Relevance of CD40/CD40L downstream pathways to Alzheimer's disease

The amyloid cascade hypothesis places amyloid-β at the origin of Alzheimer's disease (AD). Amyloid-β (Aβ) is the product of the sequential cleavage of the amyloid precursor protein (APP) by the enzymes β- and γ-secretases. An inflammatory component to AD has been suggested in association with CD40 (a member of the tumor necrosis factor receptor superfamily (TNFRS) and its cognate ligand CD40L. In this study, I hypothesized that the neutralization of pro-inflammatory cytokines produced downstream of CD40/CD40L interaction would reduce APP processing. I also hypothesized that blocking the binding of different adaptor proteins to CD40 by mutating its cytoplasmic tail would result in significant reduction of the APP metabolites: Aβ, sAPPβ, sAPPα, CTFβ and CTFα. ^ Treatment with CD40L of human embryonic kidney cells over-expressing both APP and CD40 (HEK/APPsw/CD40) significantly increased levels of the cytokine granulocyte macrophage colony stimulating factor (GM-CSF). Neutralizing antibodies against GM-CSF mitigated the CD40L-induced production of Aβ in these cells. Treatment of the HEK/APPsw/CD40 cells with recombinant GM-CSF significantly increased Aβ levels. GM-CSF receptor gene silencing with shRNA significantly reduced Aβ levels to below base line in non-stimulated HEK/APPsw/CD40 cells. Silencing of the GM-CSF receptor also decreased APP endocytosis (therefore reducing the availability of APP to be cleaved in the endosomes). ^ Using CD40 mutants, I show that CD40L can increase levels of Aβ(1-40), Aβ(1-42), sAPPβ, sAPPα and CTFβ independently of TRAF signaling. TRAFs had been shown to be necessary for most CD40/CD40L-dependent signaling. An increase in mature/immature APP ratio after CD40L treatment of CD40wt and CD40-mutant cells was observed, reflecting alterations in APP trafficking. CD4OL treatment of a neuroblastoma cell line over-expressing CTFβ suggested that CD40L affected γ-secretase activity. Inhibition of γ-secretase activity significantly reduced sAPPβ levels in the CD40L treated HEK/APPsw CD40wt and the CD40-mutant cells. The latter suggests CD40/CD40L interaction primarily acts on γ-secretase and affects β-secretase via a positive feedback mechanism. ^ Taken together, the results of this dissertation suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Aβ production by influencing APP trafficking. Moreover, the data presented suggest that CD40/CD40L interaction can modulate APP processing via a mechanism independent of TRAF signaling. ^

The Immunomodulatory Role of Alcohol on HIV-Infected Monocyte-Derived Dendritic Cells

Alcohol is known to induce inflammation in the presence of the human immunodeficiency virus (HIV). In our previous studies, we revealed that alcohol induces cannabinoid receptors which play a role in the regulation of inflammatory cytokine production in monocyte-derived dendritic cells (MDDC). However, the ability of alcohol to alter MDDC function during HIV infection has not been clearly elucidated yet. To study the potential impact of alcohol on HIV-infected MDDC (confirmed by p24 ELISA), monocytes were isolated from commercially available buffy coats and cultured for 7 days with GM-CSF and IL-4. MDDC were infected with HIV- 1Ba-L and treated with different concentrations of alcohol (0.1% band 0.2%) for 4-7 days. MDDC phenotype, endocytosis, cytokine production, and ability to transmit HIV to T cells were analyzed. Uninfected CD4+ T cells were co-cultured for 7 days with either infected/treated MDDC or the supernatants from infected/treated MDDC. Inflammatory cytokine arrays were performed using supernatants from HIV-infected MDDC treated with alcohol. Results showed that HIV positive MDDC treated with alcohol had higher levels of infection compared to untreated HIV positive controls. CD4+ T cells exposed to HIV-infected MDDC acquired 100-fold higher levels of p24 compared to CD4+ T cells exposed to only supernatants. CD4+ T cells exposed to HIV-infected and alcohol-treated MDDC had higher levels of infection compared to controls. Cytokine array data show dysregulation of cytokine production by alcohol. In addition, MDDC phenotype and endocytic capacity were altered in the alcohol treated MDDC. Our results indicate a crucial role of MDDC in HIV transmission to T cells and provide insights into the inflammatory role alcohol exerts on dendritic cell function in the context of HIV infection. Supported by the National Institute on Alcohol Abuse and Alcoholism award R00AA021264, the National Institute on Drug Abuse award R01DA034547, and the Institute on NeuroImmune Pharmacology at FIU.

The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial.

BACKGROUND: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). OBJECTIVE: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. METHODS: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n = 21) or propofol (n = 18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. RESULTS: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p = 1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24 h after drain placement (p = 2.002×10-6 and p = 1.985×10-6, respectively), mean CSF p-tau levels decreased (p = 0.005), and Aβ levels did not change (p = 0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n = 9 polymorphisms, p > 0.05 for all associations). CONCLUSION: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.

Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery.

BACKGROUND: Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery. METHODS: After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test). RESULTS: Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-γ, IL-6, IL-8, IL-10, MCP-1, MIP-1α, MIP-1β, IL-8/IL-10, and TNF-α in CSF. CONCLUSIONS: Substantial pro- and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials.

Middle Eocene Fe and Ca counts, Ca/Fe ratios, revised splices and astronomical age models form different Sites of IODP Exp342

Accurate age models are a tool of utmost important in paleoclimatology. Constraining the rate and pace of past climate change are at the core of paleoclimate research, as such knowledge is crucial to our understanding of the climate system. Indeed, it allows for the disentanglement of the various drivers of climate change. The scarcity of highly resolved sedimentary records from the middle Eocene (Bartonian - Lutetian Stages; 47.8 - 37.8 Ma) has led to the existence of the "Eocene astronomical time scale gap" and hindered the establishment of a comprehensive astronomical time scale (ATS) for the entire Cenozoic. Sediments from the Newfoundland Ridge drilled during Integrated Ocean Drilling Program (IODP) Expedition 342 span the Eocene gap at an unprecedented stratigraphic resolution with carbonate bearing sediments. Moreover, these sediments exhibit cyclic lithological changes that allow for an astronomical calibration of geologic time. In this study, we use the dominant obliquity imprint in XRF-derived calcium-iron ratio series (Ca/Fe) from three sites drilled during IODP Expedition 342 (U1408, U1409, U1410) to construct a floating astrochronology. We then anchor this chronology to numerical geological time by tuning 173-kyr cycles in the amplitude modulation pattern of obliquity to an astronomical solution. This study is one of the first to use the 173-kyr obliquity amplitude cycle for astrochronologic purposes, as previous studies primarily use the 405-kyr long eccentricity cycle as a tuning target to calibrate the Paleogene geologic time scale. We demonstrate that the 173-kyr cycles in obliquity's amplitude are stable between 40 and 50 Ma, which means that one can use the 173-kyr cycle for astrochronologic calibration in the Eocene. Our tuning provides new age estimates for magnetochron reversals C18n.1n - C21r and a stratigraphic framework for key sites from Expedition 342 for the Eocene. Some disagreements emerge when we compare our tuning for the interval between C19r and C20r with previous tuning attempts from the South Atlantic. We therefore present a revision of the original astronomical interpretations for the latter records, so that the various astrochronologic age models for the middle Eocene in the North- and South-Atlantic are consistent.

Studies of the role of nf-κb in controlling osteoclast differentiation and bone loss

Increased osteoclast (OC) bone resorption and/or decreased osteoblast (OB) bone formation contribute to bone loss in osteoporosis and rheumatoid arthritis (RA). Findings of the basic and translational research presented in this thesis demonstrate a number of mechanisms by which cytokine-induced NF-κB activation controls bone resorption and formation: 1) Tumour necrosis factor-α (TNF) expands pool of OC precursors (OCPs) by promoting their proliferation through stimulation of the expression of macrophage colony stimulating factor (M-CSF) receptor, c-Fms, and switching M-CSF-induced resident (M2) to inflammatory (M1) macrophages with enhanced OC forming potential and increased production of inflammatory factors through induction of NF-κB RelB; 2) Similar to RANKL, TNF sequentially activates transcriptional factors NF-κB p50 and p52 followed by c-Fos and then NFATc1 to induce OC differentiation. However, TNF alone induces very limited OC differentiation. In contrast, it pre-activates OCPs to express cFos which cooperates with interleukin-1 (IL-1) produced by these OCPs in an autocrine mechanism by interacting with bone matrix to mediate the OC terminal differentiation and bone resorption from these pre-activated OCPs. 3) TNF-induced OC formation is independent of RANKL but it also induces NF-κB2 p100 to limit OC formation and bone resorption, and thus p100 deletion accelerates joint destruction and systemic bone loss in TNF-induced RA; 4) TNF receptor associated factor-3 (TRAF3) limits OC differentiation by negatively regulating non-canonical NF-κB activation and RANKL induces TRAF3 ubiquitination and lysosomal degradation to promote OC differentiation. Importantly, a lysosomal inhibitor that inhibits TRAF3 degradation prevents ovariectomy-induced bone loss; 5) RelB and Notch NICD bind RUNX2 to inhibit OB differentiation and RelB:p52 dimer association with NICD inhibit OB differentiation by enhancing the binding of RBPjκ to Hes1. These findings suggest that non-canonical NF- κB signaling could be targets to develop new therapies for RA or osteoporosis. For example 1) Agents that degrade TNF-induced RelB could block M1 macrophage differentiation to inhibit inflammation and joint destruction for the therapy of RA; 2)Agents that prevent p100 processing or TRAF3 degradation could inhibit bone resorption and also stimulate bone formation simultaneously for the therapy of osteoporosis.

O Serviço Social numa Comissão Social de Freguesia: uma abordagem preliminar deste novo espaço sócio ocupacional

Aprofundar o conhecimento do Serviço Social no âmbito das Comissões Sociais de Freguesia, refletindo sobre a prática do Serviço Social, nomeadamente na Comissão Social de Freguesia da Guia, é o objetivo deste relatório. O processo de criação e implementação do Programa Rede Social, como política social baseada nos fundamentos da descentralização de poderes e responsabilidades do Estado e a sua intensificação em parcerias entre o setor público e o setor privado, assentam numa lógica de desenho de políticas sociais neoliberais. O Serviço Social revela ser um importante recurso profissional para as autarquias, nomeadamente para as freguesias, desempenhando um trabalho de proximidade com as populações, facilitando-lhes o acesso a alguns direitos sociais e executando os seus deveres cívicos. No entanto, esta atuação de natureza assistencialista, pretende a resolução emergencial da situação de pobreza e das desigualdades sociais da população de determinada freguesia. Ora, estes fenómenos não estão circunscritos a uma pequena área territorial, são problemas estruturais e universais, como tal não podem ser tratados apenas como locais. Tendo como ponto de partida, a experiência vivenciada pela assistente social que fez parte da organização da Comissão Social de Freguesia da Guia e que desenhou o seu modelo de intervenção social, é feita uma análise a este novo espaço. Conclui-se, atestando que para a efetivação como espaço sócio profissional e que legitime a profissão, a política social que define as CSF terá que sofrer algumas alterações e melhorias, partindo ao encontro do projeto profissional do Serviço Social, ao mesmo tempo que potencia o enfrentamento à pobreza e desigualdades sociais ao nível local.

Analisi del Cammino in Pazienti Affetti da Idrocefalo Normoteso Attraverso IMU Indossabili

L’idrocefalo normoteso idiopatico (iNPH) è una patologia che si sviluppa in età senile ed è caratterizzata da un insieme di sintomi generici tra cui disturbi della marcia che rendono difficoltosa la diagnosi. La presente attività di tesi mira ad identificare parametri motori specificamente alterati in pazienti affetti da iNPH rispetto a pazienti con sintomatologie simili, che siano quindi un possibile ausilio alla diagnosi differenziale oltre ad essere sensibili all’intervento terapeutico. Trenta pazienti hanno preso parte allo studio (15 idrocefali, 9 misti e 6 con altre patologie) e sono stati valutati pre, post 24h e post 72h rispetto ad un intervento di drenaggio di liquor cefalorachidiano (CSF tapping). Ciascun paziente, ad ogni valutazione ha eseguito due task motori standardizzati: l’instrumented 18m walk (i18W) e l’instrumented Timed Up and Go (iTUG). Il metodo proposto è stato in grado di estrapolare i parametri prefissati da tali prove e quindi fornire un report dettagliato del singolo paziente. Successivamente, l’analisi statistica eseguita tra pazienti appartenenti allo stesso gruppo (intra gruppo) e quella tra pazienti di gruppi diversi (inter gruppo) ha mostrato un complessivo trend di miglioramento delle performance per i soli soggetti con diagnosi di idrocefalo o con alcuni segni clinici caratteristici di idrocefalo. I pazienti affetti da altre patologie, come si era ipotizzato, non subiscono sostanziali cambiamenti a seguito dell’intervento.

Étude du profil des populations cellulaires du sang en vue d’une application au diagnostic du lupus érythémateux disséminé

Le lupus érythémateux disséminé (LED) est une maladie auto-immune systémique dont le diagnostic est très complexe. Le clinicien doit baser son diagnostic sur une liste de 11 critères reliés à des observations cliniques et à des mesures sérologiques. Afin de faciliter ce diagnostic, plusieurs groupes recherchent de nouveaux marqueurs biologiques quantifiables. C’est dans ce but que la cytométrie en flux a été utilisée afin de comparer les cellules du sang des patients et celles de sujets sains. La caractérisation exhaustive des sous-populations cellulaires montre que l’expression de HLA-DR est amplifiée chez les patients même si la maladie est inactive. De plus, l’analyse du contenu sérique en cytokines inflammatoires a montré que la quantité de GM-CSF était plus importante chez les patients LED. Nos travaux suggèrent que HLA-DR et GM-CSF pourraient être considérés comme des candidats intéressants dans les études sur le diagnostic du LED.

Cirurgia endoscópica em tumores nasosinusais: experiência do IPOLFG

Introdução: Os tumores nasais são, classicamente, abordados pela via externa mas recentemente tem-se optado, também, pela via endoscópica. No entanto, em tumores localmente avançados, poderá não ser possível a remoção completa. Material e métodos: Foram analisados os processos clínicos dos 14 doentes com tumor das fossas nasais removido por via endoscópica no IPOLFG entre 2005 e 2012. Resultados: Dos 14 doentes, 8 apresentavam tumor maligno e 5 tumor benigno. Não houve preponderância de nenhum tipo histológico. 7 doentes realizaram RT adjuvante e 1 foi submetido a esvaziamento ganglionar cervical ipsilateral. Foram registadas 2 complicações cirúrgicas: 1 fístula de LCR e 1 complicação minor. Apenas 2 doentes recidivaram, recorrendo-se à via externa em 1. Conclusões: A abordagem de tumores nasais por via endoscópica é uma opção eficaz mas é necessária uma correta avaliação da extensão tumoral para decisão da via cirúrgica a utilizar, para remoção completa e obtenção de margens livres.

Ischemic Stroke as the Initial Manifestation of Neurosyphilis in a Young Adult Patient Positive for Human Immunodeficiency Virus

A 31-year-old man with pontine infarction was referred to our hospital for further evaluation and treatment. At admission, his neurological examination was unremarkable. No lymphadenopathy or skin lesions were found. The Treponema pallidum haemagglutination test, rapid plasma regain test and fluorescent treponemal antibody absorption test of immunoglobulin G were positive in both serum and cerebrospinal fluid (CSF). CSF analysis showed lymphocytic pleocytosis. The patient had male-to-male sexual contact and was found to be HIV positive. Physicians should be aware that acute ischaemic stroke may be the first manifestation of neurosyphilis in a young adult, especially with HIV infection.

Produção de lipidios funcionais por ação de lipase fúngica

A modificação estrutural de óleos e gorduras é uma das principais áreas de interesse de pesquisa em diferentes setores industriais. No caso da indústria de alimentos, a interesterificação é empregada para melhorar propriedades nutricionais e funcionais, em que se obtêm compostos diferentes dos que lhes deram origem. As lipases microbianas são os biocatalisadores mais utilizados industrialmente, por serem mais estáveis, específicas e com propriedades bem mais diversificadas que as lipases de outras fontes. Este trabalho objetivou, primeiramente, a caracterização da gordura da pele de frango (GPF) e sua comparação com óleo de soja, como referência, visando a utilização de GPF em reações de interesterificação. Para isto foram caracterizados quanto aos índices de rancidez hidrolítica e oxidativa, bem como de matéria insaponificável, índices de saponificação, refração e iodo. Foi realizado ainda o fracionamento e perfil de ácidos graxos destes lipídios e suas frações, com o cálculo de seus índices nutricionais. Foi verificado que a GPF apresentou qualidade satisfatória devido aos baixos índices de acidez (0,65 g ácido oleico.100 g -1 ), peróxido (2,14 meq.kg-1 ), p-anisidina (0,70 unidades de absorvância.g-1 ), além de fonte de ácidos graxos mono-insaturados (40%), sendo fonte promissora para estudos de interesterificação. Em um segundo momento o objetivo foi produzir lipídios modificados ricos em ácidos graxos essenciais a partir da gordura da pele de frango e ácidos graxos ramificados, utilizando lipase sn-1,3 específica e interesterificação do tipo acidólise. Foram estudados os fatores concentração de enzima, adição de água, proporção de substratos e tempo, segundo um planejamento experimental fatorial completo 2 4 . As separações analíticas foram executadas em placas de cromatografia de camada delgada, sendo as frações posteriormente extraídas, ressuspensas e injetadas no cromatógrafo a gás. Foi verificado que a adição de água ao meio reacional apresentou efeito significativo (p<0,05) para todos ácidos graxos avaliados dos triacilgliceróis, sendo que para o ácido essencial linoleico (C18:2) o efeito do tempo de reação também foi significativo, sendo verificado que quanto maior o tempo de reação, menor a quantidade de água a ser adicionada. Em um terceiro momento, o objetivo foi produzir éster fenólico a partir do DHCA, além de realizar reações de transesterificação deste éster com tricaprilina. Para a reação de transesterificação, foi utilizado um delineamento composto central rotacional (DCCR) variando a quantidade de enzima, tempo de reação e temperatura sobre a resposta (%) dos reagentes consumidos. A lipase Novozym® 435 de Candida antarctica foi utilizada como catalisador de todas reações. Foi verificado que a maior produção de éster (50%) ocorreu em oito dias. Nas reações de transesterificação, as relações molares em que houve maior consumo do éster produzido foram 1:5 e 1:10, sendo obtidos 21,1% e 29,6% de residual de dihidrocafeato de octila, respectivamente em 24 h. Foi observado que em altas temperaturas e tempo superior a 26 h, houve o menor residual de dihidrocafeato de octila (18,2%). Foram identificados três diferentes compostos fenólicos, contendo em sua estrutura dihidrocafeato de octila e ácido caprílico.

Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092)

Background and Purpose - Loss of motor function is common after stroke and leads to significant chronic disability. Stem cells are capable of self-renewal and of differentiating into multiple cell types, including neurones, glia, and vascular cells. We assessed the safety of granulocyte-colony-stimulating factor (G-CSF) after stroke and its effect on circulating CD34 stem cells. Methods - We performed a 2-center, dose-escalation, double-blind, randomized, placebo-controlled pilot trial (ISRCTN 16784092) of G-CSF (6 blocks of 1 to 10 g/kg SC, 1 or 5 daily doses) in 36 patients with recent ischemic stroke. Circulating CD34 stem cells were measured by flow cytometry; blood counts and measures of safety and functional outcome were also monitored. All measures were made blinded to treatment. Results - Thirty-six patients, whose mean SD age was 768 years and of whom 50% were male, were recruited. G-CSF (5 days of 10 g/kg) increased CD34 count in a dose-dependent manner, from 2.5 to 37.7 at day 5 (area under curve, P0.005). A dose-dependent rise in white cell count (P0.001) was also seen. There was no difference between treatment groups in the number of patients with serious adverse events: G-CSF, 7/24 (29%) versus placebo 3/12 (25%), or in their dependence (modified Rankin Scale, median 4, interquartile range, 3 to 5) at 90 days. Conclusions - ”G-CSF is effective at mobilizing bone marrow CD34 stem cells in patients with recent ischemic stroke. Administration is feasible and appears to be safe and well tolerated. The fate of mobilized cells and their effect on functional outcome remain to be determined. (Stroke. 2006;37:2979-2983.)

Neurofilaments and NFL-TBS.40-63 peptide penetrate oligodendrocytes through clathrin-dependent endocytosis to promote their growth and survival in vitro.

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Análise do efeito de polimorfismos não-sinônimos em genes de reparo de DNA da via BER na resposta inflamatória da meningite

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis and also developed a system to enable the functional analysis of polymorphic proteins. Patients with bacterial meningitis (BM), aseptic meningitis (AM) and controls (non-infected) genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. The levels of NF-κB and c-Jun were measured in CSF by dot blot assays. A significant (P<0.05) increase in the frequency of APE1 148Glu allele in BM and AM patients was observed. A significant increase in the genotypes Asn/Asn in control group and Asn/Glu in BM group was also found. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs increased significantly in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 148Glu allele or OGG1 326Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1Asn148Glu, OGG1Ser326Cys or PARP-1Val762Ala. Reductions in the levels ofIL-6, IL-1Ra, MCP-1/CCL2and IL-8/CXCL8 were observed in the presence of APE1148Glu allele in BM patients, however no differences were observed in the levels of NF-κB and c-Jun considering genotypes and analyzed groups. Using APE1 as model, a system to enable the analysis of cellular effects and functional characterization of polymorphic proteins was developed using strategies of cloning APE1 cDNA in pIRES2-EGFP vector, cellular transfection of the construction obtained, siRNA for endogenous APE1 and cellular cultures genotyping. In conclusion, we obtained evidences of an effect of SNPs in DNA repair genes on the regulation of immune response. This is a pioneering work in the field that shows association of BER variant enzymes with an infectious disease in human patients, suggesting that the SNPs analyzed may affect immune response and damage by oxidative stress level during brain infection. Considering these data, new approaches of functional characterization must be developed to better analysis and interactions of polymorphic proteins in response to this context