculinoRESUMO
Immunosuppression is a well-established risk factor for Visceral Leishmaniasis. Post-immunosuppression leishmaniasis is characterized by an increase of parasite burden, hematopoietic disorders and unusual clinical manifestations. Although there are many reports on bone marrow findings in VL, less is known about the relationship between parasite dynamics in this organ and the function of either hematopoietic stem cells and progenitor cells themselves. In the present study, we tackle these issues using a new approach of infecting human stem cells derived from bone marrow with L. infantum. Using this strategy, we show that human hematopoietic stem cells (hHSC) are able to phagocytize L. infantum promastigotes and release modulatory and pro-inflammatory cytokines, mainly TNF-α. Our results demonstrated that L. infantum infection in vitro enhances hematopoiesis, favoring the development of erythrocitic lineage through a mechanism yet unknown. Moreover, we found that L. infantum infection alters the phenotypic profile of the hematopoietic progeny; modifying the surface markers expression of differentiated cells. Thus, our study represents a rare opportunity to monitor the in vitro differentiation of human stem cells experimentally infected by L. infantum to better understand the consequences of the infection on phenotypic and functional profile of the cell progeny.
Assuntos
Diferenciação Celular/imunologia , Eritropoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Leishmania infantum/imunologia , Fagocitose/imunologia , Adulto , Idoso , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/parasitologia , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/parasitologia , Interações Hospedeiro-Parasita/imunologia , Humanos , Leishmania infantum/fisiologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We have previously shown that human red blood cells (hRBCs) are subject to robust rejection by macrophages in immunodeficient mice. In this study, we found that mouse serum induces hRBC adherence to murine phagocytic cells, including professional phagocytic macrophages and neutrophils and non-professional phagocytic endothelial cells. Complement was found to be responsible for mouse-serum-induced hRBC adherence to murine phagocytic cells. Although hRBC survival was not improved in NOD/SCID mice with complement depletion by cobra venom factor (CVF), CVF significantly prolonged hRBC survival in mice that were depleted of phagocytic macrophages by clodronate-liposomes. This combination treatment also synergistically improved hRBC reconstitution in human CD34+ cell-grafted mice, offering a valuable model to examine human erythropoiesis and RBC function. These data indicate that complement, which might be dispensable for hRBC rejection by macrophages, is critical in hRBC rejection by other types of murine phagocytic cells, such as neutrophils and endothelial cells.
Assuntos
Proteínas do Sistema Complemento/imunologia , Eritrócitos/citologia , Eritropoese/imunologia , Sobrevivência de Enxerto/imunologia , Animais , Biomarcadores , Adesão Celular/imunologia , Sobrevivência Celular/imunologia , Inativadores do Complemento/farmacologia , Venenos Elapídicos/farmacologia , Eritrócitos/imunologia , Eritrócitos/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imuno-Histoquímica , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Fagócitos/imunologia , Fagócitos/metabolismo , Transplante HeterólogoRESUMO
BACKGROUND: Mild to severe anaemia is a common complication of malaria that is caused in part by insufficient erythropoiesis in the bone marrow. This study used systems biology to evaluate the transcriptional and alterations in cell populations in the bone marrow during Plasmodium cynomolgi infection of rhesus macaques (a model of Plasmodium vivax malaria) that may affect erythropoiesis. RESULTS: An appropriate erythropoietic response did not occur to compensate for anaemia during acute cynomolgi malaria despite an increase in erythropoietin levels. During this period, there were significant perturbations in the bone marrow transcriptome. In contrast, relapses did not induce anaemia and minimal changes in the bone marrow transcriptome were detected. The differentially expressed genes during acute infection were primarily related to ongoing inflammatory responses with significant contributions from Type I and Type II Interferon transcriptional signatures. These were associated with increased frequency of intermediate and non-classical monocytes. Recruitment and/or expansion of these populations was correlated with a decrease in the erythroid progenitor population during acute infection, suggesting that monocyte-associated inflammation may have contributed to anaemia. The decrease in erythroid progenitors was associated with downregulation of genes regulated by GATA1 and GATA2, two master regulators of erythropoiesis, providing a potential molecular basis for these findings. CONCLUSIONS: These data suggest the possibility that malarial anaemia may be driven by monocyte-associated disruption of GATA1/GATA2 function in erythroid progenitors resulting in insufficient erythropoiesis during acute infection.
Assuntos
Medula Óssea/fisiopatologia , Eritropoese/imunologia , Malária Vivax/fisiopatologia , Malária/fisiopatologia , Monócitos/imunologia , Plasmodium cynomolgi/fisiologia , Animais , Medula Óssea/parasitologia , Humanos , Macaca mulatta , Malária/parasitologia , Malária Vivax/parasitologia , Masculino , Modelos Animais , Monócitos/parasitologiaRESUMO
In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis.
Assuntos
Eritropoese/genética , Eritropoese/imunologia , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Trombopoese/genética , Trombopoese/imunologia , Alelos , Animais , Biomarcadores , Medula Óssea , Diferenciação Celular/genética , Autorrenovação Celular/genética , Genótipo , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transplante HeterólogoRESUMO
The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N-nitrosourea-induced mutation that causes a gain of function in adenosine 5'-monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection.