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1.
Artigo em Inglês | MEDLINE | ID: mdl-34224053

RESUMO

Autoimmunity is caused by an unbalanced immune system, giving rise to a variety of organ-specific to system disorders. Patients with autoimmune diseases are commonly treated with broad-acting immunomodulatory drugs, with the risk of severe side effects. Regulatory T cells (Tregs) have the inherent capacity to induce peripheral tolerance as well as tissue regeneration and are therefore a prime candidate to use as cell therapy in patients with autoimmune disorders. (Pre)clinical studies using Treg therapy have already established safety and feasibility, and some show clinical benefits. However, Tregs are known to be functionally impaired in autoimmune diseases. Therefore, ex vivo manipulation to boost and stably maintain their suppressive function is necessary when considering autologous transplantation. Similar to autoimmunity, severe coronavirus disease 2019 (COVID-19) is characterized by an exaggerated immune reaction and altered Treg responses. In light of this, Treg-based therapies are currently under investigation to treat severe COVID-19. This review provides a detailed overview of the current progress and clinical challenges of Treg therapy for autoimmune and hyperinflammatory diseases, with a focus on recent successes of ex vivo Treg manipulation.

2.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073458

RESUMO

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell-cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.


Assuntos
Doenças Autoimunes/imunologia , Proliferação de Células , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Antígeno CTLA-4/imunologia , Feminino , Granzimas/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
3.
Front Immunol ; 12: 642038, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790911

RESUMO

Background: Multiple sclerosis (MS) patients are protected from relapses during pregnancy and have an increased relapse risk after delivery. It is unknown how pregnancy controls disease-contributing CD4+ T helper (Th) cells and whether this differs in MS patients who experience a postpartum relapse. Here, we studied the effector phenotype of Th cells in relation to pregnancy and postpartum relapse occurrence in MS. Methods: Memory skewing and activation of effector Th subsets were analyzed in paired third trimester and postpartum blood of 19 MS patients with and without a postpartum relapse and 12 healthy controls. Ex vivo results were associated with circulating levels of pregnancy-induced hormones and mirrored in vitro by exposing proliferating Th cells to corresponding serum samples. Results: Based on HSNE-guided analyses, we found that effector memory proportions of Th cells were increased in postpartum vs. third trimester samples from MS patients without a postpartum relapse. This was not seen for relapsing patients or healthy controls. CXCR3 was upregulated on postpartum memory Th cells, except for relapsing patients. These changes were verified by adding sera from the same individuals to proliferating Th cells, but did not associate with third trimester cortisol, estradiol or progesterone levels. For relapsing patients, activated memory Th cells of both third trimester and postpartum samples produced higher levels of pro-inflammatory cytokines. Conclusion: Effector Th cells are differentially regulated during pregnancy in MS patients, likely via serum-related factors beyond the studied hormones. The pro-inflammatory state of memory Th cells during pregnancy may predict a postpartum relapse.


Assuntos
Esclerose Múltipla Recidivante-Remitente/imunologia , Complicações na Gravidez/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Feminino , Humanos , Período Pós-Parto , Gravidez , Recidiva
4.
Trends Mol Med ; 26(11): 1059-1060, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32978063
5.
Ther Adv Chronic Dis ; 11: 2040622320947378, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32913622

RESUMO

Background and aims: Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing-remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model. Methods: Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters. Results: We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice. Conclusion: Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32788322

RESUMO

OBJECTIVE: To investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity. METHODS: Expression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (TH) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26-treated human BBB ECs. Myelin oligodendrocyte glycoprotein35-55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry. RESULTS: IL-26 expression was induced in TH lymphocytes by TH17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs. CONCLUSIONS: Our study demonstrates that although IL-26 is preferentially expressed by TH17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH17 lymphocytes.

8.
Proc Natl Acad Sci U S A ; 117(9): 5028-5038, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071226

RESUMO

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRß knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRß KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.


Assuntos
Astrócitos/metabolismo , Oncostatina M/metabolismo , Remielinização/fisiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Astrócitos/patologia , Axônios , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina , Células Precursoras de Oligodendrócitos , Inibidor Tecidual de Metaloproteinase-1/genética
9.
Front Immunol ; 10: 1165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191538

RESUMO

For a long time, the central nervous system (CNS) was believed to be an immune privileged organ. In the last decades, it became apparent that the immune system interacts with the CNS not only in pathological, but also in homeostatic situations. It is now clear that immune cells infiltrate the healthy CNS as part of immune surveillance and that immune cells communicate through cytokines with CNS resident cells. In pathological conditions, an enhanced infiltration of immune cells takes place to fight the pathogen. A well-known family of cytokines is the interleukin (IL)-6 cytokine family. All members are important in cell communication and cell signaling in the immune system. One of these members is oncostatin M (OSM), for which the receptor is expressed on several cells of the CNS. However, the biological function of OSM in the CNS is not studied in detail. Here, we briefly describe the general aspects related to OSM biology, including signaling and receptor binding. Thereafter, the current understanding of OSM during CNS homeostasis and pathology is summarized.


Assuntos
Sistema Nervoso Central/fisiologia , Oncostatina M/genética , Oncostatina M/metabolismo , Animais , Suscetibilidade a Doenças , Homeostase , Humanos , Receptores de Oncostatina M/metabolismo , Transdução de Sinais , Especificidade da Espécie
10.
Nat Commun ; 9(1): 819, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483510

RESUMO

Extracellular matrix (ECM) proteins secreted by blood-brain barrier (BBB) endothelial cells (ECs) are implicated in cell trafficking. We discovered that the expression of ECM epidermal growth factor-like protein 7 (EGFL7) is increased in the CNS vasculature of patients with multiple sclerosis (MS), and in mice with experimental autoimmune encephalomyelitis (EAE). Perivascular CD4 T lymphocytes colocalize with ECM-bound EGFL7 in MS lesions. Human and mouse activated T cells upregulate EGFL7 ligand αvß3 integrin and can adhere to EGFL7 through integrin αvß3. EGFL7-knockout (KO) mice show earlier onset of EAE and increased brain and spinal cord parenchymal infiltration of T lymphocytes. Importantly, EC-restricted EGFL7-KO is associated with a similar EAE worsening. Finally, treatment with recombinant EGFL7 improves EAE, reduces MCAM expression, and tightens the BBB in mouse. Our data demonstrate that EGFL7 can limit CNS immune infiltration and may represent a novel therapeutic avenue in MS.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores de Crescimento Endotelial/genética , Medula Espinal/efeitos dos fármacos , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Antígeno CD146/genética , Antígeno CD146/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Proteínas de Ligação ao Cálcio , Família de Proteínas EGF , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fatores de Crescimento Endotelial/deficiência , Fatores de Crescimento Endotelial/imunologia , Fatores de Crescimento Endotelial/farmacologia , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Integrina alfa5/genética , Integrina alfa5/imunologia , Integrina beta3/genética , Integrina beta3/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Knockout , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Ligação Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Medula Espinal/imunologia
11.
Front Immunol ; 8: 1160, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979263

RESUMO

Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP (P = 0.003, R2 = 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years (P = 0.005, R2 = 0.29) and with EP and EDSS after 5 years (P = 0.008, R2 = 0.42 and P = 0.003, R2 = 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.

12.
Sci Rep ; 7(1): 663, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28386103

RESUMO

Cytomegalovirus (CMV) is a latent virus which causes chronic activation of the immune system. Here, we demonstrate that cytotoxic and pro-inflammatory CD4+CD28null T cells are only present in CMV seropositive donors and that CMV-specific Immunoglobulin (Ig) G titers correlate with the percentage of these cells. In vitro stimulation of peripheral blood mononuclear cells with CMVpp65 peptide resulted in the expansion of pre-existing CD4+CD28null T cells. In vivo, we observed de novo formation, as well as expansion of CD4+CD28null T cells in two different chronic inflammation models, namely the murine CMV (MCMV) model and the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis (MS). In EAE, the percentage of peripheral CD4+CD28null T cells correlated with disease severity. Pre-exposure to MCMV further aggravated EAE symptoms, which was paralleled by peripheral expansion of CD4+CD28null T cells, increased splenocyte MOG reactivity and higher levels of spinal cord demyelination. Cytotoxic CD4+ T cells were identified in demyelinated spinal cord regions, suggesting that peripherally expanded CD4+CD28null T cells migrate towards the central nervous system to inflict damage. Taken together, we demonstrate that CMV drives the expansion of CD4+CD28null T cells, thereby boosting the activation of disease-specific CD4+ T cells and aggravating autoimmune mediated inflammation and demyelination.


Assuntos
Autoimunidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Adulto , Animais , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Infecções por Citomegalovirus/complicações , Doenças Desmielinizantes , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
13.
Neurobiol Dis ; 91: 292-306, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27039370

RESUMO

T cells are believed to be key effector cells in multiple sclerosis (MS). In this study, we examined the roles of T cell ephrinB1 (EFNB1) and ephrinB2 (EFNB2) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and MS. We provide evidence that animals with T cell specific double deletion of EFNB1 and EFNB2 (dKO) have reduced proliferation in response to MOG35-55, defective Th1 and Th17 differentiations and significantly lower scores of MOG-induced EAE. We further demonstrate that dKO T cells are compromised in their ability to migrate into the CNS of EAE animals in vivo and towards multiple chemokines in vitro. Using deletion mutations, we identified a critical 11-aa EFNB1 intracellular domain segment that controls T cell chemotaxis towards CCL21. In humans, EFNB1 and EFNB2 are highly expressed in Th1 and Th17 cells and EFNB1- and EFNB2-expressing T cells are found among immune cell infiltrates in MS lesions. Reverse signaling through EFNB1 and EFNB2 in human Th17 cells enhances their migration through a monolayer of blood brain barrier endothelial cells. Our study demonstrates that expression of EFNB1 and EFNB2 is implicated in Th cell differentiation and migration to inflammatory sites in both EAE and MS.


Assuntos
Efrina-B1/metabolismo , Efrina-B2/metabolismo , Esclerose Múltipla/metabolismo , Linfócitos T/metabolismo , Animais , Diferenciação Celular/fisiologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Ativação Linfocitária/fisiologia , Camundongos , Esclerose Múltipla/patologia
14.
Cell Transplant ; 25(6): 1207-18, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26688298

RESUMO

The aim of this study is to examine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can generate dendritic cells (DCs) with a stable tolerogenic phenotype to counteract autoimmune responses in an animal model of multiple sclerosis. We investigated if the tolerogenic potency of DCs could be increased by continuous treatment during in vitro differentiation toward DCs compared to standard 24-h in vitro treatment of already terminally differentiated DCs. We show that in vitro treatment with SAHA reduces the generation of new CD11c(+) DCs out of mouse bone marrow. SAHA-generated DCs show reduced antigen-presenting function as evidenced by a reduction in myelin endocytosis, a decreased MHC II expression, and a failure to upregulate costimulatory molecules upon LPS challenge. In addition, SAHA-generated DCs display a reduction in proinflammatory cytokines and molecules involved in apoptosis induction, inflammatory migration, and TLR signaling, and they are less immunostimulatory compared to untreated DCs. We demonstrated that the underlying mechanism involves a diminished STAT1 phosphorylation and was independent of STAT6 activation. Although in vitro results were promising, SAHA-generated DCs were not able to alleviate the development of experimental autoimmune encephalomyelitis in mice. In vitro washout experiments demonstrated that the tolerogenic phenotype of SAHA-treated DCs is reversible. Taken together, while SAHA potently boosts tolerogenic properties in DCs during the differentiation process in vitro, SAHA-generated DCs were unable to reduce autoimmunity in vivo. Our results imply that caution needs to be taken when developing DC-based therapies to induce tolerance in the context of autoimmune disease.


Assuntos
Células Dendríticas/imunologia , Ácidos Hidroxâmicos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Antígeno CD11c/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Endocitose/efeitos dos fármacos , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Fenótipo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptores Toll-Like/metabolismo , Regulação para Cima/efeitos dos fármacos , Vorinostat
15.
Semin Immunopathol ; 37(6): 577-90, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26245144

RESUMO

The brain is the organ with the highest metabolic demand in the body. Therefore, it needs specialized vasculature to provide it with the necessary oxygen and nutrients, while protecting it against pathogens and toxins. The blood-brain barrier (BBB) is very tightly regulated by specialized endothelial cells, two basement membranes, and astrocytic endfeet. The proximity of astrocytes to the vessel makes them perfect candidates to influence the function of the BBB. Moreover, other glial cells are also known to contribute to either BBB quiescence or breakdown. In this review, we summarize the knowledge on glial regulation of the BBB during development, in homeostatic conditions in the adult, and during neuroinflammatory responses.


Assuntos
Astrócitos/fisiologia , Barreira Hematoencefálica/citologia , Encéfalo/irrigação sanguínea , Microglia/fisiologia , Adulto , Encéfalo/fisiologia , Células Endoteliais/fisiologia , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia
16.
J Immunol ; 195(3): 832-40, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26071562

RESUMO

Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS.


Assuntos
Antígeno de Maturação de Linfócitos B/biossíntese , Vacinas contra Influenza/imunologia , Esclerose Múltipla/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Anticorpos/sangue , Linfócitos B/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Memória Imunológica/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/biossíntese , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Masculino , Metilação , Esclerose Múltipla/sangue , Vacinação , Adulto Jovem
17.
J Immunol ; 194(5): 2099-109, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25617471

RESUMO

CD4(+)CD28(-) T cells arise through repeated antigenic stimulation and are present in diseased tissues of patients with various autoimmune disorders, including multiple sclerosis (MS). These cells are believed to have cytotoxic properties that contribute to the pathogenic damaging of the target organ. Endogenous cues that are increased in the diseased tissue may amplify the activity of CD4(+)CD28(-) T cells. In this study, we focused on IL-15, a cytotoxicity-promoting cytokine that is increased in the serum and cerebrospinal fluid of MS patients. Using immunohistochemistry, we demonstrate that IL-15 is mainly produced by astrocytes and infiltrating macrophages in inflammatory lesions of MS patients. Moreover, in vitro transmigration studies reveal that IL-15 selectively attracts CD4(+)CD28(-) T cells of MS patients, but not of healthy individuals. IL-15 further induces the expression of chemokine receptors and adhesion molecules on CD4(+)CD28(-) T cells, as investigated using flow cytometry, resulting in enhanced migration over a monolayer of human brain endothelial cells. Finally, flow cytometric analyses revealed that IL-15 increases the proliferation and production of GM-CSF, expression of cytotoxic molecules (NKG2D, perforin, and granzyme B), and degranulation capacity of CD4(+)CD28(-) T cells. Taken together, these findings indicate that increased peripheral and local levels of IL-15 amplify the pathogenic potential of CD4(+)CD28(-) T cells, thus contributing to tissue damage in MS brain lesions.


Assuntos
Encéfalo/imunologia , Antígenos CD28/imunologia , Antígenos CD4/imunologia , Interleucina-15/farmacologia , Esclerose Múltipla/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/patologia , Encéfalo/patologia , Antígenos CD28/genética , Antígenos CD4/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Estudos de Casos e Controles , Quimiotaxia de Leucócito , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Feminino , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Granzimas/genética , Granzimas/imunologia , Humanos , Interleucina-15/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Perforina/genética , Perforina/imunologia , Cultura Primária de Células , Transdução de Sinais , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/patologia , Migração Transendotelial e Transepitelial
18.
PLoS One ; 9(10): e111115, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25360562

RESUMO

BACKGROUND AND OBJECTIVE: The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study. METHODS: Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients. RESULTS: In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses. CONCLUSIONS: MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Feminino , Cloridrato de Fingolimode , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , Esfingosina/uso terapêutico , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Adulto Jovem
19.
Mult Scler ; 20(7): 790-801, 2014 06.
Artigo em Inglês | MEDLINE | ID: mdl-24144875

RESUMO

BACKGROUND: The importance of Qa-1 restricted CD8(+) T cells in regulating autoreactive T cell responses has been demonstrated in animal models for autoimmune disorders, including multiple sclerosis (MS). OBJECTIVE: We hypothesize that their human variant, HLA-E restricted CD8(+) T cells, fulfills a similar regulatory role in man and that these cells are of importance in MS. METHODS: A large cohort of MS patients and healthy controls was genotyped for the two known HLA-E polymorphisms. Flow cytometry was used to determine HLA-E expression kinetics and to phenotype HLA-E restricted CD8(+) T cells. Immunohistochemistry was performed to investigate HLA-E expression in the central nervous system (CNS) of MS patients. RESULTS: HLA-E is upregulated on immune cells upon in vitro activation and this upregulation is polymorphism-dependent for T and B cells. T and B cells in lesions of MS patients show enhanced HLA-E expression. Furthermore, NKG2C(+)CD8(+) T cells of MS patients have a significantly lower Foxp3 expression, while NKG2A(+)CD8(+) T cells of MS patients produce higher levels of pro-inflammatory cytokines compared to those of healthy individuals. CONCLUSION: Our study indicates that the HLA-E system is altered in MS and could play a regulatory role in disease.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Sistema Nervoso Central/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Esclerose Múltipla/genética , Polimorfismo Genético , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Sistema Nervoso Central/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Fenótipo , Linfócitos T Reguladores/metabolismo , Adulto Jovem
20.
Crit Rev Immunol ; 33(4): 283-306, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23971528

RESUMO

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), which is believed to be immune-mediated. While CD4+ T cells have been the main suspects for years, there is ample evidence that other immune cells (including those of the innate immune system) play a contributing or regulating role in this disease. After a general introduction, this review focuses on different immune cell subsets implicated in MS pathogenesis and on current and future possibilities to target them for therapeutic use.


Assuntos
Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Linfócitos B/imunologia , Predisposição Genética para Doença , Humanos , Imunidade Inata , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia
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