Little is known about the exact causes of autoimmune disease. The diverse array of such diseases creates an impasse for researchers who struggle to find a common denominator that could lead to better treatments and, potentially, a cure. For part II of our article series on autoimmune disease, BioStock talked to one of the leading researchers in Sweden working with the most common autoimmune disorder, rheumatoid arthritis, to discuss the challenges and progress within the field.

If you missed part I of this series, you can find it here:

https://www.biostock.se/2019/06/biostocks-article-series-on-autoimmune-disease-the-patients/

At least 80 autoimmune diseases have been identified, all affecting different parts of the body, different organs, different tissue types, and all causing a wide range of symptoms that often overlap with each other. The intricate mechanisms that lie behind these diseases make it challenging to study them and reach any strong conclusions as to what causes them. There is one thing they all have in common, however: the immune system – the group of soldier cells that is supposed to protect us from disease – gets hacked by an unknown catalyst and starts attacking its own healthy cells.

A glitch in the immune system

In a normal situation, the immune system produces antibodies called T-cells when it recognises foreign invaders such as a viruses or bacteria. These antibodies track the invaders and attack them relentlessly, producing an immune response. Such a response typically presents itself with an increase in body temperature, redness, swelling, pain and loss of function.

Therefore, during an autoimmune attack where a glitch in the immune system causes it to target healthy cells, typical symptoms present themselves as those listed above. However, depending on the part(s) of the body involved in an autoimmune attack, these symptoms can vary in range and severity.

Two autoimmune diseases in the spotlight

For the purpose of this article series, we are focusing on rheumatoid arthritis (RA) and multiple sclerosis (MS), two of the most common, yet very different autoimmune diseases.

In RA, the immune system recognizes proteins in the joints as foreign and begins attacking them, causing pain, stiffness and swelling at the joints. The disease is chronic and progressive, so symptoms usually begin in the small joints of the fingers and then spread to the rest of the body, resulting in disability. Other organs can also be affected in RA, causing a systemic inflammatory response that can lead to cancer or organ failure in more extreme cases.

»For RA and other rheumatic diseases such as Lupus, SLE, mainly women are affected. The reason for that is not fully known and understood. However, the role of female hormonal factors in the development of RA has been studied for many years and is thought to be of importance among other factors. Female hormones have an effect on the immune system« — Li Alemo Munters, Head of Research at the Swedish Rheumatism Association, Reumatikerförbundet

With MS, the disease starts in the nerves – more specifically, the fatty layer of myelin that enwraps the nerves, which creates an electrical pathway for nerve cells to send messages to each other. Proteins in the myelin sheath are targeted by antibodies leading to its destruction, thus creating gaps in the electrical wiring of the nervous system. This causes numbness or a tingling sensation in the limbs, blurred vision or even blindness, pain and itching, and difficulty performing movements.

Current treatments are not good enough

Both diseases are challenging to diagnose and once you finally have the correct diagnosis, the diseases are hard to treat. Current treatments for both RA and MS, as well as other autoimmune diseases mainly target the symptoms and not the root cause. These typically involve immunosuppressants and anti-inflammatory drugs, which have a very limited effect and often cause the whole immune system to weaken, leading to increased susceptibility to severe complications and other diseases.

Is immunotherapy the answer?

In recent years, immunotherapy has become the go-to method for experimental treatment for cancer and researchers believe these could work for treating autoimmune diseases as well. Checkpoint inhibitors (CIs) and chimeric antigen receptor (CAR) T-cells are two of the most common forms of immunotherapy, and both are being studied as possible treatments for autoimmune disorders.

The checkpoint inhibitor conundrum

Under normal conditions, immune checkpoint proteins are implicated in the initiation of immune responses and determination of the intensity and duration of such responses. Cancer cells typically manipulate these checkpoint proteins in order to hide from killer T-cells, therefore, CIs work well as a form of treatment because they expose cancer cells to the T-cells so they can be destroyed.

Unfortunately, by inhibiting the checkpoint proteins, CIs can actually lead to the beginnings of an autoimmune reaction, creating a conundrum for medical experts. However, some scientists still believe that CIs could have a place in treating autoimmune diseases by finding the right target.

Recent findings from a study published in Nature, show that the inhibition of a specific checkpoint protein called PD-1 improves symptoms in an animal model of autoimmune disease. While these findings are promising, lots of work is still needed to make CIs relevant treatment alternatives for autoimmune disorders.

Confidence in CAR-T therapy rises

T-cells are immune cells that are typically triggered to fight off invaders. In autoimmune disease, these cells attack healthy tissue. Using CARs, scientists may have found a way to reprogram these cells so that they only attack malignant molecules and not the healthy ones.

In recently published pre-clinical studies, researchers at the University of Tennessee in Memphis successfully tested a type of CAR-T immunotherapy in a mouse model of systemic lupus erythematosus (SLE), an autoimmune disease giving similar symptoms to those of RA.

Moreover, California-based Sangamo acquired the French biotech TxCell, who are developing a unique kind of CAR-T therapy for autoimmune diseases. The 84 MUSD deal suggests that confidence in CAR-T is quite high.

Stress could be a major trigger

Without knowing the causes of autoimmune diseases, performing the research becomes very tricky. A genetic component is surely a factor. In the case of MS, for example, 1 in 1000 people get the disease, however, that number jumps to 1 in 4 for twins, suggesting genetics play a major role. Nevertheless, genetics do not tell the whole story, and environmental factors have to be taken into consideration.

Many experts speculate that stress is a major trigger, whether it be physical or psychological stress. Several studies have linked stress disorders to a higher risk of developing autoimmune diseases, and there is plenty of evidence suggesting that severe injuries or acute infections could potentially lead to the activation of autoimmunity.

A first-hand account by top researchers

Today, BioStock’s article series on autoimmune diseases continues with a conversation about the current state of autoimmune research and healthcare. The conversation features Li Alemo Munters, PhD and Head of Research at the Swedish Rheumatism Association, Reumatikerförbundet.

*We should also note that we reached out to Neuro, a Swedish patient organisation focused on helping patients suffering from neurological disease, including MS. However, they declined to participate in this article series.

Li Alemo Munters, Head of Research at Reumatikerförbundet

Li Alemo Munters, reports suggest that the prevalence and incidence rates of autoimmune diseases in general are rising. From your knowledge, what is to blame for this rise?

– As far as I know, the prevalence and incidence for rheumatic diseases is not increasing. However, the ability to diagnose rheumatic disease has improved. Also, with the diagnostic improvement and the increased knowledge about the disease mechanism more disease sub-groups have evolved.

– In a broader perspective, autoimmune diseases such as type-1 diabetes may increase due to changes in life style factors.

From your standpoint, why are women at so much higher risk than men to suffer from autoimmune diseases?

– For RA and other rheumatic diseases such as Lupus, SLE, mainly women are affected. The reason for that is not fully known and understood. However, the role of female hormonal factors in the development of RA has been studied for many years and is thought to be of importance among other factors. Female hormones have an effect on the immune system.

What’s your personal belief about the causes of RA and autoimmune diseases in general?

– An interplay between genetic sensitivity and exposure to environmental risk factors such as life style habits.

Are there any other experimental treatment approaches that you find promising, like stem cell therapy or gene therapy for example?

– Promising results have emerged regarding stem cell therapy in systemic sclerosis, a rheumatic disease where limited treatments are available.

Could a new treatment and potential cure for RA be effective for other autoimmune disorders and, if so, why?

– Different autoimmune diseases may share similar disease mechanisms, therefore, yes, the same treatment could be effective in different diseases.

Several treatment methods are being tested. How far are we from curing RA?

– I am sorry to answer that I do not know. Since RA consist of different sub groups to find a cure may be more complicated. But I wish a cure for all rheumatic diseases and all other autoimmune diseases as well. More research is needed to understand the disease mechanism before a cure is found.

We’d like to thank Li Alemo Munters once again for her contribution to the article series. In the next two segments, we turn our attention to drug development within the autoimmune disease field. For part III, which will come out July 4, we keep the spotlight on RA and MS by talking to the CEOs of Lipum and Cyxone.

The content of BioStock’s news and analyses is independent but the work of BioStock is to a certain degree financed by life science companies. The above article concerns a company from which BioStock has received financing.