Avaliação de receptores similares a toll (tlrs) em monócitos de pacientes com doença de Parkinson
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2017-06-02
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Universidade Federal de Goiás
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Parkinson's disease (PD) is a condition of the central nervous system (CNS), chronic and progressive, resulting from
the death of brain dopamine-producing neurons. Genetic and epidemiological studies have highlighted the role of
neuroinflammation in the pathophysiology of PD, emphasizing that the process of neuroinflammation is associated
with the death of dopaminergic neurons. In peripheral blood or tissues, leukocytes activated by pathogen-associated
molecular patterns (PAMP) and / or tissue damage (DAMP), via Toll-like receptors (TLR), produce pro and antiinflammatory
mediators whose imbalance can lead to a chronic inflammation. Under physiological conditions, three
subpopulations of human peripheral blood monocytes are detected: the classical monocytes (CD14++CD16-), the
intermediates (CD14++CD16++) and the non-classical (CD14+CD16+), these cells present phenotypic and functional
differences that can influence the characteristics of the immune response against DAMPs or PAMPs. The aim of this
study was to compare the peripheral blood leukocyte potential of patients with PD or healthy individuals in the
production of cytokines (TNFα and IL-10) after stimulation of these cells with TLR4 (LPS) or TLR2 / 1 (Pam3Cys)
agonists, to evaluate the effect of the age of DP patients on the production of cytokines in blood cultures, to investigate
the percentage of monocyte subpopulations expressing TLR1, TLR2 and TLR10, to evaluate the influence of TLR10
expression on the biological activity of TLR2 to its agonist in PBMC cultures. Two groups of patients with PD were
evaluated (≤ 55 years old and ≥ 65 years old), age-matched with healthy controls (n = 26). 6 h-TNFα production was
increased after TLR4 stimulation, mainly in young PD patients, whereas TLR2-induced TNFα and IL-10 levels were
decreased in PD patients independent of age (p < 0.05). A reverse correlation between LPS-induced TNFα production
and age was observed in PD patients and controls, but TNFα induced by TLR2 agonist was not associated with age of
PD patients or controls. TNFα production induced by TLR4 but not by TLR2 was reversely associated with the age at
PD onset and disease duration. No associations between UPDRS scores and cytokine levels were detected. A higher
percentage of CD14++CD16+ monocyte subpopulation was observed in the blood of patients with PD compared to
healthy controls, as well as a higher percentage of monocytes from patients expressing TLR10. The expression of
TLR2 and TLR10 in peripheral blood monocytes from PD patients was increased relative to that of healthy controls.
The results suggest that the peripheral blood leukocyte response to the TLR2 ligand is reduced in PD and that the
elevation of TLR10 expression in monocytes influences inhibiting the biological activity of TLR2 to its agonist as
demonstrated in the neutralization experiment of TLR10. In this study, the group of DP patients with the highest
severity of the disease, evaluated by the UPDRS scale, had a lower percentage of monocytes expressing TLR10,
suggesting the expression of this receptor in peripheral blood leukocytes as a possible prognostic marker for DP. These
findings, together, may play an important role in the immunopathology of PD. The study of TLR cell expression in
peripheral leukocytes and CNS, intracellular signaling pathways and the production of pro and anti-inflammatory mediators is necessary in order to better clarify the role of TLR in the PD pathogenesis and perhaps for the
identification of biomarkers of disease prognosis in the blood PD patients.
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ROCHA SOBRINHO, Hermínio Maurício da. Avaliação de receptores similares a toll (tlrs) em monócitos de pacientes com doença de Parkinson. 2017. 120 f. Tese (Doutorado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2017.