Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Brain ; 145(6): 2018-2030, 2022 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-35552381

RESUMEN

Narcolepsy with cataplexy or narcolepsy type 1 is a disabling chronic sleep disorder resulting from the destruction of orexinergic neurons in the hypothalamus. The tight association of narcolepsy with HLA-DQB1*06:02 strongly suggest an autoimmune origin to this disease. Furthermore, converging epidemiological studies have identified an increased incidence for narcolepsy in Europe following Pandemrix® vaccination against the 2009-2010 pandemic 'influenza' virus strain. The potential immunological link between the Pandemrix® vaccination and narcolepsy remains, however, unknown. Deciphering these mechanisms may reveal pathways potentially at play in most cases of narcolepsy. Here, we developed a mouse model allowing to track and study the T-cell response against 'influenza' virus haemagglutinin, which was selectively expressed in the orexinergic neurons as a new self-antigen. Pandemrix® vaccination in this mouse model resulted in hypothalamic inflammation and selective destruction of orexin-producing neurons. Further investigations on the relative contribution of T-cell subsets in this process revealed that haemagglutinin-specific CD4 T cells were necessary for the development of hypothalamic inflammation, but insufficient for killing orexinergic neurons. Conversely, haemagglutinin-specific CD8 T cells could not initiate inflammation but were the effectors of the destruction of orexinergic neurons. Additional studies revealed pathways potentially involved in the disease process. Notably, the interferon-γ pathway was proven essential, as interferon-γ-deficient CD8 T cells were unable to elicit the loss of orexinergic neurons. Our work demonstrates that an immunopathological process mimicking narcolepsy can be elicited by immune cross-reactivity between a vaccine antigen and a neuronal self-antigen. This process relies on a synergy between autoreactive CD4 and CD8 T cells for disease development. This work furthers our understanding of the mechanisms and pathways potentially involved in the development of a neurological side effect due to a vaccine and, likely, to narcolepsy in general.


Asunto(s)
Autoinmunidad , Vacunas contra la Influenza , Narcolepsia , Animales , Autoantígenos , Hemaglutininas , Inflamación/complicaciones , Vacunas contra la Influenza/efectos adversos , Interferón gamma , Ratones , Narcolepsia/inducido químicamente , Neuronas , Orexinas , Linfocitos T/inmunología , Vacunación/efectos adversos
2.
J Autoimmun ; 100: 1-6, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30948158

RESUMEN

Convergent evidence points to the involvement of T cells in the pathogenesis of narcolepsy type 1 (NT1). Here, we hypothesized that expanded disease-specific T cell clones could be detected in the blood of NT1 patients. We compared the TCR repertoire of circulating antigen-experienced CD4+ and CD8+ T cells from 13 recently diagnosed NT1 patients and 11 age-, sex-, and HLA-DQB1*06:02-matched healthy controls. We detected a bias in the usage of TRAV3 and TRAV8 families, with public CDR3α motifs only present in CD4+ T cells from patients with NT1. These findings may offer a unique tool to identify disease-relevant antigens.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Narcolepsia , Receptores de Antígenos de Linfocitos T , Adolescente , Adulto , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Femenino , Cadenas beta de HLA-DQ/genética , Cadenas beta de HLA-DQ/inmunología , Humanos , Masculino , Persona de Mediana Edad , Narcolepsia/genética , Narcolepsia/inmunología , Narcolepsia/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología
3.
Proc Natl Acad Sci U S A ; 113(39): 10956-61, 2016 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-27621438

RESUMEN

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica , Narcolepsia/inmunología , Narcolepsia/patología , Neuronas/patología , Orexinas/metabolismo , Animales , Autoanticuerpos/metabolismo , Autoantígenos/metabolismo , Comunicación Celular , Hemaglutininas/metabolismo , Hipotálamo/metabolismo , Inflamación/patología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Neuronas/metabolismo , Fenotipo , Linfocitos T Citotóxicos/metabolismo , Células TH1/metabolismo
4.
J Autoimmun ; 94: 134-142, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30104107

RESUMEN

Despite genetic and epidemiological evidence strongly supporting an autoimmune basis for narcolepsy type 1, the mechanisms involved have remained largely unknown. Here, we aimed to investigate whether the frequency and function of circulating follicular helper and follicular regulatory T cells are altered in narcolepsy type 1. Peripheral blood mononuclear cells were collected from 32 patients with narcolepsy type 1, including 11 who developed disease after Pandemrix® vaccination, and 32 age-, sex-, and HLA-DQB1*06:02-matched healthy individuals. The frequency and phenotype of the different circulating B cell and follicular T cell subsets were examined by flow cytometry. The function of follicular helper T cells was evaluated by assessing the differentiation of naïve and memory B cells in a co-culture assay. We revealed a notable increase in the frequency of circulating B cells and CD4+CXCR5+ follicular T cells in narcolepsy patients compared to age-, sex- and HLA-matched healthy controls. However, the inducible T-cell costimulator molecule, ICOS, was selectively down-regulated on follicular T cells from patients. Reduced frequency of activated ICOS+ and PD1high blood follicular T cells was also observed in the narcolepsy group. Importantly, follicular T cells isolated from patients with narcolepsy type 1 had a reduced capacity to drive the proliferation/survival and differentiation of memory B cells. Our results provide novel insights into the potential involvement of T cell-dependent B cell responses in the pathogenesis of narcolepsy type 1 in which down-regulation of ICOS expression on follicular helper T cells correlates with their reduced function. We hypothesize that these changes contribute to regulation of the deleterious autoimmune process after disease onset.


Asunto(s)
Linfocitos B/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Narcolepsia/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Anciano , Linfocitos B/patología , Estudios de Casos y Controles , Diferenciación Celular , Proliferación Celular , Técnicas de Cocultivo , Femenino , Regulación de la Expresión Génica , Cadenas beta de HLA-DQ/genética , Cadenas beta de HLA-DQ/inmunología , Humanos , Memoria Inmunológica , Inmunofenotipificación , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Vacunas contra la Influenza/efectos adversos , Masculino , Persona de Mediana Edad , Narcolepsia/inducido químicamente , Narcolepsia/genética , Narcolepsia/patología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Receptores CXCR5/genética , Receptores CXCR5/inmunología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/patología
5.
Brain ; 139(11): 2923-2934, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27604307

RESUMEN

CTLA4 is an inhibitory regulator of immune responses. Therapeutic CTLA4 blockade enhances T cell responses against cancer and provides striking clinical results against advanced melanoma. However, this therapy is associated with immune-related adverse events. Paraneoplastic neurologic disorders are immune-mediated neurological diseases that develop in the setting of malignancy. The target onconeural antigens are expressed physiologically by neurons, and aberrantly by certain tumour cells. These tumour-associated antigens can be presented to T cells, generating an antigen-specific immune response that leads to autoimmunity within the nervous system. To investigate the risk to develop paraneoplastic neurologic disorder after CTLA4 blockade, we generated a mouse model of paraneoplastic neurologic disorder that expresses a neo -self antigen both in Purkinje neurons and in implanted breast tumour cells. Immune checkpoint therapy with anti-CTLA4 monoclonal antibody in this mouse model elicited antigen-specific T cell migration into the cerebellum, and significant neuroinflammation and paraneoplastic neurologic disorder developed only after anti-CTLA4 monoclonal antibody treatment. Moreover, our data strongly suggest that CD8 + T cells play a final effector role by killing the Purkinje neurons. Taken together, we recommend heightened caution when using CTLA4 blockade in patients with gynaecological cancers, or malignancies of neuroectodermal origin, such as small cell lung cancer, as such treatment may promote paraneoplastic neurologic disorders.


Asunto(s)
Anticuerpos/toxicidad , Antígeno CTLA-4/metabolismo , Síndromes Paraneoplásicos del Sistema Nervioso/etiología , Síndromes Paraneoplásicos del Sistema Nervioso/metabolismo , Animales , Antígenos de Neoplasias/inmunología , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Neoplasias de la Mama/patología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Línea Celular Tumoral , Cerebelo/patología , Femenino , Factores de Intercambio de Guanina Nucleótido/metabolismo , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Actividad Motora/fisiología , Trastornos del Movimiento/etiología , Neuropéptidos/metabolismo , Síndromes Paraneoplásicos del Sistema Nervioso/complicaciones , Síndromes Paraneoplásicos del Sistema Nervioso/patología , Células de Purkinje/efectos de los fármacos , Células de Purkinje/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo
6.
bioRxiv ; 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39229137

RESUMEN

Undernutrition is one of the largest persistent global health crises, with nearly 1 billion people facing severe food insecurity. Infectious disease represents the main underlying cause of morbidity and mortality for malnourished individuals, with infection during malnutrition representing the leading cause of childhood mortality worldwide. In the face of this complex challenge, simple refeeding protocols have remained the primary treatment strategy. Although an association between undernutrition and infection susceptibility has been appreciated for over a century, the underlying mechanisms remain poorly understood and the extent to which refeeding intervention is sufficient to reverse nutritionally acquired immunodeficiency is unclear. Here we investigate how malnutrition leads to immune dysfunction and the ability of refeeding to repair it. We find that chronic malnutrition severely impairs the ability of animals to control a sub-lethal bacterial infection. Malnourished animals exhibit blunted immune cell expansion, impaired immune function, and accelerated contraction prior to pathogen clearance. While this defect is global, we find that myelopoiesis is uniquely impacted, resulting in in reduced neutrophil and monocyte numbers prior to and post-infection. Upon refeeding, we observe that animals recover body mass, size, cellularity across all major immune organs, the capacity to undergo normal immune cell expansion in response to infection, and a restoration in T cell responses. Despite this broad improvement, refed animals remain susceptible to bacterial infection, uncoupling global lymphoid atrophy from immunodeficiency. Mechanistically, we find peripheral neutrophil and monocyte numbers fail to fully recover and refed animals are unable to undergo normal emergency myelopoiesis. Altogether, this work identifies a novel cellular link between prior nutritional state and immunocompetency, highlighting dysregulated myelopoiesis as a major driver. We believe these findings illustrate how exposure to food scarcity is an immunologic variable, even post-recovery, which should be accounted for in patient medical history and current global public health policy.

7.
Sci Immunol ; 9(93): eadj7238, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38489349

RESUMEN

Adaptive immunity requires the expansion of high-affinity lymphocytes from a heterogeneous pool. Whereas current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Here, we identify nicotinamide adenine dinucleotide (NAD) biosynthesis as a biochemical hub for the T cell receptor affinity-dependent metabolome. Through this central anabolic role, we found that NAD biosynthesis governs a quiescence exit checkpoint, thereby pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities, and enhancing NAD biosynthesis permits the expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) could predict division potential for both T and B cells, before the first division, unmixing proliferative heterogeneity. We believe that this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.


Asunto(s)
Linfocitos , NAD , Linfocitos/metabolismo , Metaboloma , Transducción de Señal
8.
Front Immunol ; 14: 1249405, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38077397

RESUMEN

Background: Narcolepsy Type I (NT1) is a rare, life-long sleep disorder arising as a consequence of the extensive destruction of orexin-producing hypothalamic neurons. The mechanisms involved in the destruction of orexin neurons are not yet elucidated but the association of narcolepsy with environmental triggers and genetic susceptibility (strong association with the HLA, TCRs and other immunologically-relevant loci) implicates an immuno-pathological process. Several studies in animal models and on human samples have suggested that T-cells are the main pathogenic culprits. Methods: RNA sequencing was performed on four CD4 and CD8 T-cell subsets (naive, effector, effector memory and central memory) sorted by flow cytometry from peripheral blood mononuclear cells (PBMCs) of NT1 patients and HLA-matched healthy donors as well as (age- and sex-) matched individuals suffering from other sleep disorders (OSD). The RNAseq analysis was conducted by comparing the transcriptome of NT1 patients to that of healthy donors and other sleep disorder patients (collectively referred to as the non-narcolepsy controls) in order to identify NT1-specific genes and pathways. Results: We determined NT1-specific differentially expressed genes, several of which are involved in tubulin arrangement found in CD4 (TBCB, CCT5, EML4, TPGS1, TPGS2) and CD8 (TTLL7) T cell subsets, which play a role in the immune synapse formation and TCR signaling. Furthermore, we identified genes (GZMB, LTB in CD4 T-cells and NLRP3, TRADD, IL6, CXCR1, FOXO3, FOXP3 in CD8 T-cells) and pathways involved in various aspects of inflammation and inflammatory response. More specifically, the inflammatory profile was identified in the "naive" subset of CD4 and CD8 T-cell. Conclusion: We identified NT1-specific differentially expressed genes, providing a cell-type and subset specific catalog describing their functions in T-cells as well as their potential involvement in NT1. Several genes and pathways identified are involved in the formation of the immune synapse and TCR activation as well as inflammation and the inflammatory response. An inflammatory transcriptomic profile was detected in both "naive" CD4 and CD8 T-cell subsets suggesting their possible involvement in the development or progression of the narcoleptic process.


Asunto(s)
Leucocitos Mononucleares , Narcolepsia , Animales , Humanos , Orexinas/genética , Orexinas/metabolismo , Leucocitos Mononucleares/metabolismo , Linfocitos T CD8-positivos , Narcolepsia/genética , Receptores de Antígenos de Linfocitos T/genética , Perfilación de la Expresión Génica , Inflamación
9.
J Exp Med ; 213(12): 2621-2633, 2016 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-27821550

RESUMEN

Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4+ and CD8+ T cells dominated by elevated levels of B cell-supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease.


Asunto(s)
Inmunidad , Narcolepsia/inmunología , Análisis de la Célula Individual/métodos , Adolescente , Adulto , Linfocitos B/metabolismo , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Proliferación Celular , Niño , Preescolar , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Vacunas contra la Influenza/inmunología , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Fenotipo , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Vacunación
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA