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, 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 patients. 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-γ 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.