What can we learn about MS from twin studies?
Twin studies are an important research tool to help separate nature (genetics) and nurture (environment). A famous example was the twin Jims – James Lewis and James Springer – who were identical twins separated at birth. They were reunited when they were 39 years old. Both had married and divorced a Linda; both had then married a Betty; both worked part-time in law enforcement; both bit their fingernails; and both named their sons James (Holden C. Science 1980;207:1323-1325).
While that study said more about coincidence than genetics, it did inspire other researchers to conduct further studies of twins separated at birth (called adoption studies). This type of study typically looks at identical twins – who have the same genetics – raised separately, so they have had different exposure to various environmental effects, such as childhood diseases, dietary habits, exercise habits, smoking, alcohol consumption, and so on.
Twin studies have been done in people with MS, but there are some limitations to this approach. About 30% of identical twins of people with MS also develop the disease, suggesting that genetic factors don’t play a dominant role in whether MS develops or not, but they can confer a susceptibility. As for environmental factors, most twins are raised in the same home so those factors will be similar in early life. Differences in the environment (e.g. obesity) during adolescence may be relevant. Also potentially important is the grey zone of genetic/environmental interplay – environmental factors that can alter how genetic factors are expressed (called epigenetic factors). This area has been largely unexplored.
Since MS is believed to be an autoimmune disorder, recent MS twin studies have tried to identify slight differences in the immune response that contribute to the development of MS. One such study found that a key difference between people with MS and their twin was in how one type of immune cell (called a T cell) was expressed (Gerdes and colleagues. PNAS USA 2020; epublished August 17, 2020). T cells in people with MS were more likely to have an inflammatory response compared to T cells from the non-MS twin. In comparison, non-MS twins who had some degree of inflammation in their brain and spinal cord (but not enough to be diagnosed with MS) had a similar T cell profile as the MS twin. This suggests that the inflammatory non-MS twin is at risk of developing MS, but some other factor may come into play that stops MS from fully expressing itself or which protects the brain from damage (such as a slight difference in how brain cells repair themselves).
Interestingly, other types of immune cells, such as B cells (which produce antibodies), didn’t appear to be influenced by genetics to the same degree. So B cells may only aggravate a condition that T cells create. These findings on the T and B cell response help to put together an “immune profile” for MS.
T cells are part of the adaptive immune response, which learns to respond to bodily threats based on prior exposure. The slight differences in the T cell response in this study show that genetics do regulate the immune response, but this genetic effect doesn’t act in isolation – the T cell is responding to some perceived threat, such as exposure to a virus. For example, 17% of the differing immune response in twins with and without MS was attributed to exposure to cytomegalovirus, which persists in the body without causing symptoms, but which can flare up if a person’s immune system is weakened (much like chickenpox virus causing shingles). Other viruses implicated in MS, such as Epstein-Barr, were not considered in this study. Since the twins in this study were raised in the same household – so they had a similar exposure to childhood diseases and probably had a similar diet – it may be that the environmental exposure triggering the T cell response came later in childhood or adolescence. The opposite may also be true: a later environmental effect may have protected the non-MS twin from developing MS. The possible link between viruses and MS also raises the question: if that viral exposure were prevented, would MS ever develop? Researchers are now looking at the possible role of vaccination in preventing MS.
This study reinforces the idea that the body’s immune response, specifically the T cell response, is important in the development of MS. It also supports the idea of targeting dysregulated T cells with MS medications. But it only provides part of the picture. It doesn’t identify why there’s an abnormal inflammatory reaction or what triggers that response. Other studies have suggested that there are genetic protective factors that reduce the risk of developing MS. So the immune response may only be part of the story. There may also be other downstream repair or regulatory mechanisms under genetic control that prevent non-MS twins from developing MS.
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