RESUMEN
Multiple sclerosis (MS) is a chronic disease that is characterized by the inappropriate invasion of lymphocytes and monocytes into the central nervous system (CNS), where they orchestrate the demyelination of axons, leading to physical and cognitive disability. There are many reasons immunologists should be interested in MS. Aside from the fact that there is still significant unmet need for patients living with the progressive form of the disease, MS is a case study for how immune cells cross CNS barriers and subsequently interact with specialized tissue parenchymal cells. In this review, we describe the types of immune cells that infiltrate the CNS and then describe interactions between immune cells and glial cells in different types of lesions. Lastly, we provide evidence for CNS-compartmentalized immune cells and speculate on how this impacts disease progression for MS patients.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Sistema Nervioso Central , Humanos , Inflamación , MonocitosRESUMEN
Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.
Asunto(s)
Virus del Dengue , Dengue , Dengue Grave , Niño , Humanos , Linfocitos B , Células Asesinas NaturalesRESUMEN
Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
Asunto(s)
Inmunoglobulina A/metabolismo , Interleucina-10/metabolismo , Intestinos/inmunología , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Inmunoglobulina A/inmunología , Mucosa Intestinal/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Neuroinmunomodulación/inmunología , Células Plasmáticas/metabolismoRESUMEN
Plasma cells secrete an abundance of Abs and are a crucial component of our immune system. The intestinal lamina propria harbors the largest population of plasma cells, most of which produce IgA. These Abs can bind to beneficial gut bacteria to reinforce intestinal homeostasis and provide protection against enteric pathogens. Plasma cells downregulate many cell-surface proteins commonly used to identify B cells. In mice, expression of the surface marker CD138 has been widely used to identify plasma cells in lymph nodes, bone marrow, and spleen. Intestinal plasma cells require liberation via extensive tissue processing involving treatment with collagenase. We report that detection of CD138 surface expression is reduced following collagenase treatment. Using a mouse in which yellow fluorescent protein expression is controlled by the plasma cell requisite transcription factor Blimp-1, we show that surface detection of transmembrane activator and CAML interactor captures a significant proportion of Ab-secreting plasma cells in the intestinal lamina propria and gut-draining mesenteric lymph nodes. Additionally, we describe a flow cytometry panel based on the detection of surface markers to identify murine B cell subsets in the intestinal lamina propria and, as a proof of concept, combine it with a cutting-edge fate-tracking system to characterize the fate of germinal center B cells activated in early life. By identifying plasma cells and other key intestinal B subsets in a manner compatible with several downstream applications, including sorting and culturing and in vitro manipulations, this efficient and powerful approach can enhance studies of mucosal immunity.
Asunto(s)
Inmunoglobulina A , Células Plasmáticas , Animales , Ratones , Linfocitos B , Colagenasas/metabolismo , Membrana Mucosa , Mucosa IntestinalRESUMEN
The remarkable success of anti-CD20 B cell depletion therapies in reducing the burden of multiple sclerosis (MS) disease has prompted significant interest in how B cells contribute to neuroinflammation. Most focus has been on identifying pathogenic CD20+ B cells. However, an increasing number of studies have also identified regulatory functions of B lineage cells, particularly the production of IL-10, as being associated with disease remission in anti-CD20-treated MS patients. Moreover, IL-10-producing B cells have been linked to the attenuation of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. In addition to IL-10-producing B cells, antibody-producing plasma cells (PCs) have also been implicated in suppressing neuroinflammation. This review will examine regulatory roles for B cells and PCs in MS and EAE. In addition, we speculate on the involvement of regulatory PCs and the cytokine BAFF in the context of anti-CD20 treatment. Lastly, we explore how the microbiota could influence anti-inflammatory B cell behavior. A better understanding of the contributions of different B cell subsets to the regulation of neuroinflammation, and factors that impact the development, maintenance, and migration of such subsets, will be important for rationalizing next-generation B cell-directed therapies for the treatment of MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Antígenos CD20 , Linfocitos B , Encefalomielitis Autoinmune Experimental/terapia , Humanos , Esclerosis Múltiple/terapia , Células PlasmáticasRESUMEN
The human oral cavity is normally colonized by microorganisms including bacteria, fungi, archaea, viruses and protozoa. The aim of this study was to determine the frequency of Candida spp., in de oral cavity in a group of medical students from the north of Mexico. Oral sample were obtained from 240 healthy students. The specimens were analyzed by traditional microbiology cultures and DNA sequencing. Candida spp., grew in Sabouraud dextrose agar from 57 samples and subsequently were isolated and phenotyped. The definitive identification to the species level was done by sequence analysis. The yeasts were identified as follow: 28 Clavispora lusitaniae, 20 Candida albicans, 5 Pichia kudriavzevii and 4 Candida parapsilosis. Our findings revealed that 23.75% of the healthy population has a potential pathogen in their mouth. Surprisingly, C. albicans is not the predominant yeast; instead other non-Candida species are the colonizers of the oral cavity as normal microbiota. C. lusitaniae is considered an emerging opportunistic pathogen in immunosuppressive patients. This paper pretends to highlight the presence of this yeast in the oral cavity in immunocompetent young adults. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01145-x.
RESUMEN
Parkinson's disease (PD) is a common neurodegenerative disorder whose etiology remains largely unexplained. Several studies have aimed to describe a causative effect in the interactions between the gastrointestinal tract and the brain, for both PD pathogenesis and disease course. However, the results have been controversial. Helicobacter pylori and small intestinal bacterial overgrowth (SIBO) are theorized to be agents capable of triggering chronic proinflammatory changes with a possible neurotoxic effect, as well as a cause of erratic L-dopa response in PD patients. This review evaluates the individual and possibly synergistic influence of H. pylori and SIBO on PD, to provide an opportunity to consider prospective therapeutic approaches.
Asunto(s)
Helicobacter pylori , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Levodopa/uso terapéuticoRESUMEN
B cells have been implicated in the pathogenesis of multiple sclerosis, but the mechanisms that guide B cell activation in the periphery and subsequent migration to the CNS remain incompletely understood. We previously showed that systemic inflammation induces an accumulation of B cells in the spleen in a CCR6/CCL20-dependent manner. In this study, we evaluated the role of CCR6/CCL20 in the context of myelin oligodendrocyte glycoprotein (MOG) protein-induced (B cell-dependent) experimental autoimmune encephalomyelitis (EAE). We found that CCR6 is upregulated on murine B cells that migrate into the CNS during neuroinflammation. In addition, human B cells that migrate across CNS endothelium in vitro were found to be CCR6+, and we detected CCL20 production by activated CNS-derived human endothelial cells as well as a systemic increase in CCL20 protein during EAE. Although mice that lack CCR6 expression specifically on B cells exhibited an altered germinal center reaction in response to MOG protein immunization, CCR6-deficient B cells did not exhibit any competitive disadvantage in their migration to the CNS during EAE, and the clinical and pathological presentation of EAE induced by MOG protein was unaffected. These data, to our knowledge, provide new information on the role of B cell-intrinsic CCR6 expression in a B cell-dependent model of neuroinflammation.
Asunto(s)
Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Centro Germinal/inmunología , Inmunización/métodos , Glicoproteína Mielina-Oligodendrócito/administración & dosificación , Receptores CCR6/deficiencia , Animales , Linfocitos B/metabolismo , Donantes de Sangre , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/inmunología , Movimiento Celular/genética , Movimiento Celular/inmunología , Células Cultivadas , Quimiocina CCL20/metabolismo , Encefalomielitis Autoinmune Experimental/inducido químicamente , Células Endoteliales/inmunología , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/genética , Receptores CCR6/genética , Proteínas Recombinantes/administración & dosificaciónRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.
Asunto(s)
Envejecimiento/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Miembro Posterior , Esclerosis Múltiple/patología , Animales , Sustancia Gris/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Esclerosis Múltiple/inmunología , PPAR alfa/genética , Sustancia Blanca/patologíaRESUMEN
Malaria is a febrile and potentially fatal infection. It is typically transmitted to humans through the bite of Anopheles mosquitoes and less frequently can be contracted through blood transfusions, sharing contaminated needles and syringes, mother-to-child transmission, or after solid organ transplantation. Posttransplant malaria has rarely been reported in the literature, even in endemic areas. We report the cases of three solid organ recipients in which Plasmodium vivax infection was documented during postsurgical evaluation 30 days after transplant surgery. The diagnosis of donor-derived malaria was confirmed in all patients by demonstrating Plasmodium in a peripheral blood smear and by polymerase chain reaction (PCR). All recipients had symptoms. The liver transplant recipient had myalgia, arthralgia, and thrombocytopenia; the kidney transplant recipient developed acute renal failure; and the heart transplant recipient had fever, cephalalgia, and tonic-clonic seizures. Pre-transplant screening of donors and recipients from endemic regions may not be sufficient to safely rule out persistent malaria. In Colombia, according to legislation, no mandatory testing is required for the diagnosis of malaria in organ donors in nonendemic areas. Therefore, donor screening by questionnaire is the only tool for preventing transplant-borne malaria. The migratory trend from Venezuela to Colombia has increased the number of imported cases of malaria, and the infection may be present in endemic and nonendemic regions. Although donor evaluation is not standardized in current guidelines, we suggest that donors be tested for malaria with a peripheral blood smear, detection of specific IgG antibodies against Plasmodium, and techniques such as PCR, if possible.
Asunto(s)
Malaria , Trasplante de Órganos , Animales , Femenino , Humanos , Transmisión Vertical de Enfermedad Infecciosa , Trasplante de Órganos/efectos adversos , Donantes de Tejidos , Receptores de TrasplantesRESUMEN
Chromoblastomycosis is a chronic, progressive subcutaneous mycosis that is endemic in tropical and subtropical countries. Cladophialophora carrionii and Fonsecaea pedrosoi are prevalent etiological agents. The potential role of the proteolytic activity of extracellular enzymes in these fungi and its relationship with the pathogenesis of the disease has not been proven. Some phenotypic traits have been associated with the virulence of other fungi; i.e., their different rate of protease, phospholipase, and esterase excretion, melanin, and thermotolerance. The aim of this study was the identification of extracellular enzymes that could be considered virulence markers of chromoblastomycosis agents. Therefore, we tested 29 C. carrionii and 11 F. pedrosoi clinical isolates to determine their hydrolytic and physiologic characteristics. All the tested isolates grew at a range of 30°-37 °C; except 2 strains of F. pedrosoi that grew slowly at 40 °C. We noticed that the hydrolytic capabilities of the tested isolates were positive for urea hydrolysis in almost all, while both strains were negative for DNase, hemolysin, and gelatin. C. carrionii and F. pedrosoi had phospholipase and esterase activity. These findings were similar for most isolates. All strains showed an association between phospholipase activity and moderate to severe lesions. However, only in F. pedrosoi isolates, the association remains significant. We conclude that the different enzymatic production reported here may be linked to the clinical manifestations of these pathologies. Notwithstanding, the influence of other virulence factors is not excluded.
Asunto(s)
Ascomicetos , Cromoblastomicosis , Hongos Mitospóricos , Antifúngicos/uso terapéutico , Humanos , FosfolipasasRESUMEN
Non-albicans Candida species have acquired relevance in the last decades as a cause of serious disease. The virulence factors and antifungal susceptibility of these rare pathogens remain largely unrecognized. We examined a total of 50 yeast isolates corresponding to 11 different infrequently isolated yeast species for their in vitro enzymatic profile and susceptibility pattern as first-line antifungals. We found aspartyl protease activity for 100% of the isolates tested as well as variable DNAse, hemolysin, phospholipase and esterase activities. All strains had low MICs for amphotericin B and showed a variable response to fluconazole (0.125-32 µg/mL) and the echinocandins tested (0.25-> 8 µg/mL).
Asunto(s)
Anfotericina B/farmacología , Antifúngicos/farmacología , Candida/efectos de los fármacos , Candida/genética , Equinocandinas/farmacología , Fluconazol/farmacología , Proteasas de Ácido Aspártico/genética , Candida/clasificación , Candida/aislamiento & purificación , Desoxirribonucleasas/genética , Esterasas/genética , Proteínas Hemolisinas/genética , Humanos , Pruebas de Sensibilidad Microbiana , Fosfolipasas/genética , Factores de Virulencia , Levaduras/clasificación , Levaduras/efectos de los fármacos , Levaduras/aislamiento & purificaciónRESUMEN
The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.
Asunto(s)
Inmunoglobulina A/inmunología , Intestino Delgado/citología , Intestino Delgado/inmunología , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Animales , Células de la Médula Ósea/citología , Linaje de la Célula , Células Cultivadas , Quimera/inmunología , Citrobacter rodentium/inmunología , Técnicas de Cocultivo , Femenino , Vida Libre de Gérmenes , Granulocitos/citología , Granulocitos/metabolismo , Inmunidad Innata/inmunología , Inmunoglobulina A/biosíntesis , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Intestino Delgado/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Monocitos/metabolismo , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Óxido Nítrico Sintasa de Tipo II/deficiencia , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fenotipo , Células Plasmáticas/metabolismo , Bazo/citología , Células del Estroma/citología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Mycetoma is a chronic granulomatous, subcutaneous disease endemic in tropical and subtropical countries. It is currently a health problem in rural areas of Africa, Asia and South America. Nine cases of mycetoma were analysed in a retrospective study. All isolates were identified by morphological features. The level of species identification was reached by molecular tools. Definitive identification of fungi was performed using sequence analysis of the ITS of the ribosomal DNA region and the ribosomal large-subunit D1/D2. Identification of actinomycetes was accomplished by the 16S rRNA gene sequence. Six unusual clinical isolates were identified: Aspergillus ustus, Cyphellophora oxyspora, Exophiala oligosperma, Madurella pseudomycetomatis, Nocardia farcinica and Nocardia wallacei. The prevalence of mycetoma in Venezuela remains unknown. This study represents the first report in the literature of mycetoma caused by unusual pathogens identified by molecular techniques.
Asunto(s)
Actinomycetales/genética , ADN Espaciador Ribosómico , ADN Ribosómico/genética , Hongos/genética , Micetoma/microbiología , ARN Ribosómico 16S/genética , Actinobacteria/genética , Actinomycetales/aislamiento & purificación , Adolescente , Adulto , Exophiala/genética , Exophiala/aislamiento & purificación , Femenino , Hongos/clasificación , Hongos/aislamiento & purificación , Humanos , Madurella/genética , Madurella/aislamiento & purificación , Masculino , Persona de Mediana Edad , Micetoma/tratamiento farmacológico , Micetoma/epidemiología , Micetoma/patología , Técnicas de Tipificación Micológica , Nocardia/genética , Nocardia/aislamiento & purificación , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Venezuela/epidemiologíaRESUMEN
BACKGROUND: The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition. METHODS: To assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda. RESULTS: Participants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted ORâ=â0.31; 95% CI, 0.16-0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11-0.39). Levels of the α-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten-fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 log(n) pg/mL, Pâ=â0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 log(n) pg/mL, Pâ=â0.0002 and 0.013). CONCLUSIONS: This prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk.
Asunto(s)
Antiinfecciosos/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Prepucio/inmunología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Inmunoglobulina A/inmunología , Adolescente , Adulto , Circuncisión Masculina , Infecciones por VIH/inmunología , VIH-1/inmunología , Heterosexualidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Uganda , Adulto JovenRESUMEN
Innate immune responses provoke the accumulation of leukocytes at sites of inflammation. In addition to monocytes and granulocytes, B cells also participate in antimicrobial innate immune responses; however, the mechanisms for accumulation of B cells to sites of inflammation are not well understood. To study B cell accumulation following systemic inflammation, we used a model synthetic ligand that stimulates a specific pattern recognition molecule, nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Upon exposure to Nod1 agonists, both B cells and neutrophils rapidly accumulate within the spleen, and dendritic cells migrate into the periarterial lymphoid sheath. Nod1 stimulation led to a marked increase in several chemokines within the spleen, including CXCL13, CCL2, and CCL20. Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway. In contrast, a CCR6/CCL20 chemokine loop instructed rapid increase of B cells in the spleen in response to systemic administration of Nod1 agonists in a TNF-α-dependent manner. Moreover, CCR6 was required to regulate Nod1-mediated B cell responses. These results reveal a novel mechanism of B cells during inflammation and shed light on how B cells participate in innate immune responses to microbial stimulation.
Asunto(s)
Linfocitos B/inmunología , Quimiocina CCL20/inmunología , Proteína Adaptadora de Señalización NOD1/inmunología , Receptores CCR6/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea/métodos , Línea Celular , Células Cultivadas , Quimiocina CCL20/metabolismo , Ácido Diaminopimélico/análogos & derivados , Ácido Diaminopimélico/farmacología , Femenino , Citometría de Flujo , Recuento de Linfocitos , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Proteína Adaptadora de Señalización NOD1/genética , Proteína Adaptadora de Señalización NOD1/metabolismo , Receptores CCR6/genética , Receptores CCR6/metabolismo , Bazo/citología , Bazo/inmunología , Bazo/metabolismo , Quimera por Trasplante/sangre , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Germinal centers (GCs) are clusters of activated B cells that form in secondary lymphoid organs during a T-dependent immune response. B cells enter GCs and become rapidly proliferating centroblasts that express the enzyme activation-induced deaminase (AID) to undergo somatic hypermutation and class-switch recombination. Centroblasts then mature into centrocytes to undergo clonal selection. Within the GC, the highest affinity B cell clones are selected to mature into memory or plasma cells while lower affinity clones undergo apoptosis. We reported previously that murine Aicda(-/-) GC B cells have enhanced viability and accumulate in GCs. We now show that murine Aicda(-/-) GC B cells accumulate as centrocytes and inefficiently generate plasma cells. The reduced rate of plasma cell formation was not due to an absence of AID-induced DNA lesions. In addition, we show that the deletion of caspase 8 specifically in murine GC-B cells results in larger GCs and a delay in affinity maturation, demonstrating the importance of apoptosis in GC homeostasis and clonal selection.
Asunto(s)
Apoptosis/fisiología , Síndrome Linfoproliferativo Autoinmune/inmunología , Subgrupos de Linfocitos B/inmunología , Caspasa 8/fisiología , Selección Clonal Mediada por Antígenos , Citidina Desaminasa/fisiología , Centro Germinal/inmunología , Síndromes de Inmunodeficiencia/patología , Traslado Adoptivo , Animales , Antígenos/inmunología , Subgrupos de Linfocitos B/patología , Caspasa 8/genética , División Celular , Citidina Desaminasa/deficiencia , Citidina Desaminasa/genética , Roturas del ADN de Doble Cadena , Centro Germinal/patología , Inmunización , Cambio de Clase de Inmunoglobulina , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Células Plasmáticas/patología , Quimera por Radiación , Receptores de Antígenos de Linfocitos B/inmunología , Hipermutación Somática de InmunoglobulinaRESUMEN
Gradients of the sphingolipid sphingosine-1-phosphate (S1P) are responsible for the egress of lymphocytes from lymph nodes by activating the S1P1 receptor expressed on the surface of lymphocytes. Small molecule drugs that downregulate S1P receptors induce the sequestration of lymphocytes within lymph nodes, thus preventing lymphocytes from accessing sites of inflammation. In particular, FTY720, a pan-S1P receptor agonist, has been efficacious in the treatment of multiple sclerosis as well as its animal model, experimental autoimmune encephalomyelitis (EAE), by virtue of its ability to restrain lymphocytes within the lymph nodes, thus precluding their migration into the CNS. However, multiple leukocyte subsets express S1P receptors of varying types, and although it is beneficial to prevent transmigration of proinflammatory lymphocytes into the CNS, allowing access of regulatory leukocyte subsets to the CNS is desirable. In this study, we show that an S1P1-specific agonist (AUY954) is clinically efficacious in ameliorating pre-established EAE in SJL/J mice. Efficacy of AUY954 correlated with a reduction of lymphocytes in the CNS, but access of plasmacytoid dendritic cells (pDCs) to the CNS was unimpaired, and the presence of pDCs was found to be an important cofactor in mediating the clinical efficacy of AUY954. These results indicate that pDCs are important in quieting autoimmune responses during EAE, and that trafficking inhibitors that are permissive for pDC accumulation in the CNS may be of therapeutic value for the treatment of multiple sclerosis.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/patología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Receptores de Lisoesfingolípidos/agonistas , Receptores de Lisoesfingolípidos/metabolismo , Tiofenos/farmacología , beta-Alanina/análogos & derivados , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/patología , Agregación Celular/efectos de los fármacos , Agregación Celular/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Ratones , Receptores de Lisoesfingolípidos/fisiología , Receptores de Esfingosina-1-Fosfato , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Tiofenos/uso terapéutico , beta-Alanina/farmacología , beta-Alanina/uso terapéuticoRESUMEN
Clavispora lusitaniae has been isolated from different substrates, such as soil, water, fruit, vegetables, plants, and the gastrointestinal tract of animals and humans. However, its importance lies in being isolated from in invasive infections, particularly in pediatric patients with hematologic malignancies. It is an emerging nosocomial pathogen commonly associated with fatal prognosis in immunocompromised hosts. C. lusitaniae has attracted attention in the last decade because of resistance to amphotericin B, 5- flucytosine, and fluconazole. The adaptations of this yeast to the human host may contribute to its pathogenicity. Further study will be needed to understand C. lusitaniae's ability as a potential pathogen. This mini-review highlights the importance of the growing number of invasive disease cases caused by this yeast.