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1.
Immunity ; 54(7): 1578-1593.e5, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34051147

RESUMO

Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.


Assuntos
COVID-19/imunologia , SARS-CoV-2/patogenicidade , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Apresentação de Antígeno , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , COVID-19/patologia , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Pneumonia/imunologia , Pneumonia/patologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
3.
Proc Natl Acad Sci U S A ; 120(19): e2220911120, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37126681

RESUMO

Narcolepsy with cataplexy is a sleep disorder caused by deficiency in the hypothalamic neuropeptide hypocretin/orexin (HCRT), unanimously believed to result from autoimmune destruction of hypocretin-producing neurons. HCRT deficiency can also occur in secondary forms of narcolepsy and be only temporary, suggesting it can occur without irreversible neuronal loss. The recent discovery that narcolepsy patients also show loss of hypothalamic (corticotropin-releasing hormone) CRH-producing neurons suggests that other mechanisms than cell-specific autoimmune attack, are involved. Here, we identify the HCRT cell-colocalized neuropeptide QRFP as the best marker of HCRT neurons. We show that if HCRT neurons are ablated in mice, in addition to Hcrt, Qrfp transcript is also lost in the lateral hypothalamus, while in mice where only the Hcrt gene is inactivated Qrfp is unchanged. Similarly, postmortem hypothalamic tissues of narcolepsy patients show preserved QRFP expression, suggesting the neurons are present but fail to actively produce HCRT. We show that the promoter of the HCRT gene of patients exhibits hypermethylation at a methylation-sensitive and evolutionary-conserved PAX5:ETS1 transcription factor-binding site, suggesting the gene is subject to transcriptional silencing. We show also that in addition to HCRT, CRH and Dynorphin (PDYN) gene promoters, exhibit hypermethylation in the hypothalamus of patients. Altogether, we propose that HCRT, PDYN, and CRH are epigenetically silenced by a hypothalamic assault (inflammation) in narcolepsy patients, without concurrent cell death. Since methylation is reversible, our findings open the prospect of reversing or curing narcolepsy.


Assuntos
Cataplexia , Narcolepsia , Neuropeptídeos , Camundongos , Animais , Orexinas/metabolismo , Cataplexia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neuropeptídeos/metabolismo , Narcolepsia/genética , Hipotálamo/metabolismo , Epigênese Genética , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo
4.
Ann Neurol ; 96(2): 289-301, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38747444

RESUMO

OBJECTIVE: Multiple sclerosis (MS) has a complex pathobiology, with genetic and environmental factors being crucial players. Understanding the mechanisms underlying heterogeneity in disease activity is crucial for tailored treatment. We explored the impact of DNA methylation, a key mechanism in the genetics-environment interplay, on disease activity in MS. METHODS: Peripheral immune methylome profiling using Illumina Infinium MethylationEPIC BeadChips was conducted on 249 untreated relapsing-remitting MS patients, sampled at the start of disease-modifying treatment (DMT). A differential methylation analysis compared patients with evidence of disease activity (EDA) to those with no evidence of disease activity (NEDA) over 2 years from DMT start. Utilizing causal inference testing (CIT) and Mendelian randomization (MR), we sought to elucidate the relationships between DNA methylation, gene expression, genetic variation, and disease activity. RESULTS: Four differentially methylated regions (DMRs) were identified between EDA and NEDA. Examining the influence of single nucleotide polymorphisms (SNPs), 923 variants were found to account for the observed differences in the 4 DMRs. Importantly, 3 out of the 923 SNPs, affecting DNA methylation in a DMR linked to the anti-Mullerian hormone (AMH) gene, were associated with disease activity risk in an independent cohort of 1,408 MS patients. CIT and MR demonstrated that DNA methylation in AMH acts as a mediator for the genetic risk of disease activity. INTERPRETATION: This study uncovered a novel molecular pathway implicating the interaction between DNA methylation and genetic variation in the risk of disease activity in MS, emphasizing the role of sex hormones, particularly the AMH, in MS pathobiology. ANN NEUROL 2024;96:289-301.


Assuntos
Hormônio Antimülleriano , Metilação de DNA , Esclerose Múltipla Recidivante-Remitente , Polimorfismo de Nucleotídeo Único , Humanos , Metilação de DNA/genética , Feminino , Masculino , Adulto , Hormônio Antimülleriano/genética , Hormônio Antimülleriano/sangue , Polimorfismo de Nucleotídeo Único/genética , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/genética , Análise da Randomização Mendeliana , Esclerose Múltipla/genética
5.
Immunity ; 45(4): 774-787, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27742544

RESUMO

The transcription factor Foxo3 plays a crucial role in myeloid cell function but its role in lymphoid cells remains poorly defined. Here, we have shown that Foxo3 expression was increased after T cell receptor engagement and played a specific role in the polarization of CD4+ T cells toward pathogenic T helper 1 (Th1) cells producing interferon-γ (IFN-γ) and granulocyte monocyte colony stimulating factor (GM-CSF). Consequently, Foxo3-deficient mice exhibited reduced susceptibility to experimental autoimmune encephalomyelitis. At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+ T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+ T cells restored both IFN-γ and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.


Assuntos
Diferenciação Celular/fisiologia , Proteína Forkhead Box O3/metabolismo , Interleucina-1/metabolismo , Proteínas com Domínio T/metabolismo , Células Th1/metabolismo , Células Th1/patologia , Fatores de Transcrição/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/imunologia , Linhagem Celular , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Proteína Forkhead Box O3/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Células HEK293 , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas com Domínio T/imunologia , Células Th1/imunologia
6.
Immunity ; 44(5): 1114-26, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27192577

RESUMO

Regulatory T (Treg) cells expressing Foxp3 transcripton factor are essential for immune homeostasis. They arise in the thymus as a separate lineage from conventional CD4(+)Foxp3(-) T (Tconv) cells. Here, we show that the thymic development of Treg cells depends on the expression of their endogenous cognate self-antigen. The formation of these cells was impaired in mice lacking this self-antigen, while Tconv cell development was not negatively affected. Thymus-derived Treg cells were selected by self-antigens in a specific manner, while autoreactive Tconv cells were produced through degenerate recognition of distinct antigens. These distinct modes of development were associated with the expression of T cell receptor of higher functional avidity for self-antigen by Treg cells than Tconv cells, a difference subsequently essential for the control of autoimmunity. Our study documents how self-antigens define the repertoire of thymus-derived Treg cells to subsequently endow this cell type with the capacity to undermine autoimmune attack.


Assuntos
Antígeno CTLA-4/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/metabolismo , Subpopulações de Linfócitos T/fisiologia , Linfócitos T Reguladores/fisiologia , Timo/imunologia , Animais , Autoantígenos/imunologia , Antígeno CTLA-4/genética , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/genética , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T/genética
7.
J Autoimmun ; 146: 103234, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663202

RESUMO

Narcolepsy is a rare cause of hypersomnolence and may be associated or not with cataplexy, i.e. sudden muscle weakness. These forms are designated narcolepsy-type 1 (NT1) and -type 2 (NT2), respectively. Notable characteristics of narcolepsy are that most patients carry the HLA-DQB1*06:02 allele and NT1-patients have strongly decreased levels of hypocretin-1 (synonym orexin-A) in the cerebrospinal fluid (CSF). The pathogenesis of narcolepsy is still not completely understood but the strong HLA-bias and increased frequencies of CD4+ T cells reactive to hypocretin in the peripheral blood suggest autoimmune processes in the hypothalamus. Here we analyzed the transcriptomes of CSF-cells from twelve NT1 and two NT2 patients by single cell RNAseq (scRNAseq). As controls, we used CSF cells from patients with multiple sclerosis, radiologically isolated syndrome, and idiopathic intracranial hypertension. From 27,255 CSF cells, we identified 20 clusters of different cell types and found significant differences in three CD4+ T cell and one monocyte clusters between narcolepsy and multiple sclerosis patients. Over 1000 genes were differentially regulated between patients with NT1 and other diseases. Surprisingly, the most strongly upregulated genes in narcolepsy patients as compared to controls were coding for the genome-encoded MTRNR2L12 and MTRNR2L8 peptides, which are homologous to the mitochondria-encoded HUMANIN peptide that is known playing a role in other neurological diseases including Alzheimer's disease.


Assuntos
Narcolepsia , Análise de Célula Única , Transcriptoma , Humanos , Narcolepsia/genética , Narcolepsia/líquido cefalorraquidiano , Masculino , Feminino , Adulto , Orexinas/líquido cefalorraquidiano , Orexinas/genética , Perfilação da Expressão Gênica , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Cadeias beta de HLA-DQ/genética , Pessoa de Meia-Idade , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-39004505

RESUMO

BACKGROUND: Vitamin D (VitD) affects the risk of multiple sclerosis (MS), but the impact on disease activity is controversial. We assessed whether VitD is associated with the No-Evidence of Disease Activity-3 (NEDA-3) status at 2 years from disease-modifying treatment (DMT) start, and whether this association is causal or the result of confounding factors. Furthermore, we explored if a genetic predisposition to higher VitD levels affects the risk of disease activity. METHODS: 230 untreated relapsing-remitting MS patients underwent serum 25-OH-vitamin-D measurement, and the association between seasonally adjusted VitD and disease activity was tested. Modelling a Polygenic Risk Score from a Genome-Wide Association Study on ~400 000 individuals, we studied the impact of genetic predisposition to higher VitD on the NEDA-3 status in 1408 independent MS patients. Two-sample Mendelian randomisation (MR) was used to assess causality. RESULTS: Lower baseline VitD was associated with decreased probability of NEDA-3 at 2 years (p=0.019). Particularly, VitD levels <20 ng/mL conferred an over twofold risk of disease activity (OR 2.36, 95% CI 1.30 to 3.88, p=0.0037). Genetic predisposition to higher VitD levels was associated with delayed age at MS onset (p=0.018) and with a higher probability of NEDA-3 status (p=0.034). MR confirmed causality between VitD and the risk of disease activity (p=0.041). CONCLUSIONS: VitD levels before DMT start affect the risk of disease activity in MS. Genetic predisposition to higher VitD levels confers a lower risk of disease activity and is associated with delayed MS onset. Our work prompts future prospective studies regarding VitD supplementation and lifestyle interventions to hamper disease activity in MS.

9.
Cerebellum ; 23(1): 181-196, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36729270

RESUMO

Modeling paraneoplastic neurological diseases to understand the immune mechanisms leading to neuronal death is a major challenge given the rarity and terminal access of patients' autopsies. Here, we present a pilot study aiming at modeling paraneoplastic cerebellar degeneration with Yo autoantibodies (Yo-PCD). Female mice were implanted with an ovarian carcinoma cell line expressing CDR2 and CDR2L, the known antigens recognized by anti-Yo antibodies. To boost the immune response, we also immunized the mice by injecting antigens with diverse adjuvants and immune checkpoint inhibitors. Ataxia and gait instability were assessed in treated mice as well as autoantibody levels, Purkinje cell density, and immune infiltration in the cerebellum. We observed the production of anti-Yo antibodies in the CSF and serum of all immunized mice. Brain immunoreaction varied depending on the site of implantation of the tumor, with subcutaneous administration leading to a massive infiltration of immune cells in the meningeal spaces, choroid plexus, and cerebellar parenchyma. However, we did not observe massive Purkinje cell death nor any motor impairments in any of the experimental groups. Self-sustained neuro-inflammation might require a longer time to build up in our model. Unusual tumor antigen presentation and/or intrinsic, species-specific factors required for pro-inflammatory engagement in the brain may also constitute strong limitations to achieve massive recruitment of antigen-specific T-cells and killing of antigen-expressing neurons in this mouse model.


Assuntos
Ataxia Cerebelar , Degeneração Paraneoplásica Cerebelar , Humanos , Camundongos , Feminino , Animais , Projetos Piloto , Cerebelo/patologia , Células de Purkinje/metabolismo , Ataxia Cerebelar/patologia , Autoanticorpos
10.
Mult Scler ; 30(6): 654-663, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38424741

RESUMO

BACKGROUND: The glycoprotein CD226 plays a key role in regulating immune cell function. Soluble CD226 (sCD226) is increased in sera of patients with several chronic inflammatory diseases but its levels in neuroinflammatory diseases such as multiple sclerosis (MS) are unknown. OBJECTIVE: To investigate the presence and functional implications of sCD226 in persons with multiple sclerosis (pwMS) and other neurological diseases. METHODS: The mechanisms of sCD226 production were first investigated by analyzing CD226 surface expression levels and supernatants of CD3/CD226-coactivated T cells. The role of sCD226 on dendritic cell maturation was evaluated. The concentration of sCD226 in the sera from healthy donors (HD), pwMS, neuromyelitis optica (NMO), and Alzheimer's disease (AD) was measured. RESULTS: CD3/CD226-costimulation induced CD226 shedding. Addition of sCD226 to dendritic cells during their maturation led to an increased production of the pro-inflammatory cytokine interleukin (IL)-23. We observed a significant increase in sCD226 in sera from pwMS and NMO compared to HD and AD. In MS, levels were increased in both relapsing-remitting multiple sclerosis (RRMS) and secondary-progressive multiple sclerosis (SPMS) compared to clinically isolated syndrome (CIS). CONCLUSION: Our data suggest that T-cell activation leads to release of sCD226 that could promote inflammation and raises the possibility of using sCD226 as a biomarker for neuroinflammation.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Células Dendríticas , Esclerose Múltipla , Neuromielite Óptica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alzheimer/sangue , Doença de Alzheimer/imunologia , Antígenos de Diferenciação de Linfócitos T/sangue , Biomarcadores/sangue , Células Dendríticas/imunologia , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Neuromielite Óptica/sangue , Neuromielite Óptica/imunologia , Linfócitos T/imunologia , Idoso de 80 Anos ou mais
11.
Eur J Immunol ; 52(8): 1335-1349, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35579560

RESUMO

CD4+ FOXP3+ Tregs are currently explored to develop cell therapies against immune-mediated disorders, with an increasing focus on antigen receptor-engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG-3 and CTLA-4 in LNs, while IL-10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL-10, CTLA-4, and LAG-3 were nonredundantly required for the protective function of antigen receptor-engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg-derived IL-10 and CTLA-4 were both required to suppress acute autoreactive CD4+ T-cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor-engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks.


Assuntos
Autoimunidade , Doenças do Sistema Imunitário , Animais , Antígeno CTLA-4 , Terapia Baseada em Transplante de Células e Tecidos , Fatores de Transcrição Forkhead/genética , Interleucina-10 , Camundongos , Receptores de Antígenos , Linfócitos T Reguladores
12.
Brain ; 145(6): 2018-2030, 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35552381

RESUMO

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.


Assuntos
Autoimunidade , Vacinas contra Influenza , Narcolepsia , Animais , Autoantígenos , Hemaglutininas , Inflamação/complicações , Vacinas contra Influenza/efeitos adversos , Interferon gama , Camundongos , Narcolepsia/induzido quimicamente , Neurônios , Orexinas , Linfócitos T/imunologia , Vacinação/efeitos adversos
13.
J Am Soc Nephrol ; 33(12): 2211-2231, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36280286

RESUMO

BACKGROUND: The mechanisms regulating CD8+ T cell migration to nonlymphoid tissue during inflammation have not been fully elucidated, and the migratory properties of effector memory CD8+ T cells that re-express CD45RA (TEMRA CD8+ T cells) remain unclear, despite their roles in autoimmune diseases and allotransplant rejection. METHODS: We used single-cell proteomic profiling and functional testing of CD8+ T cell subsets to characterize their effector functions and migratory properties in healthy volunteers and kidney transplant recipients with stable or humoral rejection. RESULTS: We showed that humoral rejection of a kidney allograft is associated with an accumulation of cytolytic TEMRA CD8+ T cells in blood and kidney graft biopsies. TEMRA CD8+ T cells from kidney transplant recipients exhibited enhanced migratory properties compared with effector memory (EM) CD8+ T cells, with enhanced adhesion to activated endothelium and transmigration in response to the chemokine CXCL12. CXCL12 directly triggers a purinergic P2×4 receptor-dependent proinflammatory response of TEMRA CD8+ T cells from transplant recipients. The stimulation with IL-15 promotes the CXCL12-induced migration of TEMRA and EM CD8+ T cells and promotes the generation of functional PSGL1, which interacts with the cell adhesion molecule P-selectin and adhesion of these cells to activated endothelium. Although disruption of the interaction between functional PSGL1 and P-selectin prevents the adhesion and transmigration of both TEMRA and EM CD8+ T cells, targeting VLA-4 or LFA-1 (integrins involved in T cell migration) specifically inhibited the migration of TEMRA CD8+ T cells from kidney transplant recipients. CONCLUSIONS: Our findings highlight the active role of TEMRA CD8+ T cells in humoral transplant rejection and suggest that kidney transplant recipients may benefit from therapeutics targeting these cells.


Assuntos
Linfócitos T CD8-Positivos , Transplante de Rim , Humanos , Transplantados , Selectina-P/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Rejeição de Enxerto , Memória Imunológica , Proteômica , Antígenos Comuns de Leucócito/metabolismo , Subpopulações de Linfócitos T/metabolismo
14.
J Allergy Clin Immunol ; 150(2): 312-324, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35716951

RESUMO

BACKGROUND: Comorbidities are risk factors for development of severe coronavirus disease 2019 (COVID-19). However, the extent to which an underlying comorbidity influences the immune response to severe acute respiratory syndrome coronavirus 2 remains unknown. OBJECTIVE: Our aim was to investigate the complex interrelations of comorbidities, the immune response, and patient outcome in COVID-19. METHODS: We used high-throughput, high-dimensional, single-cell mapping of peripheral blood leukocytes and algorithm-guided analysis. RESULTS: We discovered characteristic immune signatures associated not only with severe COVID-19 but also with the underlying medical condition. Different factors of the metabolic syndrome (obesity, hypertension, and diabetes) affected distinct immune populations, thereby additively increasing the immunodysregulatory effect when present in a single patient. Patients with disorders affecting the lung or heart, together with factors of metabolic syndrome, were clustered together, whereas immune disorder and chronic kidney disease displayed a distinct immune profile in COVID-19. In particular, severe acute respiratory syndrome coronavirus 2-infected patients with preexisting chronic kidney disease were characterized by the highest number of altered immune signatures of both lymphoid and myeloid immune branches. This overall major immune dysregulation could be the underlying mechanism for the estimated odds ratio of 16.3 for development of severe COVID-19 in this burdened cohort. CONCLUSION: The combinatorial systematic analysis of the immune signatures, comorbidities, and outcomes of patients with COVID-19 has provided the mechanistic immunologic underpinnings of comorbidity-driven patient risk and uncovered comorbidity-driven immune signatures.


Assuntos
COVID-19 , Síndrome Metabólica , Insuficiência Renal Crônica , Comorbidade , Humanos , Imunidade , Síndrome Metabólica/epidemiologia , SARS-CoV-2
15.
J Autoimmun ; 108: 102401, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31948790

RESUMO

The use of autoantigen-specific regulatory T cells (Tregs) as a cellular therapy for autoimmune diseases is appealing. However, it is challenging to isolate and expand large quantity of Tregs expressing disease-relevant T-cell receptors (TCR). To overcome this problem, we used an approach aiming at redirecting the specificity of polyclonal Tregs through autoreactive TCR gene transfer technology. In this study, we examined whether Tregs engineered through retroviral transduction to express a TCR cross-reactive to two CNS autoantigens, myelin oligodendrocyte glycoprotein (MOG) and neurofilament-medium (NF-M), had a superior protective efficacy compared with Tregs expressing a MOG mono-specific TCR. We observed that engineered Tregs (engTregs) exhibited in vitro regulatory effects related to the antigenic specificity of the introduced TCR, and commensurate in potency with the avidity of the transduced TCR. In experimental autoimmune encephalomyelitis (EAE), adoptively transferred engTregs proliferated, and migrated to the CNS, while retaining FoxP3 expression. EngTregs expressing MOG/NF-M cross-reactive TCR had superior protective properties over engTregs expressing MOG-specific TCR in MOG-induced EAE. Remarkably, MOG/NF-M bi-specific TCR-engTregs also improved recovery from EAE induced by an unrelated CNS autoantigen, proteolipid protein (PLP). This study underlines the benefit of using TCRs cross-reacting towards multiple autoantigens, compared with mono-reactive TCR, for the generation of engTregs affording protection from autoimmune disease in adoptive cell therapy.


Assuntos
Encefalomielite Autoimune Experimental/terapia , Fatores de Transcrição Forkhead/antagonistas & inibidores , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Animais , Autoantígenos/imunologia , Reações Cruzadas/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Engenharia Genética/métodos , Imunoterapia Adotiva/métodos , Camundongos , Glicoproteína Mielina-Oligodendrócito/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento
16.
J Autoimmun ; 100: 1-6, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948158

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Narcolepsia , Receptores de Antígenos de Linfócitos T , Adolescente , Adulto , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Narcolepsia/genética , Narcolepsia/imunologia , Narcolepsia/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia
17.
Mult Scler ; 25(3): 392-398, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29336205

RESUMO

BACKGROUND: Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency. DESIGN/METHODS: We developed a highly sensitive natalizumab ADA titration assay on the Meso Scale Discovery (MSD) platform and a pharmacokinetic (PK) assay. We included 43 patients with a positive ELISA-ADA result within 6 months of treatment initiation (baseline) of whom a follow-up serum sample was available 12-30 months after treatment start. MSD-ADA titres and drug levels were measured. RESULTS: Median MSD-ADA titre at baseline was 4881 and 303 at follow-up. A titre of >400 at baseline had a 94% sensitivity and 89% specificity to predict ADA persistency. Reversion to ADA negativity occurred in 10 patients with mean drug levels of 10.8 µg/mL. The median trough drug level in ADA-positive samples was 0 µg/mL. PK levels and ADA titres correlated strongly negatively ( r = -0.67). CONCLUSION: High baseline natalizumab ADA titres accurately predict persistency. Despite continuous treatment, the majority of patients with persistent ADA had no detectable drug levels indicating loss of efficacy in line with phase 3 study results.


Assuntos
Anticorpos/imunologia , Imunoensaio/normas , Fatores Imunológicos/imunologia , Esclerose Múltipla/tratamento farmacológico , Natalizumab/imunologia , Avaliação de Resultados em Cuidados de Saúde , Adulto , Anticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Fatores Imunológicos/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Natalizumab/sangue , Sensibilidade e Especificidade , Adulto Jovem
18.
Brain ; 141(7): 2066-2082, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29873694

RESUMO

Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain. However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations. In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls. In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse. A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen's encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest. Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis. Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells. The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions. Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen's encephalitis. Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions. Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.


Assuntos
Linfócitos/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/fisiologia , Encéfalo/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Doenças Desmielinizantes/patologia , Encefalite/metabolismo , Encefalite/patologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Linfócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Fenótipo
19.
Nature ; 562(7725): 46-48, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30275550
20.
PLoS Genet ; 12(7): e1006185, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27438086

RESUMO

The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1R63W mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1R63W variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation.


Assuntos
Encefalomielite Autoimune Experimental/genética , Variação Genética , Proteínas Proto-Oncogênicas c-vav/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Reguladores/citologia , Animais , Cálcio/metabolismo , Sistema Nervoso Central/fisiopatologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Predisposição Genética para Doença , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Polimorfismo Genético , Ratos , Transdução de Sinais , Timo/metabolismo
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