“Researchers have spent the past decade looking for tiny changes in common genes that predispose people to chronic diseases, such as asthma and diabetes. Now a new approach is starting to pay off: hunting for rare mutations in genes that are crucial to maintaining health.

In the latest example of this approach, researchers found faulty copies of a gene called sialic acid acetylesterase (SIAE) in 24 of 923 white subjects who suffered from autoimmune disorders, such as rheumatoid arthritis and lupus, compared with just 2 of 648 healthy white individuals.

The researchers knew that when the SIAE gene is switched off in mice, it allows components of the immune system called B cells to run wild and attack healthy tissue – the hallmark of autoimmune disease. They found signs of similar hyperactivity in the B cells of sick humans bearing the SIAE defects.”

“The study adds to a growing body of work suggesting that relatively rare gene mutations are at work in complex diseases, from heart disease to cancer to schizophrenia, said study researcher Shiv Pillai of Harvard Medical School. “It’s the accumulation of maybe a dozen such defects which makes someone susceptible,” he said.

“Someone gets the right number of them and things break down,” Pillai said, usually with help from triggers in the environment such as diet, a sedentary lifestyle or exposure to a pathogen.”

Most people know their ABO blood type. In some countries people carry a card indicating their blood type, in case of accident requiring an emergency blood transfusion. Few people however have heard of HLA types (human leukocyte antigens), the antigens in our blood that fight off microbes.

Contrarily to ABO blood types people do not have just one HLA type, but many (about 8 per person).

There are 3 major types of class I HLA (HLA-A, HLA-B, HLA-C) and 3 major types of class II HLA (HLA-DP, HLA-DQ and HLA-DR). Each type comprises hundreds of subtype (e.g. HLA-B27), further subdivided in hundreds of sub-subtypes (e.g. HLA-B*2705).

People will usually have 2 types of HLA-A, 2 of HLA-B, and 2 of HLA-C as well as 1 or 2 other types. HLA types are encoded in the HLA gene on chromosome 6. HLA types are therefore hereditary, just like the ABO blood type.

HLA’s role in fighting diseases

Each type and subtype is more or less efficient in fighting off viruses and noxious bacteria. There are tens of thousands of possible combinations of HLA, which is why some people never get sick, while other constantly have a cold, or are prone to some types of infections, depending on what HLA combination they have.

HLA types found in tropical countries tend to differ a lot from those in temperate parts of the world, because the viruses found there are different. Some Africans have developed HLA that give them resistance to malaria, for instance. When the Europeans arrived in the Americas, bringing with them new viruses on the continent, the biggest part of the Native American population of North America was wiped out as they didn’t have the right antigens to fight off even the common cold.

But too aggressive HLA’s can also be bad for the body. Some HLA types are known to attack the body’s own cells, causing what is known as autoimmune diseases, in other words diseases caused by one’s immune system attacking one’s own body.

Autoimmune diseases linked to HLA types

Here are a few known or suspected associations between HLA types and autoimmune conditions :

Ankylosing spondylitis (arthritis of the spine and sacroiliac joint) : caused by HLA-B27 in 95% of the cases. The combination HLA-B7/B*2705 heterozygotes exhibited the highest risk for disease.

Celiac disease (gluten allergy) : 95% of all celiacs have HLA-DQ2. 12% have HLA-DQ8.

Diabetes : The HLA types DR2, DR6 and DR11 are protective against Type 1 diabetes. The risk alleles are DR3, DR4 and DQ2.5. DR3 is linked to late-onset, whereas carriers of DR4 are at risk for early-onset Type 1 diabetes. People who carry both DR3 and DR4 types are at the highest risk and will develop diabetes the youngest.

HLA’s play a lesser role in Type 2 diabetes. There is a suspected link with HLA-Cw4, DR7, DR11 and DQA1, among others.

Graves’ disease : HLA-DR3 plays a significant role in the disease.

Hashimoto’s thyroiditis : strongly associated with HLA-DR5.

Lupus : weakly associated with HLA DR3, DR4, DR15 and DQA1.

Multiple Sclerosis : HLA-DRB1*1501 plays a role in the disease.

Myasthenia gravis : the main risk factors are HLA B8 and DR3 with DR1.

Narcolepsy : strongly associated with HLA-DQB1*0602. There is also an association with HLA DR2 and HLA DQ1.

Psoriasis : HLA-Cw*0602 is the main risk factor. HLA DR1 and DR7 may also play a role.

Rheumatoid Arthritis : HLA DR1, DR4, DR5, DR8 and DR12 are associated with the disease at various levels.

N.B. : HLA-DR11 is the short spelling for HLA-DRB1*11, just like HLA-C6 is short for HLA-Cw*06

Can STEM CELL Transplants Help?  YES

Because the immune system is housed in bone marrow, a bone marrow stem cell transplant from a healthy donor can halt the progression of autoimmune disease. The NFCTR is supporting an active clinical trial to treat multiple sclerosis (MS) with a stem cell/facilitating cell transplant. This “mini” bone marrow transplant does not require a perfect donor match and may be performed as an outpatient procedure.

Nearly 4% of the world’s population is affected by one of more than 80 different autoimmune diseases, the most common of which include type 1 diabetes, multiple sclerosis, rheumatoid arthritis, lupus, Crohn’s disease, psoriasis and scleroderma.

Autoimmune diseases represent the third most common cause of chronic illness in the United States. Although many autoimmune diseases are rare, the National Institutes for Health (NIH) estimates that they collectively affect between 5% and 8% percent of the U.S. population. For unknown reasons, the prevalence of autoimmune diseases is increasing.

Because these diseases strike women three times more often than men, the Office of Research on Women’s Health at the NIH has named autoimmunity a major women’s health issue. It is estimated by the American Autoimmune Related Diseases Association (AARDA)that as many as 50 million Americans are living with an autoimmune disease – at a cost of $86 billion a year. According to the U.S. Department of Health & Human Services (HHS), these diseases represent the fourth largest cause of disability among women in the United States and are the eighth leading cause of death for women between the ages of 15 and 64.

A normal immune system protects the body from infection and disease. The presence of an autoimmune disease, however, means that the body’s immune system mistakenly recognizes itself as an invader and attacks the organs, tissues and cells it was meant to protect. Some of these diseases, such as type 1 diabetes, attack specific organs. Others, including lupus, attack multiple organs. Almost any organ system of the body can be affected by autoimmunity.