Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D.

The COVID-19 pandemic was triggered by the coronavirus SARS-CoV-2, whose peak occurred in the years 2020 and 2021. The main target of this virus is the lung, and the infection is associated with an accentuated inflammatory process involving mainly the innate arm of the immune system. Here, we described the induction of a pulmonary inflammatory process triggered by the intranasal (IN) instillation of UV-inactivated SARS-CoV-2 in C57BL/6 female mice, and then the evaluation of the ability of vitamin D (VitD) to control this process. The assays used to estimate the severity of lung involvement included the total and differential number of cells in the bronchoalveolar lavage fluid (BALF), histopathological analysis, quantification of T cell subsets, and inflammatory mediators by RT-PCR, cytokine quantification in lung homogenates, and flow cytometric analysis of cells recovered from lung parenchyma. The IN instillation of inactivated SARS-CoV-2 triggered a pulmonary inflammatory process, consisting of various cell types and mediators, resembling the typical inflammation found in transgenic mice infected with SARS-CoV-2. This inflammatory process was significantly decreased by the IN delivery of VitD, but not by its IP administration, suggesting that this hormone could have a therapeutic potential in COVID-19 if locally applied. To our knowledge, the local delivery of VitD to downmodulate lung inflammation in COVID-19 is an original proposition.

COVID-19 and Multiple Sclerosis: A Complex Relationship Possibly Aggravated by Low Vitamin D Levels.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an exceptionally transmissible and pathogenic coronavirus that appeared at the end of 2019 and triggered a pandemic of acute respiratory disease, known as coronavirus disease 2019 (COVID-19). COVID-19 can evolve into a severe disease associated with immediate and delayed sequelae in different organs, including the central nervous system (CNS). A topic that deserves attention in this context is the complex relationship between SARS-CoV-2 infection and multiple sclerosis (MS). Here, we initially described the clinical and immunopathogenic characteristics of these two illnesses, accentuating the fact that COVID-19 can, in defined patients, reach the CNS, the target tissue of the MS autoimmune process. The well-known contribution of viral agents such as the Epstein-Barr virus and the postulated participation of SARS-CoV-2 as a risk factor for the triggering or worsening of MS are then described. We emphasize the contribution of vitamin D in this scenario, considering its relevance in the susceptibility, severity and control of both pathologies. Finally, we discuss the experimental animal models that could be explored to better understand the complex interplay of these two diseases, including the possible use of vitamin D as an adjunct immunomodulator to treat them.

Systemic Infection by Non-albicans Candida Species Affects the Development of a Murine Model of Multiple Sclerosis.

Candidiasis may affect the central nervous system (CNS), and although Candida albicans is predominant, non-albicans Candida species can also be associated with CNS infections. Some studies have suggested that Candida infections could increase the odds of multiple sclerosis (MS) development. In this context, we investigated whether systemic infection by non-albicans Candida species would affect, clinically or immunologically, the severity of experimental autoimmune encephalomyelitis (EAE), which is an animal model used to study MS. For this, a strain of C. glabrata, C. krusei, and C. parapsilosis was selected and characterized using different in vitro and in vivo models. In these analysis, all the strains exhibited the ability to form biofilms, produce proteolytic enzymes, and cause systemic infections in Galleria mellonella, with C. glabrata being the most virulent species. Next, C57BL/6 mice were infected with strains of C. glabrata, C. krusei, or C. parapsilosis, and 3 days later were immunized with myelin oligodendrocyte glycoprotein to develop EAE. Mice from EAE groups previously infected with C. glabrata and C. krusei developed more severe and more prevalent paralysis, while mice from the EAE group infected with C. parapsilosis developed a disease comparable to non-infected EAE mice. Disease aggravation by C. glabrata and C. krusei strains was concomitant to increased IL-17 and IFN-γ production by splenic cells stimulated with fungi-derived antigens and with increased percentage of T lymphocytes and myeloid cells in the CNS. Analysis of interaction with BV-2 microglial cell line also revealed differences among these strains, in which C. krusei was the strongest activator of microglia concerning the expression of MHC II and CD40 and pro-inflammatory cytokine production. Altogether, these results indicated that the three non-albicans Candida strains were similarly able to reach the CNS but distinct in terms of their effect over EAE development. Whereas C. glabrata and C. Krusei aggravated the development of EAE, C. parapsilosis did not affect its severity. Disease worsening was partially associated to virulence factors in C. glabrata and to a strong activation of microglia in C. krusei infection. In conclusion, systemic infections by non-albicans Candida strains exerted influence on the experimental autoimmune encephalomyelitis in both immunological and clinical aspects, emphasizing their possible relevance in MS development.

Effect of Rapamycin on MOG-Reactive Immune Cells and Lipopolysaccharide-Activated Microglia: An In Vitro Approach for Screening New Therapies for Multiple Sclerosis.

Rapamycin is an immunomodulatory drug that has been evaluated in preclinical and clinical trials as a disease-modifying therapy for multiple sclerosis (MS). In this study, we evaluated the in vitro effect of rapamycin on immune cells pivotally involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), which is an animal model to study MS. Splenocytes and central nervous system (CNS)-mononuclear cells obtained from EAE mice were stimulated with a myelin oligodendrocyte glycoprotein peptide, whereas the microglial BV-2 cell line was activated with LPS. The 3 immune cell types were simultaneously treated with rapamycin, incubated, and then used to analyze cytokines, transcription factors, and activation markers. Rapamycin reduced IL-17 production, TBX21, and RORc expression by splenic and CNS cell cultures. IFN-γ and TNF-α production were also decreased in CNS cultures. This treatment also decreased TNF-α, IL-6, MHC II, CD40, and CD86 expression by BV-2 cells. These results indicated that in vivo immunomodulatory activity of rapamycin in MS and EAE was, in many aspects, reproduced by in vitro assays done with cells derived from the spleen and the CNS of EAE mice. This procedure could constitute a screening strategy for choosing drugs with therapeutic potential for MS.

Is there a window of opportunity for the therapeutic use of vitamin D in multiple sclerosis?

Multiple sclerosis is an autoimmune treatable but not curable disease. There are a multiplicity of medications for multiple sclerosis therapy, including a class entitled disease-modifying drugs that are mainly indicated to reduce the number and severity of disease relapses. Not all patients respond well to these therapies, and minor to severe adverse effects have been reported. Vitamin D, called sunshine vitamin, is being studied as a possible light at the end of the tunnel. In this review, we recapitulated the similar immunopathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis, the immunomodulatory and neuroprotective potential of vitamin D and the state-of-art concerning its supplementation to multiple sclerosis patients. Finally, based on our and other groups' experimental findings, we analyzed the need to consider the relevance of the route and the different time-point administration aspects for a more rational indication of this vitamin to multiple sclerosis patients.

Candida tropicalis Systemic Infection Redirects Leukocyte Infiltration to the Kidneys Attenuating Encephalomyelitis.

Environmental factors, including infections, are strongly associated with the pathogenesis of multiple sclerosis (MS), which is an autoimmune and demyelinating disease of the central nervous system (CNS). Although classically associated with bacterial and viral agents, fungal species have also been suspected to affect the course of the disease. Candida tropicalis is an opportunistic fungus that affects immunocompromised individuals and is also able to spread to vital organs. As C. tropicalis has been increasingly isolated from systemic infections, we aimed to evaluate the effect of this fungus on experimental autoimmune encephalomyelitis (EAE), a murine model to study MS. For this, EAE was induced in female C57BL/6 mice 3 days after infection with 106 viable C. tropicalis yeasts. The infection decreased EAE prevalence and severity, confirmed by the less inflammatory infiltrate and less demyelization in the lumbar spinal cord. Despite this, C. tropicalis infection associated with EAE results in the death of some animals and increased urea and creatinine serum levels. The kidneys of EAE-infected mice showed higher fungal load associated with increased leukocyte infiltration (CD45+ cells) and higher expression of T-box transcription factor (Tbx21) and forkhead box P3 (Foxp3). Altogether, our results demonstrate that although C. tropicalis infection reduces the prevalence and severity of EAE, partially due to the sequestration of leukocytes by the inflamed renal tissue, this effect is associated with a poor disease outcome.

Preclinical Therapy with Vitamin D3 in Experimental Encephalomyelitis: Efficacy and Comparison with Paricalcitol.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). MS and its animal model called experimental autoimmune encephalomyelitis (EAE) immunopathogenesis involve a plethora of immune cells whose activation releases a variety of proinflammatory mediators and free radicals. Vitamin D3 (VitD) is endowed with immunomodulatory and antioxidant properties that we demonstrated to control EAE development. However, this protective effect triggered hypercalcemia. As such, we compared the therapeutic potential of VitD and paricalcitol (Pari), which is a non-hypercalcemic vitamin D analog, to control EAE. From the seventh day on after EAE induction, mice were injected with VitD or Pari every other day. VitD, but not Pari, displayed downmodulatory ability being able to reduce the recruitment of inflammatory cells, the mRNA expression of inflammatory parameters, and demyelination at the CNS. Lower production of proinflammatory cytokines by lymph node-derived cells and IL-17 by gut explants, and reduced intestinal inflammation were detected in the EAE/VitD group compared to the EAE untreated or Pari groups. Dendritic cells (DCs) differentiated in the presence of VitD developed a more tolerogenic phenotype than in the presence of Pari. These findings suggest that VitD, but not Pari, has the potential to be used as a preventive therapy to control MS severity.

Beneficial effects of anthocyanin-rich peels of Myrtaceae fruits on chemically-induced liver fibrosis and carcinogenesis in mice.

Hepatocellular carcinoma (HCC) arising from fibrosis/cirrhosis is the most common type of primary liver cancer. Conversely, a higher intake of fruits and vegetables might play a protective role in HCC risk. Recently, Myrtaceae family tropical fruits have raised great interest due to the high levels of anthocyanins especially in their peels, which are usually discarded upon consumption. Anthocyanins are antioxidant pigments known to have beneficial effects in vivo/in vitro cancer bioassays. Thus, we evaluated whether dietary Myrciaria jaboticaba, Syzygium cumini, and Syzygium malaccense fruit peel powders reduce fibrosis and hepatocarcinogenesis in mice. Female C3H/HeJ mice were submitted to the model of diethylnitrosamine/carbon tetrachloride-induced liver fibrosis and carcinogenesis. Concomitantly, mice received a basal diet containing 2% of M. jaboticaba, S. cumini, or S. malaccense fruit peel powders, obtained by convective drying, for 10 weeks. M. jaboticaba peel powder showed the highest levels of total anthocyanins, while S. cumini peel powder displayed the greatest diversity of these pigments. All Myrtaceae family peel powders reduced the serum levels of the liver injury marker alanine aminotransferase. M. jaboticaba peel feeding reduced the incidence of liver preneoplastic foci, hepatocyte proliferation (Ki-67), and the protein levels of hepato-mitogen tumor necrosis factor-alpha (TNF-α). M. jaboticaba peel feeding also diminished liver lipid peroxidation and increased total glutathione levels. S. cumini peel feeding reduced hepatic collagen, lipid peroxidation, and TNF-α levels while increased catalase activity. Although S. malaccense peel powder, which displayed the lowest anthocyanin levels, decreased oxidative stress, and cytokine levels, no effects were observed on liver fibrosis or preneoplastic lesion outcomes. Findings indicate a protective effect of anthocyanin-rich M. jaboticaba and S. cumini peel powder feeding on preneoplastic lesion development and fibrosis, respectively. Results indicate that differential biological responses may be attributed to distinct anthocyanin profiles and levels, assigning a functional/market value to the underutilized peel fraction.

Selenization of S. cerevisiae increases its protective potential in experimental autoimmune encephalomyelitis by triggering an intestinal immunomodulatory loop.

Multiple sclerosis is an autoimmune disease that affects the myelinated central nervous system (CNS) neurons and triggers physical and cognitive disabilities. Conventional therapy is based on disease-modifying drugs that control disease severity but can also be deleterious. Complementary medicines have been adopted and evidence indicates that yeast supplements can improve symptoms mainly by modulating the immune response. In this investigation, we evaluated the therapeutic potential of Saccharomyces cerevisiae and its selenized derivative (Selemax) in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice submitted to EAE induction were orally supplemented with these yeasts by gavage from day 0 to day 14 after EAE induction. Both supplements determined significant reduction in clinical signs concomitantly with diminished Th1 immune response in CNS, increased proportion of Foxp3+ lymphocytes in inguinal and mesenteric lymph nodes and increased microbiota diversity. However, Selemax was more effective clinically and immunologically; it reduced disease prevalence more sharply, increased the proportion of CD103+ dendritic cells expressing high levels of PD-L1 in mesenteric lymph nodes and reduced the intestinal inflammatory process more strongly than S. cerevisiae. These results suggest a clear gut-brain axis modulation by selenized S. cerevisiae and suggest their inclusion in clinical trials.

Organic Selenium Reaches the Central Nervous System and Downmodulates Local Inflammation: A Complementary Therapy for Multiple Sclerosis?

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). The persistent inflammation is being mainly attributed to local oxidative stress and inflammasome activation implicated in the ensuing demyelination and axonal damage. Since new control measures remain necessary, we evaluated the preventive and therapeutic potential of a beta-selenium-lactic acid derivative (LAD-ßSe), which is a source of organic selenium under development, to control experimental autoimmune encephalomyelitis (EAE) that is an animal model for MS. Two EAE murine models: C57BL/6 and SJL/J immunized with myelin oligodendrocyte glycoprotein and proteolipid protein, respectively, and a model of neurodegeneration induced by LPS in male C57BL/6 mice were used. The preventive potential of LAD-ßSe was initially tested in C57BL/6 mice, the chronic MS model, by three different protocols that were started 14 days before or 1 or 7 days after EAE induction and were extended until the acute disease phase. These three procedures were denominated preventive therapy -14 days, 1 day, and 7 days, respectively. LAD-ßSe administration significantly controlled clinical EAE development without triggering overt hepatic and renal dysfunction. In addition of a tolerogenic profile in dendritic cells from the mesenteric lymph nodes, LAD-ßSe also downregulated cell amount, activation status of macrophages and microglia, NLRP3 (NOD-like receptors) inflammasome activation and other pro-inflammatory parameters in the CNS. The high Se levels found in the CNS suggested that the product crossed the blood-brain barrier having a possible local effect. The hypothesis that LAD-ßSe was acting locally was then confirmed by using the LPS-induced neurodegeneration model that also displayed Se accumulation and downmodulation of pro-inflammatory parameters in the CNS. Remarkably, therapy with LAD-ßSe soon after the first remitting episode in SJL/J mice, also significantly downmodulated local inflammation and clinical disease severity. This study indicates that LAD-ßSe, and possibly other derivatives containing Se, are able to reach the CNS and have the potential to be used as preventive and therapeutic measures in distinct clinical forms of MS.

Should mast cells be considered therapeutic targets in multiple sclerosis?

Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

Calcitriol Prevents Neuroinflammation and Reduces Blood-Brain Barrier Disruption and Local Macrophage/Microglia Activation.

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that involves damage to the myelin sheath surrounding axons. MS therapy is based on immunomodulatory drugs that reduce disease recurrence and severity. Vitamin D is a hormone whose immunomodulatory ability has been widely demonstrated, including in experimental autoimmune encephalomyelitis (EAE), which is an animal model of CNS inflammation. In this study, we evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development. EAE was induced in C57BL/6J mice and 1,25-dihydroxyvitamin D3 administration began 1 day after disease induction. This procedure decreased prevalence, clinical score, inflammation, and demyelination. It also reduced MHCII expression in macrophages and microglia as well as the level of oxidative stress and messenger RNA (mRNA) expression for NLRP3, caspase-1, interleukin (IL)-1ß, CX3CR1, CCL17, RORc and Tbx21 at the CNS. Otherwise, mRNA expression for ZO-1 increased at the lumbar spinal cord. These effects were accompanied by the stabilization of blood-spinal cord barrier permeability. The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should thus be explored as an adjunct therapy for MS patients.

Transcriptional analysis of THP-1 cells infected with Leishmania infantum indicates no activation of the inflammasome platform.

Leishmaniasis is caused by intracellular parasites transmitted to vertebrates by sandfly bites. Clinical manifestations include cutaneous, mucosal or visceral involvement depending upon the host immune response and the parasite species. To assure their survival inside macrophages, these parasites developed a plethora of highly successful strategies to manipulate various immune system pathways. Considering that inflammasome activation is critical for the establishment of a protective immune response in many parasite infections, in this study we determined the transcriptome of THP-1 cells after infection with L. infantum, with a particular focus on the inflammasome components. To this end, the human cell line THP-1, previously differentiated into macrophages by PMA treatment, was infected with L. infantum promastigotes. Differentiated THP-1 cells were also stimulated with LPS to be used as a comparative parameter. The gene expression signature was determined 8 hours after by RNA-seq technique. Infected or uninfected THP-1 cells were stimulated with nigericin (NIG) to measure active caspase-1 and TNF-α, IL-6 and IL-1ß levels in culture supernatants after 8, 24 and 48 hours. L. infantum triggered a gene expression pattern more similar to non-infected THP-1 cells and very distinct from LPS-stimulated cells. Some of the most up-regulated genes in L. infantum-infected cells were CDC20, CSF1, RPS6KA1, CD36, DUSP2, DUSP5, DUSP7 and TNFAIP3. Some up-regulated GO terms in infected cells included cell coagulation, regulation of MAPK cascade, response to peptide hormone stimulus, negative regulation of transcription from RNA polymerase II promoter and nerve growth factor receptor signaling pathway. Infection was not able to induce the expression of genes associated with the inflammasome signaling pathway. This finding was confirmed by the absence of caspase-1 activation and IL-1ß production after 8, 24 and 48 hours of infection. Our results indicate that L. infantum was unable to activate the inflammasomes during the initial interaction with THP-1 cells.

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG35-55 and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control.

Gliotoxin Aggravates Experimental Autoimmune Encephalomyelitis by Triggering Neuroinflammation.

Gliotoxin (GTX) is the major and the most potent mycotoxin that is secreted by Aspergillus fumigatus, which is capable of injuring and killing microglial cells, astrocytes, and oligodendrocytes. During the last years, studies with patients and experimental models of multiple sclerosis (MS), which is an autoimmune disease of the central nervous system (CNS), suggested that fungal infections are among the possible initiators or aggravators of this pathology. The deleterious effect can occur through a direct interaction of the fungus with the CNS or by the toxin release from a non-neurological site. In the present work, we investigated the effect of GTX on experimental autoimmune encephalomyelitis (EAE) development. Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein and then intraperitoneally injected with three doses of GTX (1 mg/kg b.w., each) on days 4, 7, and 10. GTX aggravated clinical symptoms of the disease in a dose-dependent way and this outcome was concomitant with an increased neuroinflammation. CNS analyses revealed that GTX locally increased the relative expression of inflammatory genes and the cytokine production. Our results indicate that GTX administered in a non-neuronal site was able to increase neuroinflammation in EAE. Other mycotoxins could also be deleterious to many neurological diseases by similar mechanisms.

4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation.

4-methylesculetin is one of the coumarin derivatives with great anti-oxidant and anti-inflammatory activities. Recent studies have shown that 4-methylesculetin has a promising potentiality to treat inflammatory diseases, especially those related to reactive oxygen species, as inflammatory bowel disease. Based on this, the present study aims to investigate the intestinal anti-inflammatory activity of 4-methylesculetin in dextran sulfate sodium (DSS) model. For this purpose, mice received DSS 5% for 5 days followed by 2 days of filtered tap water. Treated groups received orally 5 or 25 mg/kg of 4-methylesculetin daily since the first day. Macroscopic, microscopic and biochemical parameters were evaluated. 4-methylesculetin (25 mg/kg) improved microscopic parameters, decreased MPO activity, reduced the colonic levels of IL-6 and counteracted GSH depletion when compared with DSS-control group. Our results show the intestinal anti-inflammatory activity of 4-methylesculetin in DSS model, which is related to its antioxidant and anti-inflammatory properties. This way, 4-methylesculetin, is a new potential compound for treatment of both types of IBD.

Differential Behavior of Non-albicans Candida Species in the Central Nervous System of Immunocompetent and Immunosuppressed Mice.

The genus Candida includes commensal fungi that can cause local and systemic infections, frequently involving vital organs as the central nervous system (CNS). Candida spp. occupy the fourth place among infections that affect the CNS. Although the incidence of Candida albicans is decreasing among patients under immunosuppressive therapies, the incidence of non-albicans Candida is increasing. In this context, the objective of this work was to evaluate the ability of non-albicans Candida species to spread to the CNS of immunocompetent and immunosuppressed mice. Adult female C57BL/6 mice were treated with prednisolone, intravenously infected with Candida glabrata, Candida krusei and Candida parapsilosis yeasts and then evaluated at the 3rd and 14th days after infection. All Candida species disseminated to the brain from immunocompetent animals and induced local inflammation at the third day post-infection. The immunosuppression resulted in body weight loss, leukopenia and reduced IL-2 production by spleen cell cultures. Higher fungal loads were recovered from the CNS of immunosuppressed mice. Inflammatory infiltration associated to a Th1 subset profile was higher in brain samples from C. krusei immunosuppressed mice compared with immunocompetent ones. Additionally, C. krusei was able to transform into pseudohypha inside microglia in vitro infected cells and also to induce elevated nitric oxide production. Altogether, these results indicate that C. glabrata, C. krusei and C. parapsilosis are able to disseminate to the CNS and promote local inflammation in both immunocompetent and immunosuppressed mice. C. krusei displayed a distinct behavior at the CNS triggering a local Th1 profile. The possible contribution of these non-albicans Candida species to other CNS pathologies as multiple sclerosis, Parkinson's and Alzheimer's diseases deserves further attention.

Experimental Autoimmune Encephalomyelitis Is Successfully Controlled by Epicutaneous Administration of MOG Plus Vitamin D Analog.

Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) has been widely employed to evaluate new strategies to control MS, including procedures to induce immunological tolerance. Considering that skin exposure to protein antigens can induce tolerance and that vitamin D analogs conserve immunomodulatory potential and are less toxic, we investigated the efficacy of epicutaneous application of a myelin oligodendrocyte glycoprotein peptide (MOG35-55) associated with paricalcitol (PARI) on EAE development. Three and 11 days after EAE induction, C57BL/6 mice were treated with an occlusive patch containing MOG plus PARI. Clinical parameters were daily assessed, whereas immunological and histological evaluations were performed during the acute EAE phase. MOG and MOG + PARI significantly controlled disease development reducing weight loss and clinical score. Moreover, MOG and MOG + PARI reduced the inflammatory process and preserved the myelin sheath in the CNS. High percentages of Foxp3+ regulatory T cells (Tregs) and lower MHCII fluorescence intensity in dendritic cells in draining lymph nodes were concomitantly observed. MOG + PARI association was, however, more efficient being able to reduce disease incidence and clinical scores more significantly than MOG or PARI alone. This experimental group also displayed a higher ratio between mRNA expression for Foxp3 and RORc and a higher percentage of Foxp3+ cells in the CNS. Modulation of activation markers observed in microglial cells eluted from EAE treated mice were confirmed by in vitro studies with the BV-2 microglial cell line. The results show that MOG + PARI association applied by an epicutaneous route controlled EAE development. Protective involved mechanisms include mainly a higher proportion of Tregs and also a direct immunomodulatory effect of PARI on microglial cells.

Antiretroviral Therapy Initiation Alters the Redox System of Asymptomatic HIV-Infected Individuals: A Longitudinal Study.

Background. The combination antiretroviral therapy (cART) increases the oxidative stress in HIV-infected people, which in turn favors the onset and aggravation of non-AIDS comorbidities, a common situation affecting these individuals. We aimed to evaluate the influence of cART initiation on oxidative stress parameters. This is a longitudinal study including 30 asymptomatic patients divided according to their CD4+ T cell count (G1: <500 cell/mL; G2: >500 cell/mL) before (M0) and after (M1) cART initiation. We analyzed total antioxidant capacity (TAC), fat-soluble vitamins, malondialdehyde, 8-isoprostane, and DNA damage. Results. Results showed a decrease in TAC, retinol, α-tocopherol, and some carotenoids, in addition to a significant increase in DNA damage at M1. These changes were more evident in G2 subjects. Moreover, there was a significant 8-isoprostane increase at M1 in individuals belonging to G1. Conclusion. The results indicate that cART interfered in the redox system, mainly by reducing the antioxidant defenses. In addition, patients who had CD4+ T counts higher than 500 cells/mm3 showed more susceptibility to genotoxicity, while patients with less CD4+ T counts displayed more damage triggered by lipoperoxidation. Considering the early beginning of cART, its chronic use, and its capacity to alter the redox status, further long-term studies on larger cohorts are needed to define the best time to initiate therapy and to investigate new strategies to delay the development of non-AIDS diseases.