(The Bank Statement is also available as a PDF document.)

A source of antibodies in the brain of patients with MS
Dr Francesca Aloisi
Istituto Superiore di Sanita, Rome, Italy

Another usual suspect that should be looked at very carefully whenever the immune system is involved in injury is the antibody. Circumstantial evidence suggesting a role for antibodies in causing damage in MS comes from their presence in the fluid that bathes the brain and spinal cord (cerebrospinal fluid, CSF). It is these antibodies that are detected in the sample of CSF drawn from a lumber puncture, and that help the diagnosis of MS. Dr Aloisi's research is aimed at finding out how these antibodies are made within the brains of MS patients.

Antibodies are produced by plasma cells; plasma cells develop from B cells. B cells can be found in lymph nodes and in the blood.In the nodes, the B cells are organised into small sacs called follicles that are extremely efficient at producing antibodies. Dr Aloisi asked whether these antibody producing factories were responsible for making antibodies in the brains of people with MS.

The study, initiated in Rome and continued in the Tissue Bank laboratories by Dr Roberta Magliozzi, used special staining techniques to detect cells and molecules that are unique to B cell follicles. Follicles, containing multiplying B cells, plasma cells, and other cells and chemical messengers necessary for the production of antibodies were found within the brains of patients that had had the secondary progressive form of MS. All this evidence taken together suggests that B cell follicles may indeed be responsible for the sustained production of antibodies within the brains of MS patients. Follicles were not found in tissue from patients that had had other forms of MS or in tissue from patients that did not have MS.

In this picture of a B cell follicle, the fluorescent blue dye marks the nuclei of all cells; but most of these are plasma cells. The green stain is picking out the antibodies. The mass of green stain shows that large amounts of antibody are being produced by plasma cells in this follicle. The antibody is leaking into the surrounding brain tissue.

When B cell follicles were present, they were only found in the membranes (meninges) that encase the brain; they were never seen within demyelinated lesions. However, single B- and plasma cells were present within some lesions, which raises the question: what is the relationship between the presence of antibody producing B cell follicles in the meninges and the presence of B/plasma cells in lesions, and how is all that related to the degree of demyelination? Dr Aloisi's group is now working to answer these important questions because if these antibodies prove to have a role in the destruction of myelin, then developing strategies that would inhibit the formation B cell follicles may be beneficial to patients with secondary progressive MS.

Nodes of Ranvier during demyelination and remyelination
Dr Owain Howell
Dept. of Cellular & Molecular Neuroscience, Imperial College London

If one looks carefully along the length of a myelinated axon, one finds that the myelin is not present as one uniform coating, but that there are minute gaps (called nodes of Ranvier) at which the axon is “naked”.  This structure, consisting of stretches of insulation (myelinated axon) interrupted by un-insulated gaps (the nodes), allows the “electrical” nerve impulses, to jump from one node to the next in a process called saltatory conduction.  The formation and maintenance of the nodes is therefore vital to the ability of the axon to rapidly conduct messages to and from the rest of the body and within the brain itself. 
 
Working in collaboration with Professor Brophy at the University of Edinburgh, Dr Howell has been studying the edges of the node - the very point at which myelination stops.  Here, the myelin sheets bind tightly to the axon using “sticky proteins” called adhesion molecules; Dr Howell has been looking at the presence of one such molecule called neurofascin in MS brain tissue in order to see how its presence changes during the transition from normal tissue to demyelinated lesion and from demyelinated lesion to remyelinated lesion.  In the three pictures below,

very thin slices of tissue were treated with a green fluorescent dye that stains neurofascin and a red dye that picks-up myelin.  The first picture shows the “normal” situation.  There are two axons lying next to each, running across the picture with their envelope of myelin stained red.  The arrow heads show the position of two nodes.  The nodes are flanked on both sides by the green staining neurofascin.  The middle panel shows an area in which there is on-going demyelination.  The neurofascin is no longer present as a pair of discrete bands, but has now spread along the axon - arrow.  The last panel shows an area that is remyelinating; here the neurofascin has again become concentrated into discrete bands.  It is thought that with time the middle band will be lost so that a “normal” situation similar to the one shown in first panel is re-established. 
 
The effective conduction of nerve impulses along an axon is dependent upon the presence of nodes of Ranvier; this study shows what happens to these vital structures during demyelination and remyelination.  The study again demonstrates the complexity of repair and highlights just one structure that needs to be rectified in a large re-construction in order for normal function to be restored after an injury.