Sunday, 27 July 2014

Neutrophils mediate blood brain barrier breakdown

Aubé B, Lévesque SA, Paré A, Chamma E, Kébir H, Gorina R, Lécuyer MA, Alvarez JI, De Koninck Y, Engelhardt B, Prat A, Côté D, Lacroix S.Neutrophils Mediate Blood-Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases. J Immunol. 2014 Jul . pii: 1400401. [Epub ahead of print]

Disruption of the blood-brain and blood-spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP+ myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP+ cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1 receptor type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

For many year MS was known as a disease of mononuclear cell infiltration now it is polymorphonuclear disease

Mononuclear cells have a round or horseshoe shaped nucleus and consist of T and B cells, macrophages and natural killer cells. This idea is based on looking at MS lesions and was the corner stone of EAE too. These studies began in guinea pigs and rats and then in the 1970-1980s the mouse started to be used for EAE more and more.  Then we got TH1 EAE and TH17EAE and when you look in the mouse CNS during EAE, some lesions contains loads of polymorphonuclear neutrophils. 

Polymorphonuclear cells are the most common white blood cell in the blood and they have a multilobed shaped nucleus. Indeed if you looking in the CNS of some strains mice there may be only a few % of neutrophils but in others maybe about 80% of cells are neutrophils. 

Now that MS is mouse EAE, suggests that neutrophils need to be a part of the problem. Indeed pathologists would agree that neutrophils are a common cell in lesions of neuromyelitis optica.
This study says they are present in NMO and MS and suggests that they may be cells that are an early part of the lesion. 

Depleting them delays disease, if you look in animals with disease you find them, their presence correlates with blood brain barrier problems and you find them in MS, this would true of T cells too. 

Maybe Neutrophils are a new treatment for MS? 

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