Education: What is a nerve impulse?

What is a nerve impulse? How does a nerve axon generate it and allow signalling using impulses from one place to another?

The impulse may be thought of as a message or wave.  A ‘message’, for example on a telegraph, or a ‘wave’ in the sea initiates at one point and ends up elsewhere. The message needs the medium: the wave may have travelled great distances, but it cannot exist without the sea, whereas the sea itself has not moved. Likewise, the anatomical connectivity of an axon does not change as impulses are transmitted. A telegraph message requires an unbroken line. If the telegraph line somewhere between Laramie and Denver in the old West is broken, then the message does not get through and the bandits might escape justice. There is a similarity here with the nerve impulse and the axon. The axon has to make the impulse and provide a conduit for its conduction.

Old fashioned telephonic communication required unbroken hardwiring. So does our nervous system.

You also have the idea that a wave has an energy that must be somehow provided. So for light waves in a torch, there must be a working battery that's switched on. Or a storm out in the Atlantic can make a wave on the sea. A message or a wave requires energy, and so does a nerve impulse. The message or wave requires a medium to allow travel. The nerve impulse is dependent upon the axon for its initiation, maintenance and propagation, and the energy to make nerve impulses comes from our food.

The energy to make a wave may be provided far out to sea, and then the wave propagates long distances.

The nerve impulse itself is a brief change in electrical potential across the membrane of the nerve (taking something like one half of one-thousandth of a second to occur). This depends on the distribution of salts in solution (inside and outside the membrane) and on remarkable proteins controlling which of these salts can cross the membrane. 

Some of these proteins are called sodium channels, but they certainly require their own blog post, as they are so fundamental and so important. When those proteins change their state, they can generate a change in electrical potential across the membrane. 

Such a change in electrical potential produces an event, but to turn it into a message, it has to travel without being diminished. The nerve fibre helps to do just that because it has the salt controlling proteins all the way along its length, and they are assigned to the impulse, as the impulse travels along the nerve. This event changes less and less as it moves along, and would peter out without help, but it can't because of the way the sodium channels in the membrane of the nerve actively amplify it. On the other hand, if you block the sodium channels with a drug, like a local anaesthetic, then you can block impulse conduction.

One thought might make this easier to explain, and this is that the nerve axon has to set up a battery beforehand, in order to make the impulse. The way it does this is by using the energy in food to sort charged particles of salt and distribute them in an unequal way on either side of the nerve membrane. These charged particles of salt are called ions. Using energy, the nerve arranges for there to be many fewer sodium ions on the inside of the membrane than the outside. It tries to exclude sodium ions from inside the axon. 

"Sodium" sounds quite exotic, but sodium ions are formed when we put table salt into our mouths and allow the salt to dissolve, and we have lots of sodium ions inside us, in our body fluids. The sea also has lots of sodium in it, more indeed than our body fluids. Once this gradient of sodium ions have been set-up, it is like a battery that can be utilized to generate an impulse, in a way similar to switching on a torch from time to time to make a flash of light.

The nerve impulse is the biological equivalent of a TTL pulse in electronic communication. It is propagated change in electrical potential, lasting about 0.5 milliseconds at one point, but there is a tail on it, or a so-called after potential, so the axon is affected by the passage of the impulse for a little while afterwards

How is an impulse initiated? It is initiated by another electrical signal arising in a neuron, for example, or at a sensory nerve ending, that causes the sodium channels at one end of the axon to switch on. The impulse is then propagated away from that locality by the presence of other sodium channels distributed along the length of the axon.

How fast does a nerve impulse propagate along an axon?

Up to about 50 or 60 metres per second in humans, that is over 200 km per hour, or over 125 miles per hour, if you want. So you need a sports car and an autobahn to replicate such fast transmission. 

You need a fast car to beat a nerve impulse.

I'll explain more about axons in my next post. Please ask me any questions below!

Education: How does a nerve fire?

We have talked about how does a nerve work a number of times but watching a video is much easier.

This video was spotted by one out our readers and I think that it explains how a nerve impulse travels pretty nicely.



It is well worth the ten minutes to watch it.

In MS the signs and symptoms are often caused by the nerves being too excited or under-inhibited, so that the nerve impulses occur in a way that is not adequately controlled.

MS removes the myelin that affects how quickly these impulses fire and removal of the myelin on one nerve within a network, can affect the co-ordination of the system, leading to signs.

Too much nerve excitation, can in some cases also drive the nerves to excite themselves to death, because it uses up all the nerves' energy. So blocking some of the excitatory channels or augmenting the inhibitor symptoms can be beneficial to control symptoms and may be useful in advanced MS.

If we look at some treatments that deal with MS symptoms, now hopefully you can see how and why they work.

Please add your suggestions for these education posts in the comments.

Education: What are B cell follicles?

The lymphatic system is part of the circulatory system and a very important part of the immune system, comprising a network of lymphatic vessels that carry a clear fluid called lymph (from Latin (lympha meaning "water") 

Want to learn more?

The human circulatory system processes an average of 20 litres of blood per day through capillary filtration, which removes plasma while leaving the blood cells in the blood. 

Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymph system is to provide a return route to the blood for the surplus three litres.

The lymph in the tissues is moved along the lymphatic vessel network by either intrinsic contractions of the lymphatic passages or by extrinsic compression of the lymphatic vessels via external tissue forces (e.g. the contractions of skeletal muscles). 

The organization of lymph glands and drainage follows the organization of the body into external and internal regions; therefore, the lymphatic drainage of the head, limbs, and body cavity walls follows an external route, and the lymphatic drainage of the thorax, abdomen, and pelvic cavities follows an internal route. Eventually, the lymph vessels empty into the lymphatic ducts (thoraic duct), which drain into one of the two subclavian veins, near their junction with the internal jugular veins.

The other main function is that of defence in the immune system. Lymph is very similar to blood plasma: and also contains waste products and cellular debris together with bacteria and proteins from the tissues in the body. The lymph passes through lymph glands on its way back to the blood:

Lymph glands are where lymphocyte-mediated immune reactions are started

Cells laden with antigens (Something recognized by the immune system) that pickup from their surroundings, or perhaps free-floating antigen flows down the lymphatics into the lymph glands. In the skin these cells are called Langerhans cells (named after a German Scientist Paul Langerhans in 1868) and there are 700 cells for every square mm of skin. These present the antigens to T cells but by the time they arrive in the lymph node they have a new name called interdigitating cells as they have long processes that can inter weave with T cells. They are also known as dendritic cells. When a T cell is activated for the first time they proliferate.

These areas are organised to activate T and B cells. As mentioned they are structured to aid function.

In the B cell areas there are CD4 T helper cells to help the B cells to produce antibodies. These are known as follicular helper cells.

How do T cells help B cells as they relate to the lymphatic system?
Follicular B helper T cells (also known as just follicular helper T cells or TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. 

Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centres through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate into these seeded germinal centres, predominantly composed of rapidly dividing and mutating B cells. 

Within germinal centres, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into special plasma cells capable of producing high affinity antibodies against foreign antigen, or memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. 

Memory B cells and plasma cells (antibody making cells) forming in the germinal centres

Then we have been talking about memory B cells and whilst we have been saying that memory B cells and antibody forming cells are formed in the germinal centres (GC), looking at that the  expression of CD27 (CD27+), there are a few in the germinal centres. They accumulate in the marginal zone surrounded by the T cells, so they shuttle out of the germinal centre.

This can be see in histology. CD20 binds B cells but not plasma cells so you can see most of the cells in the germinal centre have CD20 so they are not plasma cells. CD27 is on the memory B cells but can be found on activated T cells. CD1c  is a molecule associated with a form of antigen presentation.IgD is immunoglobulin D which is on B cells and is lost once memory cells class switch to produce IgA, IgG and IgE. So you can see the memory B cells are largely outside the follicle.

Where are the plasma cells?
Based on the fancy diagrams and all the hoo hah about ectopic follicles in the brain of MS, I was also under the assumption that the plasma cells would be located inside the follicle. 

These cells stain with CD138. 

When I had a look at the distribution of CD138 in lymphoid tissue I got a shock. The plasma cells are a few cells scattered outside the follicles and B cell areas.

Like the memory cells the plasma cells must rapidly leave the follicles where they are formed and the plasma cells then are found outside the follicles!

Here they are in the spleen, so you can see they are not really in the follicles. This is a revelation to me, because we are probably wasting our time looking for follicles, the plasma cells may be the odd cell next to a macrophage/microglia pumping out antibodies.

So maybe those pesky pathologists have done it again:-)....We are looking for the wrong thing.

I'll have to do some more reading. It's good that we learn together.
Some of you can hopefully spot my mistakes and misunderstandings.

Training the next generation of UK's MSologists

Tony Blair is famously quoted as saying 'Education, education, education, ...' and putting education at the centre of New Labour's manifesto in 1997. However, is it the type or the quality of education that makes the difference and changes the world?

We are trying to change the world of MS treatment.


I have learned that information in itself may pique attention, but it rarely changes behaviour.

I have been very impressed by the feedback we have had from our initial two MS Academies. Healthcare delegates participate in a 3-day course. They then go to a research or service development project or even an audit in relation to MS. The act of going away and doing something active makes delegates think about their MS practice and consider the service(s) they provide for their patients with MS. In other words, the doing induces a change in behaviour and complements the educational element of the course in changing behaviour.

Doing makes a difference!

If you are interested in joining the MS Academy and attending an MS Masterclass please register your interest via the MS Academy website. Please note these courses are open to non-UK clinicians and having HCPs from other countries helps NHS employees. After all aren't we still European, or even better citizens of the world?

CoI: At present, the Neurology Academy is supported by an unrestricted educational grant from Biogen. Biogen has no input into the design and running of the Academy that is based on the very influential Parkinson's Disease Academy, which has been running for more than a decade. We are also looking for additional sponsors.  

What is programmed death 1?

This is about a protein expressed by the immune system. It is a protein involved in limiting the immune response.

This post is going to be hard to understand unless you click on the links in this post and do some reading.

PD-1 is known as an immune checkpoint, which is a molecule in the immune system that either turn a signal (co-stimulatory molecules) or turn down a signal.

However, you need to know this to read the next post.

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There are many other immune checkpoints:

Four stimulatory checkpoint molecules are members of the 

tumor necrosis factor (TNF) receptor superfamily - 

CD27. This molecule supports antigen-specific expansion of naïve T cells and is vital for the generation of T cell memory. CD27 is also a memory marker of B cells. 

CD40. This molecule, found on a variety of immune system cells including antigen presenting cells This is expressed on B cells

CD122. This molecule, which is the Interleukin-2 receptor beta sub-unit, is known to increase proliferation of CD8+ effector T cells. This is expressed on memory B cells

OX40. This molecule, also called CD134, has OX40L, or CD252, as its ligand. Like CD27, OX40 promotes the expansion of effector and memory T cells, however it is also noted for its ability to suppress the differentiation and activity of T-regulatory cells, and also for its regulation of cytokine production. It is only upregulated on the most recently antigen-activated T cells within inflammatory lesions.This is expressed by B cells

This may be relevant to the effect of anti-TNF that can make MS worse as it shows that TNF is very important in the life and Dead of B cells. Anti-TNF makes memory cell survive, is this why it is bad for MS. However, it could also kill other B cell populations.

There are another two stimulatory checkpoint molecules that are members of the CD28 family:

ICOS. This molecule, short for Inducible T-cell costimulator, and also called CD278, is expressed on activated T cells. Its ligand is ICOSL, expressed mainly on B cells and dendritic cells.)This is expressed by B cells.

CD28. This molecule is constitutively expressed on almost all human CD4+ T cells and on around half of all CD8 T cells. Binding with its two ligands are CD80 and CD86, expressed on dendritic cells, prompts T cell expansion.  This is expressed on memory B cells.

There are inhibitory check points:

A2AR. The Adenosine A2A receptor 

B7-H3, also called CD276,

B7-H4, also called VTCN1, 

BTLA. This molecule, short for B and T Lymphocyte Attenuator and also called CD272. 

CTLA-4, short for Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152

IDO, short for Indoleamine 2,3-dioxygenase, is a tryptophan catabolic enzyme with immune-inhibitory properties. 

KIR, short for Killer-cell Immunoglobulin-like Receptor, is a receptor for MHC Class I molecules on Natural Killer cells. Bristol-Myers Squibb is working on Lirilumab, a monoclonal antibody to KIR.

LAG3, short for Lymphocyte Activation Gene-3, works to suppress an immune response by action to Tregs^[ as well as direct effects on CD8+ T cells.^[36] Bristol-Myers Squibb is in Phase I with an anti-LAG3 monoclonal antibody called BMS-986016.

PD-1, short for Programmed Death 1 (PD-1) receptor, has two ligands, PD-L1 and PD-L2. 

TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, expresses on activated human CD4+ T cells and regulates Th1 and Th17 cytokines.^[

VISTA (protein), Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on bone marrow-derived cells

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Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a cell surface receptor that plays an important role in down-regulating the immune system and promoting self tolerance, so you block autoimmunity by suppressing T cell inflammatory activity. PD-1 is an immune checkpoint and guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T-cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).

So PD-1 inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

Over-expression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion 

T-cell exhaustion is the progressive loss of T-cell function. It can occur after infections.