Yet another idea of how MS starts

Both immune-mediated and neurodegenerative processes play a role in the pathogenesis of multiple sclerosis (MS). There is still considerable debate, however, on how to link these two seemingly unrelated elements in disease. It has also remained unclear how the immune system can be involved without harboring any obvious myelin-directed abnormality in MS patients. Here, we propose that the unique properties of a small heat shock protein, HSPB5 (alpha B crystallin), can help reconcile the role of the immune system with the neurodegenerative element in MS, and explain the absence of any peripheral immune abnormality in people with MS. By being selectively induced as a protective stress protein in oligodendrocytes, and subsequently triggering activation of nearby microglia, HSPB5 accumulation translates neurodegenerative signals into a local innate immune response. The immune-regulatory profile of HSPB5-activated microglia, as well as animal model data, indicate that the HSPB5-induced innate response is neuroprotective. However, the presence of pro-inflammatory HSPB5-reactive memory T cells in the human immune repertoire, a unique feature among mammals, can subvert this response. Recruited by the innate response, such T cells respond to the accumulation of HSPB5 by an adaptive immune response, dominated by IFN-gamma production, that ultimately overwhelms the originally protective microglial response, and culminates in tissue damage. Thus, HSPB5 accumulation caused by neurodegeneration can provoke a destructive local adaptive response of an otherwise normal immune system. This scenario is fully consistent with known causative factors and the pathology of MS, and with the effects of various therapies. It also helps explain why MS develops only in humans.

There is very little evidence to support the role of myelin basic protein autoimmunity in the development of MS. This myth has been peddled by "fundementalist immunologists", who could only make MBP. This is because it was water soluble and easy to make not because it was a logical target for autoimmunity. But when you take an unbiased approach and ask what T cells react with in MS brains the answer appears to be HSPB5. This is the number one protein that is upregulated in MS lesions.

People talk about "outside-in" and "inside out" mechanisms of autoimmunity, but if it is autoimmunity that comes into play it is in my opinion likely to be "outside-in" because the CNS does not support the generation of an aggressive immune response. This is because it does not contain the cell types that would trigger this. The naive immune response does not enter the CNS because the vascular does not produce the right signals to pull immune cell into the brain. This occurs in the lymph glands. T cells are educated to recognise their potential targets in the thymus. The thymus of essentially all animals contain HSPB5 and therefore T cells are deleted from the immune repertoire by a process called negative selection. Therefore in virtually all animals HSPB5-reactive cells do not exist. 


However, this does not occur in humans and so HSPB5-reactive cells can be generated and are not deleted. They can enter the blood and will home to the lymph glands. When humans are infected by EBV the immune response is stimulated and his causes the production of HSPB5 by the B cells. These can act as antigen presenting cells and stimulate HSPB5 reactive T cells such that they mature. These cell up-regulate markers used by white blood cells to get into the brain. If they get in the brain and do not find something that stimulates them, they die and are cleared away. But if they see HSPB5 damage can occur.

Healthly and MSers have cells that react with HSPB5 and 1 in 30,000 T cells react with this target. In the CNS of healthy individuals there is no expression of this protein, but in MS it is the number one upregulated protein.

We produce thousands of new immune cells every day so there is not reason that we need to let them escape. However if HSPB5 is stimulated to be expressed in the CNS it can be a targeted for destruction by the HSPBB5 reactive cells.

When the trigger of oligodendrocyte damage occurs in MS whether this is due hypoxia, viral or antibody or cytokine attack oligodendrocytes produce HSPB5, because this is a cell protection protein. It is aimed at helping them cope with disease such that they can stop nerve damage. When stressed to produce HSPB5 the oligodendrocytes stimulate the activation of microglia, if they produce certain growth factors it may alow the oligodendrocyte to deal with the damaging stimulus but in the presence of pro-inflammatory cytokines they can stimulate damage particularly in the presence of HSPB5 reactive T and B cells and damge to the oligodendrocyte can ensue. So the trigger for MS occurs in the CNS but independent events outside the CNS contribute to this..and I don't mean neck veins

There are many more possible explanationsof how disease develops but this can accomodate many of the the observations that occcur in MS.

CoI. Written by members of Team G