Leonilda Maria Barbosa dos Santos

Chloroquine Treatment Enhances Regulatory T Cells and Reduces the Severity of Experimental Autoimmune Encephalomyelitis

Background The modulation of inflammatory processes is a necessary step, mostly orchestrated by regulatory T (Treg) cells and suppressive Dendritic Cells (DCs), to prevent the development of deleterious responses and autoimmune diseases. Therapies that focused on adoptive transfer of Treg cells or their expansion in vivo achieved great success in controlling inflammation in several experimental models. Chloroquine (CQ), an anti-malarial drug, was shown to reduce inflammation, although the mechanisms are still obscure. In this context, we aimed to access whether chloroquine treatment alters the frequency of Treg cells and DCs in normal mice. In addition, the effects of the prophylactic and therapeutic treatment with CQ on Experimental Autoimmune Encephalomyelitis (EAE), an experimental model for human Multiple Sclerosis, was investigated as well. Methodology/Principal Findings EAE was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide. C57BL/6 mice were intraperitoneally treated with chloroquine. Results show that the CQ treatment provoked an increase in Treg cells frequency as well as a decrease in DCs. We next evaluated whether prophylactic CQ administration is capable of reducing the clinical and histopathological signs of EAE. Our results demonstrated that CQ-treated mice developed mild EAE compared to controls that was associated with lower infiltration of inflammatory cells in the central nervous system CNS) and increased frequency of Treg cells. Also, proliferation of MOG35–55-reactive T cells was significantly inhibited by chloroquine treatment. Similar results were observed when chloroquine was administrated after disease onset. Conclusion We show for the first time that CQ treatment promotes the expansion of Treg cells, corroborating previous reports indicating that chloroquine has immunomodulatory properties. Our results also show that CQ treatment suppress the inflammation in the CNS of EAE-inflicted mice, both in prophylactic and therapeutic approaches. We hypothesized that the increased number of regulatory T cells induced by the CQ treatment is involved in the reduction of the clinical signs of EAE.

Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission

Cytokines and intrathecal IgG synthesis were determined in the cerebrospinal fluid (CSF) and sera to evaluate inflammatory activity in multiple sclerosis (MS) patients during clinical remission. Although the disease was stable, there had been a significant increase of proinflammatory cytokines such as TNFalpha and IFNgamma in the CSF and serum, with no significant changes of IL12 and IL10 production. The changes in the cytokine production patterns were associated with an increase of leukocytes in the CSF, as well as the presence of oligoclonal bands suggesting intrathecal IgG synthesis. These results suggest that even when the disease is clinically silent, one can observe inflammatory activity in these MS patients.

Disruption of melatonin circadian rhythm production is related to multiple sclerosis severity: A preliminary study.

Sunlight can influence the immune system independently of vitamin D, such as through melatonin production in the pineal gland. Inflammatory disorders can suppress nocturnal melatonin production, but only a few studies have investigated melatonin status in multiple sclerosis (MS). We aimed to study melatonin production in association with clinical and immunological data in MS patients. Eleven treated relapsing-remitting MS (RRMS) patients and eight controls underwent neurological examination and were assessed for fatigue severity and depressive symptoms. Inflammatory cytokines were analyzed in blood samples and concentration of 6-sulfatoxymelatonin (6-SMT) was determined in 24h urine. Patients with an abnormal proportion of overnight 6-SMT (n=8, 72.7%) had higher disability and fatigue severity (p<0.05). Overnight 6-SMT was inversely related with fatigue severity (p=0.016), number of relapses in the previous 12 months (p=0.010) and EDSS scores (p=0.049). In conclusion, disruption of melatonin circadian rhythm production is frequent among RRMS patients and seemingly related to higher disability and fatigue scores. Future studies with larger sample size are necessary to establish melatonin status as a biomarker of disease severity in MS.

A spring to summer shift of pro-inflammatory cytokine production in multiple sclerosis patients ☆

Higher MS relapse frequency is observed during warmer months in different regions, but evidence for an underlying immunological variation is lacking. Therefore, we investigated seasonal variations of cytokine production in relapsing-remitting MS patients. Twenty-one patients and eight controls had blood samples drawn in each season, evaluating for IL-10, IL-6, TNF-α and IFN-γ. The lowest levels of cytokine production were observed in spring samples, with a significant increase from spring to summer for most cytokines, and especially IFN-γ and TNF-α. This phenomenon may underlie the higher prevalence of clinical and subclinical MS activity observed in warmer months.

Serum BDNF levels are not reliable correlates of neurodegeneration in MS patients.

Current research in multiple sclerosis (MS) has focused on the development of new neuroprotective therapeutic strategies. In this scenario, it is fundamental to develop reliable biomarkers for neurodegeneration. Among these, brain-derived neurotrophic factor (BDNF) has recently received a lot of attention and has been shown to relate to neuronal survival and differentiation, playing a role in neuroprotection (Lühder et al., 2013). However, serum levels of BDNF have yielded conflicting results in MS studies (Lühder et al., 2013; Lalive et al., 2008; Comini-Frota et al., 2012; Yoshimura et al., 2010). Thus, we investigated associations among serum BDNF, clinical/cognitive data, and MRI neurodegenerative metrics in a sample of relapsing-remitting MS patients during remission phase. Twenty-one patients and nine ageand gendermatched controls underwent MRI scans (3T), including FLAIR, DIR and volumetric T1. Brain white-matter and cortical lesion volumes were quantified on FLAIR and DIR respectively, blinded to clinical data. Brain gray-matter (cortical and subcortical) and corpus callosum volume evaluations were performed on volumetric T1 using FreeSurfer v5.1 (http:// surfer.nmr.mgh.harvard.edu/). Serum BDNF concentration was determined using commercially available ELISA kits

Infecção e autoimunidade: antígenos derivados do M. tuberculosis na evolução da encefalomielite experimental autoimune

Resumo Este trabalho tem como objetivo estudar como a administração de antígenos derivados de Mycobacterium tuberculosis (Mt) atua na evolução da encefalomielite experimental autoimune (EAE). A EAE foi induzida em camundongos C57bl/6 de 6-8 semanas, fêmeas através da imunização com o peptídeo de Glicoproteina de mielina do oligodendrócitos MOG 35-55 e a inoculação de 200 ng/camundongo de toxina pertussis. Atribuiu-se scores para avaliação da doença.

Systemic inflammation is linked to default mode network functional connectivity in mild alzheimer's disease and mild cognitive impairment

The desriptive statistics, limitation, strenghts especially in primaty care units be discussed. Results: The database was initiated in May 2007 and covers almost all of Sweden. There were 50 000 patients registered during 2007– 2014. The role of primary care units increased in that time and helped for diagnosis of new cases. Conclusion: SveDem provides knowledge about current dementia care in Sweden and serves as a framework for ensuring the quality of diagnostics, treatment and care across the country. The special role of primary care in dementia work up is important.

Long-term retention of non-funcionalized carbon nanotubes in nod mice and its influence on the evolution of autoimmune diabetes

Results Histological data confirmed that the non-functionalized MWCTN had been absorbed and kept retained into the phagocytes of the peri-pancreatic lymph nodes, spleen and liver, causing a granulomatous inflammatory response. Even though no differences were found in the frequency of the development of clinical diabetes or in the morphological characteristics of the pancreatic insulitis, female NOD mice treated with MWCTN presented a significant higher fluctuation of the average glycaemia compared to the control group during the entire study (p<0.0001; Wilcoxon), with a tendency to an abbreviation of clinical diabetes onset. Analyses of the pro-inflammatory and the antiinflammatory responses in the peri-pancreatic lymph nodes revealed the induction of a Th1 response in the treated animals, between 8 and 14 after MWCTN exposition, with an increase of the expression of IFNg and a reduced expression of TGFb. This profile remained until the end of the study, 24 weeks after MWCTN injection.

Phenotype of regulatory T cells in human type 1 diabetes at diagnosis and partial remission phase

Background Human type 1A diabetes (T1AD) has a broad spectrum of clinical presentations, which may be associated with the severity of autoimmune response and consequently, different levels of pancreatic beta cells destruction. The T1AD presents a partial remission phase. The remission phase is classically a short period in childhood-onset diabetes, but longer periods may occur especially in young.