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Previous issue date: 2018-03-14 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Rheumatoid Arthritis (RA) is an autoimmune and inflammatory disease which leads to
premature immunosenescence and the development of articular and extra-articular
manifestations, including joint damage and cognitive dysfunction, respectively. Peripheral
immune system cells and the chronic inflammation, both of great importance for RA, are
potentials mechanisms involved in cognitive dysfunction. In contrast, experimental studies have
shown the beneficial contribution of immune cells, mainly T cells reactive to central nervous
system (CNS) antigens, to neurogenesis and neuroplasticity. Previous data have shown that RA
patients besides to have worse performance in cognitive tests, have significantly lower levels of
B cells and higher levels of senescent T cells (CD8+CD28-). However, is not known yet which B
cells subpopulations are related to poor cognitive performance, if clinical severity of disease
(active and controlled disease) impacts on cognition and which factor is responsible for
remodeling of peripheral immunity (immunosenescence). Hypotheses about the contribution of
latent infections (Cytomegalovirus; CMV), for the development of immunosenescence
(observed by telomere shortening and increase of CD28- cells) have been raised. However, it
remains in discussion the CMV soroprevalence and its relation with the development of
premature immunological senesce in RA. Based on this findings, in this work we have broadly
assessment the cognition of RA patients with active and controlled disease, peripheral levels of
lymphocytes subsets (T and B cells), neurotrophic factors, cytokines besides that CMV
soroprevalence and immunosenescence profile (telomere length and CD28- cells). This work
also proposed to explore the relationship between immune mediators, neurotrophic factors and
cognitive performance, besides the association between CMV and immunosenescence. For this
purpose, 102 RA patients (67 active and 35 controlled disease) and 30 healthy controls adjusted
for age, gender and schooling were recruited. The cognitive function, levels of stress and
depression were assessment by means of neurocognitive tests (Mini Mental State Examination,
Logical memory, digit span, Trail Making Test, N-back, Stroop word-colors) and specific
questionnaires (Beck Depression Inventory ?II for depression and Perceived Stress Scale for
stress). Twenty ml of blood were collected and, after plasma separation, the peripheral blood
mononuclear cells (PBMCs) were isolated by centrifugation gradient. PBMCs were
immunophenotyped by flow cytometry to investigate the frequency of T and B cells subsets. The
genomic DNA was isolated from PBMCs and the telomere length was evaluated by real time
PCR. Neurotrophic factors, cytokines, IgM and IgG anti-CMV were measured in plasma by means
of ELISA (NF and CMV) and Citometric Bead Array (CBA; cytokines). In general, patients with
active disease had worse cognitive performance, followed by patients with controlled disease
producing cells, in addition to high levels of cytokines, with the exception of IL-17A. Higher
levels of BDNF were found in patients with active RA followed by controlled disease and control
group. The peripheral levels of GDNF were lower in patients with active RA than control group.
The IL-6 was predictor of the performance in Trail Making test. IgM and IgG anti-CMV antibody
titers did not differ between patients and controls. Only IgG anti-CMV was positively associated
with age and senescent cells. In conclusion, RA patients with active disease had worse
performance in cognitive tasks that were related to peripheral immune mediators (cells and
cytokines). Besides that, we found that late infection (IgG) by CMV were associated only with
CD4+CD27-CD28- and haven?t correlated with other immunosenescence characteristics.
However, understand in which sense e how the relationship between the peripheral
environment and the CNS is established, may contribute to development of preventive
interventions to cognitive impairments and premature immunosenescence, since both factors
are associated to health and well-being of individuals. / A artrite reumatoide (AR) ? uma doen?a autoimune inflamat?ria que leva ?
imunossenesc?ncia prematura e ao desenvolvimento de manifesta??es articulares e extraarticulares,
entre elas a destrui??o da articula??o e o decl?nio cognitivo, respectivamente.
C?lulas do sistema imune perif?rico e a inflama??o cr?nica, ambos de grande import?ncia para
a AR, s?o potenciais mecanismos envolvidos na disfun??o cognitiva. Em contrapartida, estudos
experimentais tem revelado a contribui??o ben?fica das c?lulas imunol?gicas, principalmente
c?lulas T reativas a ant?genos do sistema nervoso central (SNC), para a neurog?nese e
neuroplasticidade. Dados pr?vios apontam que pacientes com AR al?m de apresentarem piores
desempenhos nos testes cognitivos, tem significativamente menos c?lulas B e mais c?lulas T
com perfil senescente (CD8+CD28-). Entretanto ainda n?o se sabe quais subpopula??es de
c?lulas B est?o relacionadas ao pior desempenho cognitivo, se a severidade cl?nica da doen?a
(doen?a ativa e controlada) impacta sobre a cogni??o e qual fator seria respons?vel pelo
remodelamento da imunidade perif?rica (imunossenesc?ncia). Hip?teses sobre a contribui??o
de infec??es latentes, como a causada pelo citomegalov?rus (CMV), para o desenvolvimento da
imunossenesc?ncia, observada pelo encurtamento telom?rico e aumento na frequ?ncia de
c?lulas CD28-, tem sido levantadas. Por?m, permanece em discuss?o a soropreval?ncia da
infec??o pelo CMV e sua real rela??o com o desenvolvimento da senesc?ncia imunol?gica
prematura na AR. Com base nestas constata??es, nesta tese n?s avaliamos amplamente a
cogni??o de pacientes com AR ativa e controlada, n?veis perif?ricos de subtipos linfocit?rios
(c?lulas T e B), fatores neurotr?ficos (FN), citocinas, al?m da soropositividade para CMV e perfil
de imunossenesc?ncia prematura (encurtamento telom?rico e aumento de c?lulas CD28-). Esta
tese tamb?m se prop?s explorar a rela??o entre mediadores imunes, FN e desempenho
cognitivo, e a associa??o entre CMV e caracter?sticas de imunossenesc?ncia. Para esta
finalidade, 102 pacientes com AR (67 com doen?a ativa e 35 com doen?a controlada) e 30
controles saud?veis ajustados para idade, g?nero e escolaridade foram recrutados. A fun??o
cognitiva, n?veis de estresse e depress?o foram avaliados por meio de testes neurocognitivos
(Mini Exame do Estado Mental, Mem?ria L?gica, Subteste de D?gitos, Trail Making Test, N-back,
Stroop palavras-cores) e question?rios espec?ficos (Beck Depression Inventory ?II e Escala de
Estresse Percebido). Foram coletados 20 ml de sangue e, ap?s a separa??o do plasma, as c?lulas
mononucleares do sangue perif?rico (PBMCs) foram isoladas por gradiente de centrifuga??o.
PBMCs foram imunofenotipadas por citometria de fluxo para investigar a frequ?ncia de
subpopula??es de c?lulas T e B. FN, citocinas, IgM e IgG anti-CMV foram dosados no plasma
atrav?s da t?cnica de ELISA (FN e CMV) e Citometric Bead Array (CBA; citocinas). De forma geral,
pacientes com doen?a ativa tiveram o pior desempenho nos testes cognitivos, seguido pelos
indiv?duos com doen?a controlada e grupo controle. Pacientes com AR tiveram elevados n?veis
perif?ricos de c?lulas B imaturas e produtoras de anticorpos, al?m de elevados n?veis das
citocinas, com exce??o da IL-17. Maiores concentra??es de BDNF foram observadas nos
indiv?duos com AR ativa, seguido pelo grupo controlado e controle. Os n?veis perif?ricos de
GDNF foram menores em pacientes com AR ativa do que em indiv?duos controle. A IL-6
apresentou-se como preditora do desempenho do Trail Making Test. T?tulos dos anticorpos IgM
e IgG anti-CMV n?o diferiram entre pacientes e controles. Somente o IgG anti-CMV foi
relacionado positivamente com idade e c?lulas senescentes. Concluindo, pacientes com AR ativa
apresentam pior desempenho em tarefas cognitivas as quais est?o relacionadas a mediadores
imunes perif?ricos. Al?m disso, observou-se que infec??es tardias pelo CMV (t?tulos de
anticorpos IgG anti-CMV) foram somente associadas a c?lulas T senescentes e n?o se
correlacionaram com outras caracter?sticas da imunossenesc?ncia. Portanto, compreender em
qual sentido e como a rela??o entre o ambiente perif?rico e do SNC se estabelece, pode
contribuir para o desenvolvimento de interven??es preventivas ao d?ficit cognitivo e
senesc?ncia prematura, uma vez que ambos fatores est?o associados a sa?de e o bem ? estar
dos indiv?duos.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/7984 |
| Date | 14 March 2018 |
| Creators | Petersen, Laura Esteves |
| Contributors | Bauer, Mois?s Evandro |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Escola de Ci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 500, 500, 600, -1634559385931244697, 2075167498588264571 |
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