RESUMEN
Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)alpha (iTCRalpha) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and gammadelta T cells.
Asunto(s)
Antígenos de Histocompatibilidad Clase I/inmunología , Inmunidad Mucosa/inmunología , Células T Asesinas Naturales/fisiología , Subgrupos de Linfocitos T/fisiología , Timo/inmunología , Animales , Linfocitos B/fisiología , Niño , Sangre Fetal/inmunología , Tracto Gastrointestinal/citología , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Antígenos de Histocompatibilidad Menor , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Receptores de Antígenos de Linfocitos T alfa-beta , Linfocitos T , Timo/citologíaRESUMEN
BACKGROUND AND OBJECTIVES: Since the first description of pathology of the kidney in Waldenström disease in 1970, there have been few reports on kidney complications of IgM-secreting monoclonal proliferations. Here, we aimed to revisit the spectrum of renal lesions occurring in patients with a serum monoclonal IgM. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fourteen patients with a circulating monoclonal IgM and a kidney disease related to B cell proliferation were identified retrospectively. Demographic, clinical, and laboratory data were assessed for each patient at the time of kidney biopsy. RESULTS: Seven patients had a nephrotic syndrome. Patients without nephrotic syndrome all had impaired renal function. Mean serum creatinine was 238 micromol/L. For five patients, the diagnosis of monoclonal IgM preceded the kidney disease by 28.8 mo (range 12 to 60). Seven patients had Waldenström disease, two had a small B cell non-Hodgkin lymphoma, one had an IgM-excreting multiple myeloma, one had a marginal zone B cell lymphoma, and three had an IgM-related disorder. Renal lesions included (1) intracapillary monoclonal deposits disease with granular, electron-dense IgM thrombi occluding capillary lumens (5); (2) atypical membranoproliferative glomerulonephritis (3); (3) lambda light chain amyloidosis (2) associated with mu deposits in one patient; (4) acute tubular necrosis (1); and (5) CD20(+) lymphomatous infiltration (3). Remission of the nephrotic syndrome was attained in three of seven patients, and renal function improved after chemotherapy. CONCLUSIONS: Although renal complications of IgM proliferations are rare, a wide spectrum of kidney lesions is observed, without correlation with the type of hematologic disorder.
Asunto(s)
Anticuerpos Monoclonales/análisis , Linfocitos B/inmunología , Proliferación Celular , Inmunoglobulina M/análisis , Enfermedades Renales/inmunología , Trastornos Linfoproliferativos/inmunología , Anciano , Amiloidosis/inmunología , Linfocitos B/patología , Femenino , Glomerulonefritis Membranoproliferativa/inmunología , Humanos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Linfoma de Células B/inmunología , Linfoma de Células B de la Zona Marginal/inmunología , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Síndrome Nefrótico/inmunología , Estudios Retrospectivos , Resultado del Tratamiento , Macroglobulinemia de Waldenström/inmunologíaRESUMEN
Numerous studies have shown that several red blood cell polymorphisms protect against severe malaria. Such a relation is much less clear for mild malaria attacks and for the asymptomatic carriage of Plasmodium falciparum. The impact of red blood cell polymorphisms on the level of parasite density was assessed in a group of 464 Senegalese children from the Sereer ethnic group, studied for 18 months. These genetic factors were also related to the malarial morbidity, investigated during 2 successive transmission seasons among 169 of these children. The frequencies of the host genetic factors in the whole group were 0.52 for blood group O, 0.13 for hemoglobin S, 0.16 for the G6PD A-deficient variant and 0.24 for alpha+-thalassemia (-alpha(3.7) deletion). Hemoglobin S was associated with protection against mild malaria attacks. None of the genetic factors was implicated in a better control of parasite densities. These associations may be particular to this ethnic group due to the specificities of malaria endemicity in this area. The pressure exerted in the area by other non-malarial infectious diseases as well as the genetic heterogeneity of circulating parasites may also contribute to these observations.
Asunto(s)
Eritrocitos/fisiología , Eritrocitos/parasitología , Malaria Falciparum/sangre , Malaria Falciparum/genética , Plasmodium falciparum/aislamiento & purificación , Animales , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Masculino , Morbilidad , Polimorfismo Genético , Riesgo , Senegal/epidemiologíaRESUMEN
The evidence of protection afforded by red blood cell polymorphisms against either clinical malaria or Plasmodium falciparum blood levels varies with the study site and the type of malaria transmission. Nevertheless, no clear implication of an antibody-related effect has yet been established in the protection related to red blood cell polymorphisms. We performed a prospective study, where plasma IgG and IgG subclasses directed to recombinant proteins from the merozoite surface protein 2 (MSP2/3D7 and MSP2/FC27) and the ring-infected erythrocyte surface antigen (RESA) were determined in a cohort of 413 Senegalese children before the annual malaria transmission season. The antibody response was dependent on age, and to a lesser extent, on the village of residence. IgG3 responders to all proteins, IgG responders to RESA and MSP2/3D7, as well as IgG2 to RESA and IgG1 responders to MSP2/3D7, presented enhanced mean values of parasite density, as evaluated during an 18-month follow-up. The levels of IgG and IgG3 to MSP2/3D7 were negatively associated with the risk of occurrence of a malaria attack during the following transmission season. Compared to normal children, sickle cell trait carriers presented lower levels of IgG to MSP2/3D7. Similarly, G6PD A- girls had lower levels of IgG and IgG3 to MSP2/FC27 than did G6PD normal girls. The impact of these particular genetic polymorphisms on the modulation of the antibody response is discussed.