Modified red blood cells prevents harmful immune response

About 80-100 different autoimmune diseases have been identified and at least 40 additional diseases are suspected of having an autoimmune basis, according to the American Autoimmune Related Diseases Association. These diseases, collectively, plague more than 250 million people worldwide and many more suffer from chronic inflammatory conditions. Moreover, the incidence of autoimmune diseases is growing at an alarming rate. In a word, autoimmune diseases are emerging as a health burden.

Some of the most common autoimmune diseases are Graves' disease, Hashimoto's thyroiditis, Systemic lupus erythematosus (SLE or lupus), Type 1 diabetes (TID), Multiple sclerosis (MS), Rheumatoid arthritis (RA), and Inflammatory bowel disease (IBD). These diseases are chronic and sometimes can be life-threatening. It is necessary to raise awareness of these diseases.

What is an autoimmune disease?

As its name implies, an autoimmune disease is a condition related to our immune system.

Our immune system is a system of many biological components and processes that protect us against disease. There are numerous microbes in the environment we live in as well as in our bodies. Some of those microbes have the ability to make us sick. Normally, our immune system functions to sense and fight these foreign invaders so that we can stay healthy.

However, our immune system may mistakenly attack the body's own tissues. The resulting inflammation and tissue damage can cause mild to severe symptoms and even death. Autoimmune diseases can affect almost any part of our body, such as the skin, the joints, the intestines, the thyroid, the eye, the spinal cord, and the brain. Symptoms may vary by the type and location of the defective immune response. Although the symptoms of different autoimmune diseases vary, there are often some similarities such as fatigue, dizziness, achy muscles, swelling and redness, and low-grade fever.

Simply put, an autoimmune disease is a malfunction of the immune system that causes the body to attack its own tissues.

What causes autoimmune diseases?

The exact cause of autoimmune diseases has not been fully understood. In many cases, doctors don't know why the patient's immune system goes wrong. But there are many theories and hypotheses regarding what causes or increases the risk of these diseases.

Firstly, the risk of developing an autoimmune disease is not the same between men and women. Epidemiological studies have shown that for more than eighty autoimmune diseases, the overall estimated prevalence is 4.5%, with 2.7% for males and 6.4% for females^[1]. This means that basically, women are more likely to develop autoimmune diseases than men. There are many possible ways to explain this female predominance. Reasons might include hormones, genetic differences, behavior, environment, and other unknown things.

Secondly, it is clear that genetic factors influence the incidence rates of autoimmune diseases. For instance, some families are more affected by autoimmune disorders than others. But not all members of those families develop the same disease. They inherit a susceptibility to an autoimmune disorder. Additionally, scientists have identified a number of risk gene candidates for autoimmune diseases. For example, people carrying certain variants of the HLA-DQA1, HLA-DQB1, and HLA-DRB1 genes appear to be more likely to develop Type 1 diabetes^[2].

Thirdly, environmental factors may affect the morbidity of autoimmune diseases. These environmental factors include infections, occupational exposures, and general exposures. For instance, enterovirus infections have been linked to Type 1 diabetes^[3]; Systemic sclerosis has been associated with occupational exposure to silica dust or solvents^[4]; Lupus antibodies (anti-Sm& anti-RNP) have been detected in patients with silicone implants, and these antibodies disappeared once the implant was removed.

Fourthly, what you eat may also matter. A diet that is high in fat and sugar and contains large amounts of processed foods is thought to increase the risk of autoimmune diseases. But there is a lack of strong evidence to support this hypothesis.

Fifthly, an environment that is too clean can be part of the problem. Due to the use of vaccines and antiseptics, children today get exposed to germs much less frequently compared to children in the past. This might make the immune system overreact to harmless substances.

How to treat autoimmune diseases?

Currently, there is no known cure for autoimmune diseases, but there are many types of drugs available to treat them. Which type of treatment you receive depends on the form and stage of disease, its severity, and specific symptoms. The main goal of treatment is to improve symptoms, minimize tissue damage, and preserve organ function. The commonly used drugs include immunosuppressants, anti-inflammatory drugs, and replacement of end-organ functions.

Immunosuppressants, a class of drugs that reduce the strength of the immune system, can be classified into several different categories such as corticosteroids, calcineurin inhibitors, mTOR inhibitors, IMDH inhibitors, biologics, and monoclonal antibodies.

Different classes of immunosuppressants work by inhibiting different parts of the immune system. Most of them target the T cells, as these cells are key players in cell-mediated immune responses.

Immunosuppressants are vital for treatment of autoimmune diseases but many of them come with mild-to-severe unwanted side effects. When an immunosuppressant suppresses the strength of the immune system, it not only turns down the defective immune response that triggers disease but also inhibits the protective immune response that fights against pathogens. So treatment with immunosuppressants may increase the patient's risk of infections. Other side effects of immunosuppressants may include loss of appetite, vomiting, diarrhea, high blood pressure, weight gain, and so on.

Non-steroidal anti-inflammatory drugs (NSAIDS) and corticosteroid anti-inflammatory drugs are also used to treat autoimmune diseases. These drugs help reduce inflammation, and related pain, swelling, and fever.

In some autoimmune diseases, the body no longer makes specific substances, which are needed by the body to function properly, such as insulin in diabetes and thyroxine in autoimmune thyroid disease. For these diseases, replacement of insulin or thyroxine is a critical treatment strategy.

Besides, in extreme cases, patients with autoimmune diseases may have to undergo surgery.

What's the latest research finding regarding treatment of autoimmune diseases?

New treatments for autoimmune diseases are being studied all the time.

In a new study published in the journal PNAS, researchers from the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology (MIT) report a novel approach to prevent and mitigate two common autoimmune diseases, Type 1 diabetes and Multiple sclerosis^[5].

In their study, red blood cells are genetically engineered to deliver disease-causing antigens -- protein fragments from cells that cause the abnormal immune responses in autoimmune diseases. When injected into mouse models, these engineered red blood cells teach the mouse immune system to ignore the antigens, thus preventing harmful immune responses and symptoms.

The aim the of the new study is to circumvent the side effects induced by nonspecific immunosuppression. To achieve this, the researchers set out to explore another method called tolerance induction.

Tolerance induction has emerged as a potential way to control autoimmune diseases. In the method, the body is trained to recognize the treatment product as a normal part of the body, without reacting to it. However, there are still many problems to be solved. For example, the treatment product may be degraded by the body before it reaches target sites.

The current study uses red blood cells to deliver antigens. The researchers collected blood from mice and modified the red blood cells to carry the antigens that trigger the harmful immune response. The modified red blood cells were then transfused back into the mouse models of Type 1 diabetes and Multiple sclerosis. Results showed that treatment with the modified red blood cells significantly reduced disease symptoms.

This approach takes advantage of the red blood cell clearance pathway in the body. As the red blood cells are processed, the immune system determines they are "self", so the antigens carried by the cells are being tolerated.

"Essentially what we're doing is hijacking the red blood cell clearance pathway, such that the foreign antigen masquerades as the red blood cells' own, such that these antigens are being tolerated in the process," explained Novalia Pishesha, who is an MIT student and who the first author of the paper.

In summary, the study demonstrates in mice the efficacy of cargo-carrying red blood cells in treating Type 1 diabetes and Multiple sclerosis. "Antigen-decorated RBCs (red blood cells) may thus provide a simple means to treat autoimmune disorders without compromising systemic immunity," the researchers concluded.

Harvey Lodish, who is a co-senior author of the study and an MIT professor, noted that "This is a very promising step in the development of therapies for autoimmune diseases."

But the findings of the study are made in mice, whether they are true in humans remains unknown. Nonetheless, the study provides new avenues for the development of therapeutic agents for autoimmune diseases.

Reference:

[1] Scott M.Hayter et al, Updated assessment of the prevalence, spectrum and case definition of autoimmune disease, Autoimmunity Reviews (2012).

[2] Xinli Hu et al, Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk, Nature Genetics (2015).

[3] L. C. Stene et al, Immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies, Clinical and experimental immunology (2011).

[4] E Diot et al, Systemic sclerosis and occupational risk factors: a case–control study, Occupational & Environmental Medicine (2002).

[5] Novalia Pishesha et al, Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease, PNAS (2017).