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1.
Eur J Immunol ; 53(3): e2250154, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36564641

RESUMO

The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have emerged as important suppressive populations that expand during sepsis. In particular, sepsis supports CD39hi plasmablast metabolic reprogramming associated with adenosine-mediated suppressive activity. Arginine deficiency has been linked to an increased risk of secondary infections in sepsis. Overcoming arginine shortage by citrulline administration efficiently improves sepsis-induced immunosuppression and secondary infections in the cecal ligation and puncture murine model. Here, we aimed to determine the impact of citrulline administration on B cell suppressive responses in sepsis. We demonstrate that restoring arginine bioavailability through citrulline administration markedly reduces the dominant extrafollicular B cell response, decreasing the immunosuppressive LAG3+ and CD39+ plasma cell populations, and restoring splenic follicles. At the molecular level, the IRF4/MYC-mediated B cell reprogramming required for extrafollicular plasma cell differentiation is shunted in the splenic B cells of mice fed with citrulline. Our study reveals a prominent impact of nutrition on B cell responses and plasma cell differentiation and further supports the development of citrulline-based clinical studies to prevent sepsis-associated immune dysfunction.


Assuntos
Coinfecção , Sepse , Camundongos , Animais , Citrulina/metabolismo , Arginina , Imunossupressores , Diferenciação Celular
3.
Artigo em Inglês | MEDLINE | ID: mdl-36266053

RESUMO

BACKGROUND AND OBJECTIVES: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS). METHODS: The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event. RESULTS: The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis. DISCUSSION: Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity.


Assuntos
Esclerose Múltipla , Linfócitos T Auxiliares-Indutores , Humanos , Linfócitos B , Ativação Linfocitária , Contagem de Linfócitos , Esclerose Múltipla/patologia , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia , Células Th1
4.
Front Immunol ; 12: 653577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34017332

RESUMO

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206+ classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Monócitos/imunologia , Esclerose Múltipla/imunologia , Adulto , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Biomarcadores/sangue , Separação Celular/métodos , Estudos de Coortes , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Esclerose Múltipla/sangue , Receptores Imunológicos/metabolismo , Proteínas com Domínio T/metabolismo , Adulto Jovem
5.
Semin Arthritis Rheum ; 50(5): 867-872, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32896702

RESUMO

BACKGROUND: Immunopathogenesis of rheumatoid arthritis (RA) is not yet clearly defined. Besides known B-cell involvement, RA development and evolution involves CD4+ T helper cell homeostasis dysregulation. Imbalance between Th17 cells and regulatory T cells have been reported and may contribute to sustained inflammation. Since the last decade, increasing reports focused on a newly described CD4+ T helper cell subset, called T follicular helper (Tfh) cells, functionally distinct from other subsets due to their own property to provide help to B cells by enhancing their survival and differentiation into long-lasting antibody secreting cells. More recently, another B cell helper subset, named T peripheral helper (Tph) cells, has been specifically described in synovial tissues and blood of RA patients. METHODS: We conducted an exhaustive and careful literature search focusing our interest on T cells specialized on B cell help, Tfh cells and Tph cells, in RA pathogenesis and focused on their modulation during treatments. RESULTS: Tfh cells and in higher proportions Tph cells were described in synovial tissue and liquid of RA patients. In blood of RA patients, despite the use of diverse Tfh cell definitions, a vast majority of reports revealed an increase of circulating Tph and Tfh cell frequency, compared to healthy controls. However, discordant correlations between disease activity score and either effector or activated circulating Tfh cell subsets were highlighted, probably due to heterogeneity of cohort design in term of definition of disease activity, cohort size and use of different treatments. Indeed, frequencies of circulating Tfh and Tph cells are modulated depending on the nature and duration of RA treatment. Interestingly, it has been demonstrated that the proportion of ICOS-expressing blood Tfh cells before abatacept initiation was an independent and significant predictor of DAS28-ESR improvement at week 24. This report may encourage to conduct further investigations based on T-cell subsets as predictive biomarkers of response to biotherapies. CONCLUSION: Mounting evidences hypothesize that circulating Tfh and Tph cells may be involved in RA pathogenesis and response to treatment.


Assuntos
Artrite Reumatoide , Artrite Reumatoide/tratamento farmacológico , Linfócitos B , Humanos , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores
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