Why Do Women Have More Autoimmune Diseases? Study Points to X Chromosome

 

By Carl Zimmer

Feb. 1, 2024

Women are much more likely than men to have their immune system turn against them, resulting in an array of so-called autoimmune diseases, like lupus and multiple sclerosis. A study published on Thursday offers an explanation rooted in the X chromosome.

The research, published in the journal Cell, suggests that a special set of molecules that act on the extra X chromosome carried by women can sometimes confuse the immune system.

Independent experts said that the molecules are unlikely to be the sole reason autoimmune disease skews female. But if the results hold up in further experiments, it might be possible to base new treatments on these molecules, rather than on the current drugs that blunt the entire immune system.

“Maybe that’s a better strategy,” said Dr. Howard Chang, a geneticist and dermatologist at Stanford who led the new study.

Male and female embryos carry 22 identical pairs of chromosomes. The 23rd pair is different: Females carry two Xs, while males carry an X and a Y, which lead to the development of male sex organs.

Each chromosome holds genes that, when “switched on,” produce proteins to do work inside of cells. You might expect that women, with two copies of X, would make twice as many X proteins as men do. Instead, they produce about the same level. That’s because one of the two X chromosomes is silenced.

A molecule called Xist clings to the second X chromosome “like Velcro,” Dr. Chang said. As hundreds of Xist molecules wrap themselves around the X chromosome, they completely shut it down.

Keeping one X silent is crucial to women’s health. If a gene on the second X chromosome escapes Xist’s control, it will result in an excess supply of proteins, some of which could be toxic.

In 2015, it occurred to Dr. Chang that the silencing itself might also have a downside. His epiphany occurred while he was preparing to take his medical board exams to renew his license as a dermatologist.

As part of his studies, Dr. Chang had to brush up on autoimmune diseases, memorizing the names of human proteins that can be targeted by a misdirected immune system. When he looked at the list, he was surprised to see some familiar names.

When Dr. Chang isn’t working as a dermatologist, he researches the X chromosome in his lab. He noticed that many of the proteins involved in autoimmune diseases also helped Xist silence the X chromosome.

Maybe, Dr. Chang thought, that was no coincidence.

The new study emerged from years of research testing his hunch that Xist molecules could cause autoimmune disease. He and his colleagues studied a strain of mice in which the females are at high risk of the autoimmune disease lupus, while the males never develop severe cases.

The researchers genetically engineered the male mice so that they, like the females, produced Xist. “Once the male mice express Xist, they get much worse levels of immune disease,” Dr. Chang said.

The researchers also found that people with lupus or two other autoimmune disorders had high levels of antibodies to Xist-related proteins in their blood.

What to Know About Lesions and MS

Multiple sclerosis (MS) is an autoimmune disease. For people with MS, the immune system mistakenly attacks the protective covering on nerve fibers. This covering is called myelin.¹

The attacks by the immune system lead to the formation of lesions in the central nervous system (CNS). Lesions are areas of damage or inflammation.¹

What are lesions?

The myelin sheath is a layer around the nerves. It allows for efficient transmission of signals between the brain, spinal cord, and the rest of the body. When the myelin is damaged, the nerve signals become disrupted and neurons can degenerate. This can lead to various MS symptoms.^1,2

A lesion is a damaged or scarred area. In MS, they are caused by the inflammation from the immune system attacking the myelin. Lesions are sometimes called plaques. Not all lesions in the CNS are caused by MS. But lesions are an important sign of MS. Doctors use the presence and location of lesions to help diagnose and track MS.^1,2

MS lesions can occur throughout the CNS, including the brain, spinal cord, and optic nerves (the nerves that transmit signals from the eyes). Lesions are caused by focal inflammation that results in damage to the myelin and nerves. This damage ultimately leads to scar tissue. Lesions can vary in size and location. Lesions can be detected with imaging techniques such as magnetic resonance imaging (MRI).

What do lesions look like on MRI scans?

Doctors use MRI scans to look for lesions. In MS they often use an MRI scan with contrast. This means they inject a contrast fluid that contains gadolinium. The gadolinium shows up white (“lights up”) on certain MRI sequences where inflammation is happening. So, doctors look for white patches on these MRI sequences to detect active lesions with inflammation. Lesions older than 3 months typically will not light up with gadolinium.

While gadolinium only highlights newer lesions with ongoing inflammation, other MRI sequences can reveal all lesions, new or old, without any gadolinium. Combining these different MRI techniques allows doctors to identify both newer active and older inactive lesions.

Over time, some lesions may show up as a black spot on some MRI sequences. This means the CNS tissue has suffered so much damage that it completely degenerates or disappears. Some lesions have been shown to grow slowly over time. These are called chronic active lesions or smoldering lesions. Research shows that smoldering lesions may be a risk factor for progressive MS.

How are lesions used to diagnose and monitor MS?

Lesions play an important role in the diagnosis and monitoring of MS. Diagnosing MS often involves imaging, like an MRI, to look for signs of damage in the CNS. But MS is not the only cause of lesions. Radiologists review every MRI and look for signs of diseases. An MRI report may include lists of all possible conditions that could explain the results.

An MRI with lesions does not mean you definitely have MS. For a final MS diagnosis, a doctor will typically use a physical exam and questions about your medical history. They may confirm the diagnosis or rule out other conditions with other tests like bloodwork or a spinal tap.

If you are already diagnosed with MS, your doctors may use MRI images to look for evidence of ongoing disease activity such as new lesions. Current MS disease modifying therapies help prevent development of new lesions. New lesions on an MRI might suggest your current therapy is not working for you. MRIs taken over time can also show changes in old lesions. Sometimes old lesions can shrink or fade overtime. If lesions are growing or spreading, it may mean you need to consider new treatments.

If you are getting multiple MRIs over time of the same area of your body, try to get the MRIs at the same facility. This helps with tracking because the MRI machine and technique will be more consistent.

You may have access to MRI results before meeting with your doctor. But it can be a good idea to wait to review results with a professional. Doctors are trained to interpret the results and can address any concerns you may have.

 

 From: https://multiplesclerosis.net/clinical/what-are-lesions?utm_confid=32f64fac94bd683a885744accd9fcdfdb16ae862446753ab1f7cc160d11f8d21&utm_term=Article_1_Button&utm_source=ActiveCampaign&utm_medium=email&utm_content=Understanding%20MS%20Lesions&utm_campaign=MultipleSclerosis%20net-Newsletter-10%2F19%2F2023

 

Can Vitamin D Help MS?

 By Stephanie Watson

You might have heard that vitamin D helps to lower the risk for multiple sclerosis (MS). Or that it helps lessen symptoms in people who already have the disease. Evidence suggests that getting enough of this vitamin might protect against MS by holding back your immune system from attacking your own nerve cells.

But the link between vitamin D and MS isn't proven yet.

The MS-Vitamin D Link

This fat-soluble vitamin acts like a hormone in your body. Vitamin D also helps your immune system work better and to tamp down inflammation.

Those protective actions are important in autoimmune diseases like MS where your body turns against itself. In MS, cells of your immune system attack the coating around nerve fibers, called myelin, and leads to such hallmark symptoms as numbness, weakness, and blurry vision.

Research finds that vitamin D might help repair myelin and guards your nerves from damage.

Can Vitamin D Prevent or Slow MS?

Researchers aren’t sure if vitamin D can keep you from getting MS in the first place. Your body makes most of the vitamin D it needs from sunlight on your skin. People in northern climates like Scotland and Scandinavia are more likely to have MS compared with those who live in much sunnier climates. Studies show that people who get more sunlight and more vitamin D in their diets have a lower risk for MS overall.

There's some evidence that vitamin D might slow MS and make the disease less severe. Studies have found a link between higher vitamin D levels in the blood and less active disease, fewer lesions in their brain and spinal cord, and fewer relapses of symptoms.

In other studies, people with MS who had higher vitamin D levels had less severe disease and disability.

Do I Need More Vitamin D?

It's common for people with MS to be low on this vitamin. It may be hard for you to get outside to get sun often enough. Low vitamin D can also be a side effect of corticosteroids and other MS medications.

Your doctor can run a blood test to check your vitamin D level. You might be able to make up the difference by eating more fatty fish, eggs, and other foods that are high in vitamin D. Or, your doctor might suggest you take a supplement.

It's not clear whether taking a daily vitamin D supplement protects people from getting MS, or slows the disease in those who already have it. Studies suggest it might help, but this hasn't been proven. But since supplements are usually safe to take, it may not hurt to try them.

What Dosage Is Best?

Experts can’t say how much vitamin D is needed to prevent or slow MS. Different medical groups disagree on the ideal amount.

Official recommendations for adults is 400 to 600 international units (IUs) of vitamin D daily.

Ask your doctor what’s right for you. Be careful not to overdo it. Vitamin D helps your body absorb calcium, and you might end up with too much of that mineral. High calcium levels can weaken bones, damage the heart, and increase the risk for kidney stones.

If you already have MS, your doctor can check whether your vitamin D levels are too low. If so, it might make sense for you to take a supplement.

 

Your Genes and Multiple Sclerosis (MS)

 

By Paul Frysh

Medically Reviewed by Sabrina Felson, MD on April 19, 2022

In basic terms, scientists simply don’t know what causes multiple sclerosis, or MS. Your genes – the genetic material that you inherit from your biological parents – play at least some part. But they are not the sole cause.

In MS, your immune system goes haywire and starts to damage your central nervous system (brain and spinal cord). Scientists are still trying to figure out how this response works and what causes it. Scientists think that for some people, genes may cause your immune system to interact with something in some way to cause the disease.

These may include:

Environment. Environmental factors, like smoking, low levels of vitamin D, and obesity in childhood, have been shown to raise the risk for MS. People who live in certain parts of the world – for instance, those further away from the equator – tend to get MS more often. The reasons for this aren’t yet clear. Some scientists think it involves higher vitamin D levels near the equator.

There are also some theories that exposure to things like chemical solvents and allergens, among other things, contribute to MS risk. But research hasn’t shown this yet.

Infections. Infection with certain germs may raise your risk for MS. Research points in particular to the virus that causes mononucleosis (Epstein-Barr virus). But scientists are also investigating measles, human herpesvirus-6, and others.

Who Gets MS?

One of the reasons scientists assume a role for genes in the development of MS is that some closely related groups get the disease more than others.

To start with, women are twice as likely as men to develop MS. It’s also more commonly diagnosed in white Americans than Black Americans or those of Asian heritage. And MS is rare or doesn’t exist in many Native American societies. This all suggests that genes may also play a role in who gets MS.

In addition, though many groups share some of the same genes or gene mutations that raise MS risk, this is not always the case. For example, in one study, of 73 genes that raised MS risk in white Americans, only eight did the same in Black Americans. Are there other genes that raise the risk of this disease for Black Americans but not for white Americans? What are they, and might they change the approach to treatment?

More research needs to be done on the causes of MS, both in general and in different ethnic groups so that we can understand both the risk factors for MS and the right way to treat it in different people.

 

Can You Inherit MS From Your Parents?

Not really. There is no known gene or set of genes that guarantees that you will get MS if your parents have it. But a family history of MS does raise your risk for the disease.

For example, the rate of MS in the general population is about 1 in 1,000. But if you have a parent with MS, your chances go up to 1 in 50. And if both parents have MS, your risk goes up further to about 1 in 8. Other possible family history situations show that the closer your relationship to someone with MS, the higher your chances of having it:

If a second-degree relative (grandparents, uncles, aunts) or third-degree relative (great grandparents, great uncles and aunts, first cousins) have MS, your risk is about 1 in 100.

If your sibling or non-identical twin has MS, your risk is about 1 in 20.

If your identical twin has MS, your risk is about 1 in 4.

Scientists are especially interested in statistics about twins because identical twins have exactly the same genetic material. So if genes were the sole cause, both should have MS. But most of the time only one twin gets it, which means other things are at work.

Which Genes Raise Your Risk for MS?

Scientists know of more than 200 genes or genetic variations (mutations) that may contribute to MS. A lot of these genes help build and maintain the immune system. Some of them are linked to other diseases that also involve a malfunction of the immune system, such as Crohn’s disease and rheumatoid arthritis.

Others simply increase your chances for developing certain risk factors for MS. For example, lower vitamin D levels raise the risk of MS in some people. Certain gene variations are linked to lower vitamin D levels and thus a higher risk of MS. And genes that raise your risk of having high BMI (a measure of body fat) – another risk factor for MS – also make you more likely to get the disease.

In some cases, there may be particular gene mutations that raise your risk of MS, but in many people, it seems to be that no single gene raises your MS risk, but that it’s the interaction of several of them.

Researchers continue to look for more clues about the relationship between genes and MS.

 

Inside An MS Exacerbation

By Devin Garlit · 

Exacerbation, relapse, flare-up, attack: these are all names for the same thing with regard to Multiple Sclerosis. The general definition of this event is the occurrence of new or worsening of old symptoms lasting for more than 24 hours and taking place at least 30 days after a similar event. While this can be standard occurrence for those with Multiple Sclerosis, not everyone actually understands what’s going during this period. Understanding what is happening during an exacerbation is critical for those with MS. With that in mind, I’ll do my best to help break it down as simply as I can.

What’s happening to the body during an MS exacerbation?

During one of these moments, the disease has caused your own immune system to attack your body. Specifically, your immune system begins to assault your central nervous system. Its weapon of choice? Inflammation (caused by various immune cells). This inflammation damages myelin, a fatty substance that surrounds and helps insulate our nerves. This insulating layer makes sure our nerves properly conduct the electrical signals that our brain sends to the other parts of our body (think of it as the plastic covering on an electrical wire). When this layer is damaged, those signals don’t move fast enough or at all, which is where we start to see our symptoms. Can’t lift your leg fast enough or at all? The myelin around a nerve between your brain and leg has been compromised and the signal isn’t traveling as efficiently as it should be. Not only does our immune system damage the myelin, but it also damages the cells needed to regrow it.

When the immune system attacks

These moments that we call exacerbations (or whichever term you like) are when the immune system is making its attack. It’s when the immune system has created a lot of inflammation in your central nervous system, and it’s damaging that myelin layer. Not only does this inflammation damage that protective coating, but it also has an effect on those signals that are traveling through that part of the central nervous system. We use steroids to fight exacerbations as they help to reduce this inflammation.

When a relapse is over: the aftermath

When an exacerbation is over, these damaged areas of myelin develop some scar tissue (that’s where we get the term sclerosis in multiple sclerosis, we are left with multiple scars; these scars are also referred to as plaques or lesions). Once all that inflammation is gone or significantly reduced, some of that myelin can regrow, but it never grows back completely or strong enough due to the scarring and because the cells needed to facilitate regrowth have been damaged. This regrowth, coupled with the reduction in inflammation, is why people can seem to bounce back after an exacerbation. They may even seem like they are completely well again. That’s why people often use the term “relapse,” because they seem to improve or go back to the way they were. This is a pattern that is extremely common in people diagnosed with the Relapsing-Remitting form of the disease. However, the more exacerbations you have, the more your ability to bounce back becomes hindered.

Accumulating damage over time

The more scars you have and the more cells that help regrow myelin are damaged, the less you are able to recover. In the past, maybe a damaged nerve could still get the brain’s signal where it needed to go, even if not the most efficiently (unless an outside influence temporarily triggered an issue). As more damage occurs over time though, the ability of that nerve to do its job, no matter the situation, becomes compromised. Basically, that’s how people with MS can worsen over time. That’s why doctors try to not only shorten the length of exacerbations through steroids, but to minimize the overall number of them with disease-modifying drugs.

Dawson's Fingers ???

"Dawson's fingers" is the name for the lesions around the ventricle-based brain veins of patients with multiple sclerosis. The condition is thought to be the result of inflammation or mechanical damage by blood pressure around long axis of medular veins.

Dawson's fingers spread along, and from, large periventricular collecting veins, and are attributed to perivenular inflammation. 

Lesions far away from these veins are known as Steiner's splashes. 

Sometimes experimental autoimmune encephalomyelitis has been triggered in humans by accident or medical mistake. The damage in these cases fulfils all the pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lucchinetti system. This case of human EAE also showed Dawson fingers.