Department of Internal Medicine, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil.
Translational Stroke Research 09/2012; 3(3). DOI: 10.1007/s12975-012-0177-6
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron death, leading to muscle atrophy, paralysis, and death usually within 3 to 5 years after diagnosis. Most cases are sporadic, with still undefined etiopathogenesis. Both the innate and adaptive immune systems are involved in ALS, with special participation of T lymphocytes and microglia. Inflammation plays a dual role in the disease, protective and T regulatory cell rich in the early stages and deleterious as disease progresses. Attempts to modulate immune/inflammatory system response are reported in the literature, and while beneficial effects are achieved in ALS animal models, results of most clinical trials have been disappointing. The impaired blood–brain barrier is an important feature in the pathogenesis of ALS and likely affects the immune system response. The present review describes the role of the immune system in ALS pathogenesis and the tight coupling of immunity and central nervous system barrier function.
[Show abstract][Hide abstract] ABSTRACT: The migration of immune cells into the stroke-damaged brain has been reported for decades [1, 2] but its relationship to neurodegeneration is still not completely understood. Cells of the innate immune system are among the first immune cells to extravasate along with the adaptive immune cells infiltrating at later time points . The inflammatory response elicited from these immune cells directly exacerbates the neurodegeneration in the ischemic area as well as indirectly by activating microglia . This observation has led to the use of anti-inflammatory therapies in stroke treatment. One problem with this approach is the potentiation of the post-stroke immune suppression, which leads to increased infection rates . The clinical trial evaluating anti-ICAM-1 therapy is an example of this issue in which one of the adverse events was increased incidence of pneumonia in the treatment group . Thus, therapies that are more selective or targeted at the neurodegenerative response by th ...
Translational Stroke Research 09/2014; 5(6). DOI:10.1007/s12975-014-0372-8 · 2.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons in the CNS and leading to paralysis and death. There are currently no effective treatments for ALS due to the complexity and heterogeneity of factors involved in motor neuron degeneration. A complex of interrelated effectors have been identified in ALS, yet systemic factors indicating and/or reflecting pathological disease developments are uncertain. The purpose of the study was to identify humoral effectors as potential biomarkers during disease progression.
Thirteen clinically definite ALS patients and seven non-neurological controls enrolled in the study. Peripheral blood samples were obtained from each ALS patient and control at two visits separated by 6 months. The Revised ALS Functional Rating Scale (ALSFRS-R) was used to evaluate overall ALS-patient functional status at each visit. Eleven humoral factors were analyzed in sera. Cytokine levels (GM-CSF, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α) were determined using the Bio-Rad Bio-Plex® Luminex 200 multiplex assay system. Nitrite, a breakdown product of NO, was quantified using a Griess Reagent System. Glutathione (GSH) concentrations were measured using a Glutathione Fluorometric Assay Kit.
ALS patients had ALSFRS-R scores of 30.5 ± 1.9 on their first visit and 27.3 ± 2.7 on the second visit, indicating slight disease progression. Serum multiplex cytokine panels revealed statistically significant changes in IL-2, IL-5, IL-6, and IL-8 levels in ALS patients depending on disease status at each visit. Nitrite serum levels trended upwards in ALS patients while serum GSH concentrations were drastically decreased in sera from ALS patients versus controls at both visits.
Our results demonstrated a systemic pro-inflammatory state and impaired antioxidant system in ALS patients during disease progression. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage. These novel findings, showing dynamic changes in humoral effectors during disease progression, could be important for development of an effective treatment for ALS.
Journal of Neuroinflammation 06/2015; 12(1):127. DOI:10.1186/s12974-015-0350-4 · 5.41 Impact Factor
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