From the Gut: How Beneficial Bacteria Inside Our Bodies Might Trigger and Treat Autoimmune Disease

Doctors often describe the body’s immune system in military terms.

Physical barriers such as skin and mucus prevent invasion by disease-causing pathogens such as bacteria and viruses. If the obstacles fail, the body fires off an immediate general attack to deprive the invaders of shelter. In advanced organisms, the body sends specialized cells to target and kill the infiltrating microbes, forming a memory of their adversary for future battles.

But sometimes this memory proves faulty. The body attacks its own cells, mixing them up with the invaders. Such cases of mistaken identity comprise what are called autoimmune diseases that can result in serious complications.

“We don’t know exactly how the immune system decides between what is foreign and not,” said Dr. Martin Kriegel, an Assistant Professor of Immunobiology and of Medicine at Yale School of Medicine. “The immune system can be confused, and then the body reacts against itself.”

Two years after obtaining a Women’s Health Research at Yale seed grant, Kriegel has leveraged his findings to obtain substantially greater funding from the National Institutes of Health to continue exploring how beneficial bacteria that live in the gut might trick the body into an autoimmune reaction known as antiphospholipid syndrome.

Known as APS, the disorder can create life-threatening blood clots that might travel to the lung and cause strokes and heart attacks. Affecting up to 5 percent of the general population and more common in women, APS can cause pregnancy complications and miscarriages.

“The NIH estimates some 23.5 million Americans and rising suffer from autoimmune disease, compared to 9 million with cancer and 22 million with heart disease,” said Dr. Carolyn M. Mazure, Director of Women’s Health Research at Yale. “Among those with APS, between 75 and 90 percent are women who must learn to live with the threat of sudden death. Dr. Kriegel’s ongoing research seeks to better understand the causes of their diseases and possibly develop treatments that can offer a lifeline of hope for these women.”

For Kriegel, that lifeline finds anchor among the microorganisms that share our bodies in numbers 10 times higher than the number of cells that actually make up our bodies.

Dr. Kriegel’s ongoing research seeks to develop treatments that can offer a lifeline of hope for these women.

Carolyn M. Mazure, Ph.D.

“We are full of bacteria,” Kriegel said, describing what’s called the body’s microbiome. “We are walking culture dishes.”

While this genetically diverse microbiome serves a mutually beneficial purpose in healthy humans, imbalances have been implicated in depression, anxiety and even autism — as well as traditional autoimmune illnesses such as type 1 diabetes, multiple sclerosis, and lupus.

In exploring the origins of APS, Kriegel has identified a promising gut bacterium, R. intestinalis, that contains bits and pieces similar to the body’s natural protein, which then is mistakenly targeted by the immune cells in APS.

In subjects with a certain genetic predisposition, the researchers have found good evidence of what is called cross-reactivity, a phenomenon in which the body’s pathogen-targeting immune cells called lymphocytes mistake a self protein as foreign. Confusing a natural response to gut bacteria with the self may trigger an unnecessary and damaging immune response outside of the gut.

“Our key bacterial candidate seems to tickle the system, activate these self-reactive lymphocytes,” Kriegel said.

Kriegel’s lab has begun testing this bacterial candidate in cultures. They’ve found an antibiotic that prevents death of mice with APS. And because the standard blood-thinning therapy to treat patients with APS can lead to bleeding and only deals with the effects of the disease, Kriegel hopes microbiome research will lead to therapies that prevent the events that lead to autoimmunity in the first place.

“It is still early,” Kriegel said of the growing field of research. “But this work and these findings are very promising.”

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This article was submitted by Carissa R Violante on January 5, 2016.

Questions about Antiphospholipid Syndrome

What is APS?
Antiphospholipid Antibody Syndrome, or APS, is an autoimmune disorder in which the body recognizes certain normal components of blood and/or cell membranes as foreign substances and produces antibodies against them. Patients with these antibodies may experience blood clots, causing heart attacks and strokes, and miscarriages. APS may occur in people with systemic lupus erythematosus, other autoimmune diseases, or in otherwise healthy individuals.

What is an Autoimmune Disease?
One way in which our immune system fights infections is by making antibodies. Antibodies are proteins in the blood and body fluids that bind to foreign invaders like bacteria and viruses and help the immune system destroy and remove them. Sometimes the immune system doesn’t function properly and makes antibodies against normal organs and tissues in the body. These self-reactive antibodies are called autoantibodies.

The autoantibodies in APS were originally thought to recognize certain phospholipids, fatty molecules that make up part of normal cell membranes, hence the name “antiphospholipid” antibodies.
It is now known that most of the autoantibodies in APS patients actually recognize certain blood proteins that bind to phospholipids, not the phospholipids themselves. Two blood proteins that are major targets of antiphospholipid antibodies are
β 2-glycoprotein I and prothrombin.

Who Gets APS?
• 1-5 percent of the general population is believed to have APS.

• 15-20 percent of all cases of blood clots in large veins (deep vein thrombosis), including blood clots that go to the lungs (pulmonary embolism) are due to APS.

• 10-25 percent of women with recurrent miscarriages have APS.

• One third of strokes occurring in younger people (under the age of 50) are due to APS.

• APS is a major women’s health issue: 75-90 percent of those affected by APS are women.

• 30-40 percent of patients with lupus also have antiphospholipid antibodies.

How Are People Affected By APS?
People with antiphospholipid antibodies have an increased risk of developing one or more of the following problems:

• Blood clots

• Pregnancy complications and miscarriages

• Heart attacks, angina

• Strokes

• Heart valve problems, sometimes requiring valve surgery or valve replacement

• Persistent or transient blotchy, lacy bluish rash (livedo reticularis)

• Skin ulcers, most commonly on the legs or feet

How is APS Treated?
There is no cure for APS, but there is treatment. The treatment of choice for patients with APS who have had a blood clot is blood thinning (anticoagulant) therapy. This is usually successful in preventing further clots.

Related People

Martin Alexander Kriegel

Assistant Professor Adjunct

Carolyn M. Mazure

Norma Weinberg Spungen and Joan Lebson Bildner Professor in Women's Health Research and Professor of Psychiatry and of Psychology