A stochastic chemical dynamic approach to correlate autoimmunity and optimal vitamin-D range

Motivated by several recent experimental observations that vitamin-D could interact with antigen presenting cells (APCs) and T-lymphocyte cells (T-cells) to promote and to regulate different stages of immune response, we developed a coarse grained kinetic model in an attempt to quantify the role of vitamin-D in immunomodulatory responses. Our kinetic model, developed using the ideas of chemical network theory, leads to a system of nine coupled equations that we solve both by direct and by stochastic (Gillespie) methods. Both the analyses consistently provide detail information on the dependence of immune response to the variation of critical rate parameters. We find that although vitamin-D plays a negligible role in the initial immune response, it exerts a profound influence in the long term, especially in helping the system to achieve a new, stable steady state. The study explores the role of vitamin-D in preserving an observed bistability in the phase diagram (spanned by system parameters) of immune regulation, thus allowing the response to tolerate a wide range of pathogenic stimulation which could help in resisting autoimmune diseases. We also study how vitamin-D affects the time dependent population of dendritic cells that connect between innate and adaptive immune responses. Variations in dose dependent response in anti-inflammatory and pro-inflammatory T-cell populations to vitamin-D correlate well with recent experimental results. Our kinetic model allows for an estimation of the range of optimum level of vitamin-D required for smooth functioning of the immune system and for control of both hyper-regulation and inflammation. Most importantly, the present study reveals that an overdose or toxic level of vitamin-D or any steroid analogue could give rise to too large a tolerant response, leading to an inefficacy in adaptive immune function.Comment: arXiv admin note: substantial text overlap with arXiv:1304.719

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Myeloid cells in autoimmune diseases

Multiple Sclerosis (MS) and Type 1 Diabetes (T1D) are autoimmune diseases caused by dysregulation of the immune system. Monocytes/macrophages are myeloid cells that play a pivotal role in both induction and resolution of these diseases depending on the stage and microenvironment of disease course. Similar to monocytes/macrophages, microglia are CNS resident macrophages that during MS may also exhibit both pro‐inflammatory and anti‐inflammatory properties. The main purpose of my PhD project was to develop a method to induce a regulatory or suppressive phenotype of myeloid cells for use in adoptive transfer as a novel therapy in preclinical studies of autoimmunity. In Paper I we tested the hypothesis whether there are any differences in activation states between mouse strains with different genetic backgrounds. We used congenic Nramp1 ‐susceptible and ‐resistant macrophages on BALB/c and C57BL/6 mouse backgrounds and determined fundamental differences in macrophage activation states between the two different strains as well as Nramp1‐specific effects. In Paper II we tested the therapeutic effect of M2 macrophages in T1D. Our results reveal that after a single adoptive transfer of IL‐4/IL‐10/TGF‐β‐stimulated macrophages > 80% of the treated mice were protected from disease development. In Paper III we explored the same treatment in a MOG‐induced EAE model. We were able to demonstrate that intranasal administration of IL‐4/IL‐10/TGF‐β‐stimulated microglia can attenuate EAE development in DBA/1 mice. In Paper IV we translated the rodent M2 macrophage induction protocol to a human monocyte‐macrophage setting. Our findings indicate a robust stimulation protocol for generation of an optimal, specific, stable, and immunosuppressive human monocyte‐derived macrophage phenotype. The results presented in this thesis collectively demonstrate induction of a regulatory phenotype IL‐4/IL‐10/TGF‐β in various myeloid cells including rodent macrophages, microglia and human monocytes. The IL‐4/IL‐10/TGF‐β‐induced M2 cells had a potent deactivating effect on pro‐inflammatory LPS/IFNγ‐activated macrophages (M1), significantly suppressed T cell proliferation and induced Tregs. Several modes of action are thus indicated to explain the therapeutic clinical effects, which were particularly apparent during chronic disease states. Based on these results, further clinical development of this therapy is thus warranted

Inflammation in the CNS: advancing the field using intravital imaging

Inflammation of the CNS can have devastating, long-lived, and in some cases fatal consequences for patients. The stimuli that can induce CNS inflammation are diverse, and include infectious agents, autoimmune responses against CNS-expressed antigens, and sterile inflammation following ischemia or traumatic injury. In these conditions, cells of the immune system play central roles in promulgation and resolution of the inflammatory response. However, the immunological mechanisms at work in these diverse responses differ according to the nature of the response. Our understanding of the actions of immune cells in the CNS has been restricted by the difficulty in visualising leukocytes as they undergo recruitment from the cerebral microvasculature and following their entry into the CNS parenchyma. However, advances in in vivo microscopy over the last 10-15 years have overcome many of these difficulties, and studies using these forms of microscopy have revealed a wealth of new information regarding the cellular and molecular mechanisms of CNS inflammation. This Research Topic brings together state of the art reviews examining the use of in vivo imaging in investigating inflammation and leukocyte behaviour in the CNS. Papers in this Research Topic describe how in vivo microscopy has increased our understanding of the actions of immune cells in the inflamed CNS, following various stimuli including autoimmunity, infection and sterile inflammation

Understanding the Role of Androgen Receptor Signaling in Modulating p38-alpha Mitogen-Activated Protein Kinase in Experimental Autoimmune Encephalomyelitis

Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, characterized by axonal demyelination and multifocal inflammation. Like many autoimmune diseases, it is a sexually dimorphic disease, being 3-4 times more common in females than in males. p38α MAP kinase (MAPK) has an integral role in modulating inflammatory processes in autoimmunity. Conditionally ablating p38α MAPK in myeloid cells in B6 mice shows a sex difference in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In the absence of sex hormones, this sex difference was reversed, suggesting a role for sex hormones in modulating p38α MAPK signaling in EAE. Based on these findings, we hypothesized that pro-inflammatory functions in EAE is p38-indepdendent in the presence of androgens and p38-dependent in the presence of estrogens. For the purposes of this project, the role of androgens was evaluated. Both in vivo and in vitro techniques were used to assess how androgen receptor (AR) signaling: 1) impacts EAE pathogenesis, and 2) impacts the role of p38α in EAE pathogenesis and macrophage function. To this end, using Cre-Lox technology, we generated mice deficient in: 1) AR globally or conditionally in macrophages, as well as 2) mice doubly deficient in AR and p38α. In vivo results from p38α-sufficient global AR knockout mice show no effect of global AR deletion on EAE pathogenesis. Surprisingly, results from p38α-sufficient conditional AR knockout mice showed significant worsening in disease compared to WT counterparts, suggesting that AR signaling in myeloid cells has a protective role in EAE pathogenesis. These findings implicate a protective role for AR signaling in EAE. Studies with mice doubly deficient in p38α and AR to determine whether AR regulates the role of p38α in EAE are ongoing, but so far show no effect on AR deletion on the role of p38α MAPK. Further studies with larger cohorts of mice are needed elucidate the relationship between AR and p38α MAPK signaling in myeloid cells in EAE pathogenesis. In vitro studies using the immortalized macrophage cell line RAW 264.7 showed that pharmacologic inhibition of p38 MAPK after stimulation with LPS reduced the production of classic pro-inflammatory cytokines IL-6 and TNFα, and effect that was not affected by treatment with 5-dihydrotestosterone, suggesting that the AR does not modulate the role of p38α in cytokine production. These findings implicate no direct role of AR signaling on the functional role of p38α MAPK in the myeloid cell lineage in inflammatory and autoimmune responses

In vivo imaging of lymphocytes in the CNS reveals different behaviour of naïve T cells in health and autoimmunity

<p>Abstract</p> <p>Background</p> <p>Two-photon laser scanning microscopy (TPLSM) has become a powerful tool in the visualization of immune cell dynamics and cellular communication within the complex biological networks of the inflamed central nervous system (CNS). Whereas many previous studies mainly focused on the role of effector or effector memory T cells, the role of naïve T cells as possible key players in immune regulation directly in the CNS is still highly debated.</p> <p>Methods</p> <p>We applied <it>ex vivo </it>and intravital TPLSM to investigate migratory pathways of naïve T cells in the inflamed and non-inflamed CNS. MACS-sorted naïve CD4+ T cells were either applied on healthy CNS slices or intravenously injected into RAG1 -/- mice, which were affected by experimental autoimmune encephalomyelitis (EAE). We further checked for the generation of second harmonic generation (SHG) signals produced by extracellular matrix (ECM) structures.</p> <p>Results</p> <p>By applying TPLSM on living brain slices we could show that the migratory capacity of activated CD4+ T cells is not strongly influenced by antigen specificity and is independent of regulatory or effector T cell phenotype. Naïve T cells, however, cannot find sufficient migratory signals in healthy, non-inflamed CNS parenchyma since they only showed stationary behaviour in this context. This is in contrast to the high motility of naïve CD4+ T cells in lymphoid organs. We observed a highly motile migration pattern for naïve T cells as compared to effector CD4+ T cells in inflamed brain tissue of living EAE-affected mice. Interestingly, in the inflamed CNS we could detect reticular structures by their SHG signal which partially co-localises with naïve CD4+ T cell tracks.</p> <p>Conclusions</p> <p>The activation status rather than antigen specificity or regulatory phenotype is the central requirement for CD4+ T cell migration within healthy CNS tissue. However, under inflammatory conditions naïve CD4+ T cells can get access to CNS parenchyma and partially migrate along inflammation-induced extracellular SHG structures, which are similar to those seen in lymphoid organs. These SHG structures apparently provide essential migratory signals for naïve CD4+ T cells within the diseased CNS.</p

Immune monitoring of relapsing-remitting multiple sclerosis patients submitted to interferon beta treatment

Traditionally, the central nervous system (CNS) is described as an immune-privileged site that receives limited immune surveillance by peripheral lymphocytes under physiological conditions. The discovery of the CNS lymphatic system suggests that the CNS is an immune competent organ, closely interacting with the systemic immune compartment under physiological conditions, in which almost all pathological changes in the CNS elicit a prominent inflammatory reaction. Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS which affects the white and gray matter. MS is believed to be an autoimmune disorder, but the antigen specificity of the immune response is unknown. The pathological hallmark of chronic MS is demyelinated plaque or lesions, which results from an attack on the CNS by immune cells, relative preservation of axons, and the formation of astrocytic scars. Complex multifactorial factors are implicated, in which the environmental are hypothesized to interact with genetically susceptible individuals. In Portugal it is estimated that around 5000 people are affected with MS. The notion that MS is primarily a CD4+ T cell-mediated disease arises from the similarities between the experimental autoimmune encephalomyelitis (EAE) and MS, including the fact that T lymphocytes greatly outnumber B lymphocytes within MS lesions. Diagnosis of MS depends on clinical and paraclinical exams; there is no single diagnostic test to recognize the disease. 85% of patients present a relapse-remitting (RR) MS form, characterized by discrete episodes of neurological dysfunction (relapses or exacerbations) separated by clinical stable periods with lack of disease progression (remissions). Interferon (IFN)-β is the most widely prescribed treatment for MS. IFN-β is a highly pleiotropic cytokine which antagonizes the proinflammatory milieu by increasing production of anti-inflammatory factors. It inhibits leukocyte trafficking and regulates expression of the adhesion molecule. The mechanism of action of IFN-β is complex and multifactorial but has been shown to reduce the biological activity of RRMS in several clinical class I trials. CNS tissue is difficult to access and immune responses within this tissue cannot be easily monitored. Peripheral blood seems to mirror the immunological disturbances that underlie MS, which could represent the migration patterns between the periphery and other tissues according to the clinical phase of the disease. Based on this assumption, the main aim of this thesis was to characterize the circulating immune cell populations of RRMS patients submitted to IFN-β treatment in remission and relapse phases of the disease and compared with healthy subjects. Several studies point to significant alterations in peripheral blood homeostasis of different subpopulations of T cells, like γδ T cells or T helper (Th) 1, Th2, Th17 and T cytotoxic (Tc) 1, Tc2, Tc17 functional subsets; of B cells subpopulations; and of innate cells like monocytes and dendritic cells (DCs). First, we started with the selection of the RRMS patients and collected blood from each one after an informed consent was signed. Through direct immunofluorescence membrane and intracytoplasmic staining protocols, by flow cytometry, were identified and characterized the circulating cell subsets. For the functional assessment of the cells intracellular cytokines at single cell level were measured after in vitro stimulation. To evaluate gene expression, RNA isolation and quantitative real-time reverse transcriptase-polymerase chain reaction was performed. The systemic circulation of IFN-β-treated RRMS patients in remission showed lower frequency of the (myeloid dendritic cells) mDCs subset and higher frequency in the relapse phase, while the frequency of the (plasmacytoid dendritic cells) pDCs subset remains unchanged. Consequently, the mDCs/pDCs ratio decreases in remission and increases in relapse episodes. In remission RRMS patients, the DCs subsets increased their capability to interact with T cells revealed through the increased expression of the HLA-DR and decreased in relapse episodes. In RRMS, the mDCs/pDCs ratio and the activation status of both DCs subsets constitutes a good peripheral biomarker between phases. In circulation of remission RRMS patients, the total monocyte cells and intermediate monocyte (iMo) subset increased and the non-classical monocyte (ncMo) subset decreased. In the relapse phase, the ncMo subset remains decreased. The monocyte subsets present the same pattern of the expression of HLA-DR as the DCs subsets, increasing in remission and decreasing in relapse. The frequency of immature/transitional B cells increases in circulation of remission IFN-β treated RRMS patients. Inside the memory B cell subsets, there was an increase in CD27− B cell subset, more precisely the CD27−IgG+ cells, and a decrease in CD27−IgA+ cells. Relapse RRMS patients showed lower total B cells when compared with remission phase patients, accompanied by an increase in the CD27- memory B cell phases were the increase in the plasmablast B cell subset. The ratio between immature/transitional B cells and plasmablasts decreased in relapse when compared with remission RRMS. The T cell subsets exhibit a shift toward Th2 and Tc2 polarization with a reduction of the Th1 and Tc1 functional subset, in remission episodes. This is accompanied by a reduction in the production of proinflammatory cytokines, mainly IFNγ. Conversely, the frequency of the Th17, Tc17 subsets and the serum level of IL17 increased. In the relapse phase, the Th17 subset decreases the cytokines produced, while the Tc17 subset maintains high levels of tumor necrosis factor (TNF)-α production. The signature of cytokines produced by Th(c)1 and Th(c)17 cells was different. The present study demonstrates that the action mode of IFN-β on Th(c)1 and Th(c)17 cells promotes different results in systemic circulation of RRMS patients. IFN-β therapy supports the decrease in pro-inflammatory cytokines produced by Th(c)1 cells and increase the production of pro-inflammatory cytokines by the Th(c)17. Th17 subset perpetuates and promote the chronic inflammation in periphery in remission RRMS patients, through the production of IL-17 and Th1 type cytokines. No differences were found between the frequency of regulatory T and T follicular helper -like subsets. However, CXCR5+CD4+T cells exhibit a more proinflammatory activity, presenting higher frequencies of TNF-α+ cells in both phases of RRMS. CXCR5+CD8+T cells exhibited an increased ability to produce IL-2 (assuming a Th1 profile) in the remission phase of the disease, thus decreasing in relapsing episodes. The frequency of γδ T cells was the same between healthy subjects and RRMS patients. In remission phase, the central memory γδ T (TCM) subset decreased, and the naive compartment increased. In relapse RRMS patients, the terminally differentiated effector memory γδ T (TEMRA) subset decreased when compared with remission episodes. CCR5+ γδ TEMRA cells were significantly depleted, as a consequence of the migratory pattern in order to play effector functions. This subset presents as a possible participator in the demyelination process and an attractive peripheral blood biomarker between RRMS phases. The identification and characterization of circulating cells can contribute to clarify the pathophysiology of MS, their progression, and the function of each subset in this process. Some of the more relevant results obtained in this study could have the potential to be considered as peripheral biomarkers between remission and relapse RRMS patients treated with IFN-β, namely: the mDCs/pDCs ratio, the activation profile of DCs and monocyte subsets, the commitment of the Th17 cells with a Th1 signature, the CCR5+γδTEMRA cell subset and the ratio between immature/transitional B cells and plasmablasts. In both phases of RRMS, the ncMo subset was decreased and the IgM+CD27+ memory B cells and the compartment CD27- memory B cells increased in RRMS patients. The identification of peripheral markers that could reflect the clinical course of MS and the efficacy of treatment is a stimulating field of research and debate. In the future, further studies including larger cohorts of patients and a larger follow-up are needed in order to establish whether this immune shift correlates with a favorable clinical response.Tradicionalmente, o sistema nervoso central (SNC) é descrito como um tecido com privilégio imunitário que em condições fisiológicas é sujeito a uma vigilância imunológica limitada por linfócitos periféricos. A descoberta do sistema linfático do SNC sugere que este é um órgão imunocompetente, interagindo intimamente com o sistema imunitário sistêmico e quase todas as alterações patológicas no SNC desencadeiam uma reação inflamatória proeminente. A esclerose múltipla (EM) é uma doença inflamatória crônica do SNC que afeta a substância branca e cinzenta, apesar de ser uma doença auto-imune desconhece-se o antigénio que desencadeia a resposta imune. As placas ou lesões desmielinizantes que resultam de um ataque ao SNC por células imunes, a preservação relativa dos axônios e a formação de cicatrizes astrocíticas são as características patológicas da EM. Na origem da patologia supõe-se que estejam fatores multifatoriais complexos, nos quais características ambientais interajam com indivíduos geneticamente suscetíveis. Em Portugal estima-se que cerca de 5000 pessoas sejam afetadas pela EM. A noção de que a EM é principalmente uma doença mediada por linfócitos T CD4+ surge das semelhanças entre o modelo animal, encefalomielite autoimune experimental (EAE), e a EM, incluindo o facto de que o número de linfócitos T supera em muito os linfócitos B nas lesões da EM. O diagnóstico da EM baseia-se em exames clínicos e paraclínicos; não existe um único teste diagnóstico para identificar a doença. 85% dos doentes apresentam a forma de EM surto-remissão (SR), caracterizada por episódios discretos de disfunção neurológica (exacerbações ou surtos) separados por períodos clínicos estáveis com ausência de progressão da doença (remissões). O interferão (IFN)-β é o tratamento mais prescrito para a EM. O IFN-β é uma citocina pleiotrópica que antagoniza o meio pró-inflamatório ao aumentar a produção de citocinas anti-inflamatórios, regular a migração dos leucócitos e a expressão de moléculas de adesão. O mecanismo de ação do IFN-β é complexo e multifatorial, no entanto, em vários ensaios clínicos de classe I foi demonstrado que reduz a atividade biológica da EMSR. O SNC é de difícil acesso, assim como a avaliação das respostas imunes neste tecido. O sangue periférico parece refletir as alterações imunológicos que estão por trás da EM, tal como o padrão de migração entre a periferia e outros tecidos de acordo com a fase clínica da doença. Com base neste pressuposto, o objetivo principal desta tese foi caracterizar as células circulantes do sistema imunitário nas fases de remissão e surto de doentes com EMSR tratados com IFN-β, em comparação com indivíduos saudáveis. Vários estudos referem alterações significativas na homeostase de diferentes subpopulações de células T, como os linfócitos γδ ou subconjuntos funcionais T helper (Th)1, Th2 e Th17; de subpopulações de células B; e de células do sistema inato como monócitos e células dendríticas. Numa fase inicial foram selecionados os doentes com EMSR. Após assinatura do termo de consentimento livre na participação do trabalho foi colhido sangue periférico. Por citometria de fluxo, através de protocolos de marcação de membrana e intracitoplasmática foram identificadas e caracterizadas as subpopulações circulantes. Para avaliação funcional das células, após estimulação in vitro foram avaliadas as citocinas intracelulares produzidas. Com o intuito de avaliar a expressão gênica foi isolado RNA e realizada a reação em cadeia da polimerase-transcriptase reversa quantitativa em tempo real. Nos doentes com EMSR tratados com IFN-β observou-se uma diminuição das células dendríticas mieloides (mDCs) em remissão e um aumento na fase de surto, enquanto a frequência das células dendríticas plasmocitóides (pDCs) permaneceu inalterada. Consequentemente, a proporção mDCs/pDCs diminuiu na remissão e aumentou nos episódios de surto. As células dendríticas (DCs) aumentaram a sua capacidade de interagir com os linfócitos T, revelado pelo aumento da expressão do HLA-DR, em remissão e diminuição em surto. A razão mDCs/pDCs e a ativação das subpopulações de DCs podem constituir um bom biomarcador periférico entre as fases da EMSR. Os monócitos totais e a subpopulação de monócitos intermédios (iMo) aumentaram na circulação de doentes com EMSR em remissão, enquanto a subpopulação de monócitos não-clássicos (ncMo) diminuiu, mantendo-se diminuída em surto. As subpopulações de monócitos apresentam o mesmo padrão de expressão de HLA-DR que as DCs, aumentam em remissão e diminuem em surto. Os monócitos submetidos ao IFN-β promovem a produção de citocinas anti-inflamatórias por parte dos linfócitos T; isto é descrito como um efeito imunomodulador positivo da terapia. Em remissão, a subpopulação de B imaturas/transicionais aumenta. Dentro das células B de memória, a subpopulação de memória B CD27−aumentou, mais precisamente as células CD27−IgG+ e diminui a subpopulação memória B CD27−IgA+. Os doentes em surto apresentaram os linfócitos B totais diminuídos quando comparados com doentes em remissão, acompanhada por um aumento da subpopulação de células B de memória CD27-, conforme descrito para a fase de remissão. A principal diferença entre as fases de EMSR foi o aumento da subpopulação de plasmablasto. A proporção entre células B imaturas/transicionais e plasmablastos diminuiu no surto quando comparada com EMSR em remissão. Relativamente aos linfócitos T, estes promovem a polarização nas subpopulações Th2 e Tc2 com uma redução das subpopulações Th1 e Tc1, em episódios de remissão. Simultaneamente observou-se uma redução na produção de citocinas próinflamatórias, principalmente IFNγ. A frequência das subpopulações Th17, Tc17 e o nível sérico de IL17 aumentaram. Na fase de surto, a subpopulação Th17 diminui as citocinas produzidas, enquanto a Tc17 mantém elevados níveis de produção de TNF-α. As subpopulações Th(c)1 e Th(c)17 circulantes produziram citocinas diferentes. O presente estudo demonstra que o modo de ação do IFN-β nas células Th(c)1 e Th(c)17 promove resultados diferentes na circulação sistêmica de doentes com EMSR. O IFN-β diminui a produção de citocinas pró-inflamatórias produzidas pelas células Th(c)1 e aumenta a produção de citocinas pró-inflamatórias pelas Th(c)17. A subpopulação Th17 perpetua e promove a inflamação crônica na periferia em doentes em remissão, por meio da produção de IL-17 e de citocinas tipo Th1. Entre a frequência das subpopulações de linfócitos T reguladores e T helper foliculares não foram encontradas diferenças. No entanto, as células T CD4+CXCR5+ exibem uma maior atividade pró-inflamatória, apresentando frequências mais elevadas de TNF-α+ em ambas as fases da EMSR. As células T CD8+CXCR5+ exibiram uma capacidade aumentada de produzir IL-2 (assumindo um perfil Th1) na fase de remissão da doença, diminuindo em surto. A frequência das células T γδ foi a mesma entre indivíduos saudáveis e doentes com EMSR. No entanto, nos compartimentos imunológicos, a subpopulação Tγδ memória central (TCM) diminuiu e a naive aumentou, em fase de remissão. Em surto, a subpopulação Tγδ memória efetora terminalmente diferenciada (TEMRA) diminuiu quando comparada com doentes em remissão. As células CCR5+ Tγδ EMRA encontram-se significativamente diminuídas, saindo da circulação sistémica de forma a desempenhar funções efectoras. Esta subpopulação apresenta-se como um possível participante no processo de desmielinização e um bom biomarcador de sangue periférico entre as fases de EMSR. A identificação e caracterização das células imunitárias circulantes podem esclarecer a fisiopatologia da EM, sua progressão e a função de cada subpopulação neste processo. Algumas subpopulações podem ser consideradas potenciais biomarcadores periféricos entre doentes com EMSR em remissão e surto tratados com IFN-β: tais como a razão mDCs/pDCs, o perfil de ativação das DCs e dos monócitos, o comprometimento das células Th17 com uma assinatura Th1, a subpopulação CCR5+ Tγδ EMRA e a razão entre células B imaturas/transicionais e plasmablastos. Em ambas as fases da EMSR, a subpopulação ncMo diminui e as células B de memória CD27+IgM+e CD27- aumentaram em doentes com EMSR. A identificação de marcadores periféricos pode refletir o curso clínico da EM e a eficácia do tratamento. No futuro são necessários mais estudos, incluindo maiores números de doentes de forma a estabelecer a correlação entre as alterações observadas no sistema imune periférico e a resposta clínica

Mechanisms underlying the beneficial effects of physical exercise on multiple sclerosis: focus on immune cells

Multiple sclerosis (MS) is a prevalent neuroimmunological illness that leads to neurological disability in young adults. Although the etiology of MS is heterogeneous, it is well established that aberrant activity of adaptive and innate immune cells plays a crucial role in its pathogenesis. Several immune cell abnormalities have been described in MS and its animal models, including T lymphocytes, B lymphocytes, dendritic cells, neutrophils, microglia/macrophages, and astrocytes, among others. Physical exercise offers a valuable alternative or adjunctive disease-modifying therapy for MS. A growing body of evidence indicates that exercise may reduce the autoimmune responses triggered by immune cells in MS. This is partially accomplished by restricting the infiltration of peripheral immune cells into the central nervous system (CNS) parenchyma, curbing hyperactivation of immune cells, and facilitating a transition in the balance of immune cells from a pro-inflammatory to an anti-inflammatory state. This review provides a succinct overview of the correlation between physical exercise, immune cells, and MS pathology, and highlights the potential benefits of exercise as a strategy for the prevention and treatment of MS