Mechanisms in the Development of Multiple Sclerosis Lesions: Reconciling Autoimmune and Neurodegenerative Factors

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.