Background
Disruption to the blood brain barrier (BBB) – a gateway that controls which cells and molecules enter the central nervous system – is a defining feature of the disease process underlying MS. However, the timing of BBB breakdown relative to other disease events, such as the formation of lesions in the brain that are responsible for the debilitating symptoms of MS, is still poorly understood. Mapping out the chronology of these events is important because it can potentially lead to methods of detecting early hallmarks of MS before symptoms become visible.
A study that probed alterations to the BBB during the course of MS was recently published in Neurobiology of Disease by Dr. Jorge Alvarez – recipient of the endMS David L. Torrey Transitional Career Development Award – and a team of colleagues led by MS Society-funded researcher Dr. Alexandre Prat. The aim of the study was to examine molecular and immunological changes in the BBB – as well as in other areas of the body – before and during the formation of lesions, both in the brain tissue of people with MS and in mice with an MS-like disease.
The Study
To analyze the composition of the BBB over the course of lesion development in humans, various markers of BBB structure, immune cell infiltration, lesion formation and demyelination were studied in brain autopsy samples obtained from persons with MS at various stages of the disease. In the second part of the study, the researchers induced a disease state in genetically-engineered mice that mirrors relapsing-remitting MS (RRMS) and examined how the BBB breaks down and when this takes place relative to other time points in the development of MS. Since the MS-like disease in mice follows a very predictable time-course such that symptoms emerge at about 65 days after birth, the researchers were able to reliably study the sequence of events leading up to lesion formation and the development of symptoms.
Results
In the MS-like mice which were observed, the BBB showed signs of disruption nearly 3 weeks before the onset of demyelination and disease symptoms. The composition and structure of the BBB became progressively more compromised over the ensuing weeks, triggering infiltration of immune cells into the brain. Previous studies have shown that immune activity in the periphery (outside of the central nervous system) can influence inflammation in the central nervous system. In this study, researchers found that a peripheral inflammatory response occurs prior to BBB disruption, suggesting that peripheral immune activation may be responsible for the weakening of the BBB and resulting infiltration of immune cells.
When they examined brain tissue of people with MS, the researchers discovered that at certain disease-susceptible sites there was a similar pattern of BBB disruption over time, which further supported the evidence observed in the MS-like mice.
Comment
Early diagnosis and timely treatment of MS and its symptoms represents one of the best indicators of a positive prognosis in people affected by the disease. Identifying and understanding disease events that can predict the formation of harmful lesions in the brain before the onset of symptoms is a key step in developing therapeutic strategies that will have the greatest impact on people living with MS. This study makes important inroads into our understanding of the evolution of disease mechanisms in RRMS, particularly with respect to how changes in the integrity of the BBB herald the emergence of inflammatory lesions in the brain, as well as how BBB disruption may be prompted by immune activity occurring outside of the central nervous system. Mapping out the sequence and timing of disease events underlying the development of MS will allow clinicians to more fully understand the nature of the disease, which in turn will improve diagnosis, disease monitoring, and administration of therapies that target the interaction between immune cells and the BBB (like the one profiled in a recent MS Update).
Source
Alvarez JI et al. Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol Dis. 2014. 74C:14-24