The price for a vigilant immune system that can pounce on tumor cells or pathogens is occasional friendly fire—an autoimmune attack. Scientists have now identified a new type of human T cell that quells assaults on healthy tissues, a finding that could suggest treatments for conditions as diverse as lupus and cancer. “It’s a major step forward in understanding how the immune response and autoimmunity are regulated,” says immunologist Harvey Cantor of the Dana-Farber Cancer Institute, who wasn’t involved in the work.
Immunologists already knew mice and people deploy one type of regulatory T cell—a subset called Tregs that sports the protein CD4—and suppresses autoimmune attacks. The newer enforcers belong to a category of T cells distinguished by a different surface protein, CD8. CD8 T cells are best known for killing infected or cancerous cells, but in mice some of them also kill T cells that orchestrate autoimmune reactions. Although researchers have long suspected humans have similar cells, nobody had confirmed their existence.
One obstacle was that humans don’t make the distinctive receptors that mark the subset of CD8 cells in mice. However, some human CD8 T cells flaunt comparable receptors, the KIR proteins. To determine whether these human cells are immune inhibitors, Jing Li, a postdoc in the lab of immunologist Mark Davis at Stanford University’s School of Medicine, and colleagues measured their abundance in patients with autoimmune diseases such as multiple sclerosis, lupus, and celiac disease. The cells were more common in blood from patients than in blood from healthy people, the team reports online today in Science. Tissue samples revealed they congregated in parts of the body damaged by the autoimmune attack, such as the joints in people with rheumatoid arthritis and the small intestine in people with celiac disease.
The researchers detected similar surges of the KIR-producing T cells in people fighting infections, especially the pandemic coronavirus. In 56 COVID-19 patients, “We saw the KIR-positive cells going through the roof,” Davis says. And the sicker COVID-19 patients were, the more of the cells they harbored. The cells’ numbers also shot up in patients with influenza, the team found.
To investigate the cells’ role in autoimmunity, the scientists homed in on celiac disease, which is triggered by the gluten proteins in bread and other grain-based foods. In patients with the condition, so called helper T cells recognize gluten proteins such as gliadin and then spill molecules that promote inflammation. But in cell culture studies, Li and colleagues found, human CD8 T cells carrying KIR proteins killed the gliadin-detecting helper T cells. “That really opened up a window for us to understand the biology of these [KIR+] cells,” Li says.
To find out how much protection the cells provide against autoimmunity, Li and her colleagues analyzed genetically altered mice that have 50% to 75% fewer of the suppressive CD8 cells than normal. After exposure to certain viruses that can trigger autoimmune disease, the rodents developed signs of damage such as kidney inflammation. In contrast, control mice with a full complement of suppressive CD8 T cells didn’t show evidence of autoimmune diseases after infections.
Cantor and other scientists are convinced the team has fingered the long-sought human counterparts to the rodent immune regulators. “The paper provides really solid data that these cells exist in humans,” says immunologist Nu Zhang of the University of Texas Health Science Center, San Antonio. They may have remained obscure because they “are rare and are easily missed,” accounting for only about 5% of CD8-positive T cells, Davis says.
Immunologist Stephen Jameson of the University of Minnesota Medical School says approaches that increase the cells’ numbers abundance might help soothe difficult-to-treat autoimmune illnesses such as celiac disease. It’s also possible, he adds, that the cells are “sitting in tumors” and shielding them from immune attacks, in which case reducing the cells' could unleash a person’s immune system to fight cancer. Researchers have attempted to harness the traditional, CD4-carrying Tregs for therapies, but no treatments have been approved, Cantor notes. “The hope is that with this new set of regulatory cells, we can use them more efficiently.”
A key question is why the immune system needs another type of suppressive T cell when it already has Tregs. But Tregs are generalists that inhibit a variety of immune cells without killing them. Davis posits that the KIR-positive CD8 cells target particular T cells that switch on during an assault by a pathogen. Although these freshly activated T cells help clear the invaders, they can also attack healthy tissues. The KIR subclass serves as a “SWAT team” to kill off these potentially ruinous T cells once an infection is quelled, Davis proposes.
The explosion of KIR-positive CD8 T cells the researchers detected in patients with autoimmune diseases or COVID-19 may reflect an attempt to rein in destructive immune reactions—the immune overreaction to the novel coronavirus is what kills many COVID-19 patients in the end. How the suppressive CD8 cells distinguish T cells with self-destructive tendencies is one of the mysteries scientists still need to answer.
- An autoimmune disorder occurs when a person's immune system mistakenly attacks their own body.
- There are around 80 different autoimmune disorders ranging in severity from mild to disabling, depending on which system of the body is under attack and to what degree.
- There is generally no cure, but the symptoms of autoimmune disorders can be managed.
The immune system is a collection of special cells and chemicals that fight infection-causing agents such as bacteria and viruses. An autoimmune disorder occurs when a person's immune system mistakenly attacks their own body tissues.
Autoimmune disorders are broadly grouped into two categories – 'organ-specific' means one organ is affected, while in 'non-organ-specific' disorders, multiple organs or body systems may be affected.
There are around 80 different autoimmune disorders ranging in severity from mild to disabling, depending on which system of the body is under attack and to what degree. For unknown reasons, women are more susceptible than men, particularly during their childbearing years. It is thought that sex hormones may be at least partly responsible. There is generally no cure, but the symptoms of autoimmune disorders can be managed.
Types of autoimmune disorders
Autoimmune disorders can affect nearly every organ and system of the body. Some autoimmune disorders include:
- Diabetes (Type I) – affects the pancreas. Symptoms include thirst, frequent urination, weight loss and an increased susceptibility to infection.
- Graves' disease – affects the thyroid gland. Symptoms include weight loss, elevated heart rate, anxiety and diarrhoea.
- Inflammatory bowel disease – includes ulcerative colitis and possibly, Crohn's disease. Symptoms include diarrhoea and abdominal pain.
- Multiple sclerosis – affects the nervous system. Depending on which part of the nervous system is affected, symptoms can include numbness, paralysis and vision impairment.
- Psoriasis – affects the skin. Features include the development of thick, reddened skin scales.
- Rheumatoid arthritis – affects the joints. Symptoms include swollen and deformed joints. The eyes, lungs and heart may also be targeted.
- Scleroderma – affects the skin and other structures, causing the formation of scar tissue. Features include thickening of the skin, skin ulcers and stiff joints.
- Systemic lupus erythematosus – affects connective tissue and can strike any organ system of the body. Symptoms include joint inflammation, fever, weight loss and a characteristic facial rash.
Immune system malfunction
Immune system cells called T lymphocytes (T cells) use special receptors on their surfaces to identify foreign microbes, such as bacteria and viruses. Usually, T cells that react to the tissues of the body are destroyed by the thymus, an organ of the immune system located behind the breastbone. The 'self-attacking' T cells that escape destruction may be activated by a trigger. The exact triggers are unknown, but viral infections and hormones are among the suspects. The rogue T cells then instruct B lymphocytes (B cells) to make antibodies against the particular tissue, organ or system. Such antibodies are called 'autoantibodies'.
Risk factors for autoimmune disorders
The exact causes of autoimmune disorders are not known. The risk factors seem to include:
- genetics – a predisposition to autoimmune disorders seems to run in families. However, family members can be affected by different disorders; for example, one person may have diabetes, while another has rheumatoid arthritis. It seems that genetic susceptibility alone is not enough to trigger an autoimmune reaction, and other factors must contribute.
- environmental factors – a family's susceptibility to autoimmune disorders may be linked to common environmental factors, perhaps working in conjunction with genetic factors.
- gender – around three quarters of people with autoimmune disorders are women.
- sex hormones – autoimmune disorders tend to strike during the childbearing years. Some disorders seem to be affected, for better or worse, by major hormonal changes such as pregnancy, childbirth and menopause.
- infection – some disorders seem to be triggered or worsened by particular infections.
Diagnosis of autoimmune disorders
It can be hard to diagnose an autoimmune disorder, especially in its earlier stages and if multiple organs or systems are involved. Depending on the disorder, diagnosis methods may include:
- physical examination
- medical history
- blood tests, including those to detect autoantibodies
- biopsy
- x-rays.
Treatment for autoimmune disorders
Autoimmune disorders in general cannot be cured, but the condition can be controlled in many cases. Historically, treatments include:
- anti-inflammatory drugs – to reduce inflammation and pain
- corticosteroids – to reduce inflammation. They are sometimes used to treat an acute flare of symptoms
- pain-killing medication – such as paracetamol and codeine
- immunosuppressant drugs – to inhibit the activity of the immune system
- physical therapy – to encourage mobility
- treatment for the deficiency – for example, insulin injections in the case of diabetes
- surgery – for example, to treat bowel blockage in the case of Crohn's disease
- high dose immunosuppression – the use of immune system suppressing drugs (in the doses needed to treat cancer or to prevent the rejection of transplanted organs) have been tried recently, with promising results. Particularly when intervention is early, the chance of a cure with some of these conditions seems possible.
Where to get help
- Autoimmune disease in women - the facts, American Autoimmune Related Diseases Association (AARDA), Detroit, MI.
- Questions & Answers , American Autoimmune Related Diseases Association (AARDA), Detroit, MI.
- Immune system, Better Health Channel, Department of Health, State Government of Victoria, Melbourne.
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