MS is caused by chronic inflammation in the brain and spinal cord. In so-called MS lesions, memory T cells patrolling the CNS become activated, and start producing the strongly pro-inflammatory factor interferon-gamma (IFN-γ). This triggers surrounding macrophages and microglia to develop a tissue-damaging response, and leads to recruitment of yet more immune cells into the tissue. Damage to the protective myelin layer that covers nerve tracts is the result, as well as damage to nerve tracts themselves. In the absence of adequate repair, this damage seriously hinders the conduction of nerve signals, which leads to the clinical symptoms of MS.

Because inflammation during MS occurs at various sites in the CNS, a wide range of neurological functions can be affected. Symptoms typically include disturbed vision, fatigue, weakness or paralysis of limbs, impaired speech, incontinence and depression. MS symptoms usually become apparent between the ages of 20 and 40, markedly more often in women than men. The variation of symptoms renders it difficult to recognize MS merely by clinical symptoms, and definitive diagnosis requires assessment by magnetic resonance imaging (MRI). By MRI scanning, inflammatory lesions in the brain and spinal cord can be revealed, even in the absence of neurological symptoms. In the majority of people affected by MS, episodes of clinical worsening (relapses) are initially followed by temporary partial recovery or improvement (remissions). This manifestation is referred to as relapsing-remitting MS. In most patients, relapses become less frequent and less apparent over time, ultimately resulting in a form of MS that is referred to as secondary-progressive. In a minority of people with MS, disability gradually accumulates without clear relapses from the start. This is called primary-progressive MS.

Over recent years, the approximately 2.3 million people with MS worldwide have been offered an increasing number of therapeutic options, now creating an annual 16 billion $ drug market. In a variety of different ways, current MS drugs modulate the immune system as non-selective immune suppressants. They may be helpful to people with relapsing-remitting MS since these drugs can help reduce the frequency of relapses. However, the precise mode of action of several of these drugs is still not fully clarified. Side effects and limited efficacy remain of concern, also to people with MS themselves. Generally no more than 40% of patients remain loyal to the MS drug offered to them. For the progressive forms of MS, no effective drugs are available yet. It is generally recognized that the availability of more selective and safer MS drugs remains an urgent unmet need, as well as of neuroprotective therapeutics that can help promote repair and suppress progressive forms of the condition.

About alpha B-crystallin

During MS, abnormalities in the brain and spinal cord provoke immune cells to start an inflammatory reaction. Delta Crystallon’s research has shown that unusual accumulation of the heat shock protein alpha B-crystallin is critical among those MS-specific abnormalities. Alpha B-crystallin is a stress-inducible protein that protects myelin-forming cells from death. Despite its protective function, memory T cells in all humans regard alpha B-crystallin as a ‘foreign’ substance, and produce IFN-γ in response to it. This somewhat surprising immune reactivity results from certain virus infections that program T cells to respond to alpha B-crystallin as if it were part of a virus. Also antibodies against alpha B-crystallin are formed. Such priming of immune-reactivity to alpha B-crystallin only happens in humans, like MS only develops in humans.

A natural immune-reactive state to alpha B-crystallin is no problem in most people, since there is little alpha B-crystallin around for T cells or antibodies to react against. In people with MS, however, persistent disturbances keep troubling myelin-forming cells in the brain and spinal cord. These cells, called oligodendrocytes, defend themselves against such disturbances by producing unusually large quantities of alpha B-crystallin. While in small quantities, the protein has protective functions, very large quantities are dangerous since these will provoke the above-mentioned IFN-γ response by memory T cells, some of which are always on patrol in the CNS. When this happens, an MS lesion will develop. While their presence as such is therefore not abnormal, memory T cells against alpha B-crystallin still act as the major driver of MS lesions when provoked by the stressed oligodendrocytes of people with MS.

The critical role of T cells against alpha B-crystallin in the formation of MS lesions.

During MS, stressed myelin-forming oligodendrocytes repeatedly start to produce unusually large quantities of alpha B-crystallin to protect themselves. Part of such protection is offered by local microglia and macrophages that recognize alpha B-crystallin released by oligodendrocytes via Toll-like receptor 2 (TLR2), and produce neuroprotective factors in response to it. The large quantities of alpha B-crystallin, however, also end up being presented to memory T cells that are continuously on patrol in the spaces around blood vessels in CNS. In humans, but not in other mammals, some of those T cells regard alpha B-crystallin as ‘foreign’, and produce interferon-gamma (IFN-γ) in response to it. The appearance of IFN-γ changes the originally protective response of macrophages and microglia to alpha B-crystallin. IFN-γ delivers a second signal to macrophages and microglia via the IFN-γ receptor (IFNGR), and the combined signals of TLR2 and IFNGR now induce a highly destructive response. This will cause an MS lesion to form.