Lupus

Posted on Lupus

Neoself-antigens induce autoimmunity in lupus

Fig.

This study revealed that T cells can discriminate between self- and neoself-antigens and that neoself-reactive T cells are involved in causing autoimmune diseases. Hisashi Arase, Osaka University

Autoimmune diseases are widespread and notoriously difficult to treat. This is partly because why the immune system attacks its tissues in patients with these conditions remains poorly understood.

In a study recently published in Cell, researchers from Osaka University have revealed that the body’s proteins with unusual structures trigger immune cells to unleash a wave of inflammation that leads to autoimmunity.

Autoimmune diseases develop when the body’s immune system mistakenly attacks its tissues instead of fighting off foreign invaders like bacteria or viruses. However, it has long been a mystery why this happens, as the immune system has many checks and balances to ensure it only reacts to ‘non-self’ triggers.

“T cells have been thought to discriminate between small fragments of protein derived from self and non-self proteins presented on the major histocompatibility complex II (MHC-II), and ‘trained’ not to respond self-antigens” explains senior author of the study Hisashi Arase. “However, when the MHC-II is missing a crucial piece called the invariant chain (Ii), it can present larger, misfolded self-antigens, called herself-antigens, to T cells.”

Given that autoantibody to oneself-antigens are frequently found in patients with autoimmune diseases, the researchers explored T cell reactivity in patients with lupus and in mice, in which I was depleted from an adult. They also investigated the effect of Epstein–Barr virus (EBV) infection, a risk factor for lupus, on T cell reactivity to neoself-antigens.

“The results were striking,” says Shunsuke Mori, lead author. “Approximately 10% of clonally expanded T cell repertoire in lupus patients recognized neoself-antigens. Furthermore, induction of neoself-antigens induced lupus-like disease in mice, meaning that they mounted an immune response to the body’s tissues, thereby causing autoimmune disease.”

Furthermore, the researchers found that reactivation of EBV, which most people are infected with but are usually dormant, increases the presentation of oneself-antigens on MHC-II by downregulating the expression of Ii, triggering the activation of T cells directed against the body. This could explain why EBV reactivation is linked to the onset or exacerbation of lupus.

“Our findings demonstrate that T cells discriminate self- and neoself-antigens and do not recognize neoself-antigens as self-antigens, thus leading to the development of autoimmunity when neoself-antigens are presented on MHC-II,” says Arase.

This study substantially increases our understanding of the self-tolerance of T cells as well as the causes of autoimmune disease by identifying oneself-antigens as a distinct class of antigens that trigger an inappropriate immune response. This insight into why the body begins to attack itself could help develop new treatments for autoimmune disorders like lupus.

Posted on autoimmune conditions, Diabetes, Lupus

Women with premature ovarian insufficiency are at greater risk of autoimmune diseases

Women with premature ovarian insufficiency are at greater risk of severe autoimmune diseases

Dr Susanna Savukoski – Credit

Severe autoimmune conditions such as Type I diabetes, Addison’s disease, lupus and inflammatory bowel disease are between two to three times more common in women who have been diagnosed with premature ovarian insufficiency (POI) compared to the general population.

The research, published today (Thursday) in Human Reproduction, one of the world’s leading reproductive medicine journals, is the largest to investigate the link between autoimmune conditions and POI, has followed nearly 20,000 women for longer than any other study and is the only one to match women with POI with women of similar ages in the general population for comparison.

The researchers say their findings significantly strengthen the hypothesis that autoimmune processes play a “pivotal role” in the onset of POI.

POI occurs when ovaries no longer work properly and have stopped producing eggs in women younger than 40 years. Periods become irregular and then stop, and some women experience menopause symptoms.

Dr Susanna Savukoski, a gynaecology and obstetrics doctor at Oulu University Hospital and University of Oulu, Finland, led the study. She said: “Estimates of the prevalence of premature ovarian insufficiency of autoimmune origin have ranged from 4% to 50%. Our study has found that autoimmune diseases were two-to-three-fold more common in women diagnosed with POI at the time they were diagnosed, and the incidence of these diseases was two-to-three-fold higher during the first years after being diagnosed with POI, compared to a control group of similarly aged women from the general population. The incidence was higher than in the control group even more than a decade after being diagnosed with POI.”

Dr Savukoski and her colleagues analysed health data from Finland’s comprehensive registries. From the medicine reimbursement registry maintained by the Social Insurance Institution of Finland, they identified 3972 women who had been granted the right to full reimbursement for hormone replacement therapy (HRT) because of POI diagnosis under the age of 40 years between the years 1988 and 2017. Each woman with POI was matched with four women of similar ages, forming a control group of 15708 women. Both groups of women analysed data on severe autoimmune conditions – diseases diagnosed and treated in specialist health centres – between 1970 and 2017.

They found that among women who were diagnosed with POI, 223 women (5.6%) had been diagnosed with at least one autoimmune disorder before the date when reimbursement for HRT because of POI was granted, and 503 women (12.7%) were diagnosed with at least one autoimmune disorder after the date of HRT during the follow-up period.

Women were 2.6 times more likely to have an autoimmune disorder before a POI diagnosis when compared to the control group. Among women with POI, the risk of autoimmune conditions ranged from nearly double for over-active thyroid glands to almost 26 times for polyglandular autoimmune diseases – rare diseases of the hormone (or endocrine) system.

Women without existing autoimmune diseases at the time they were diagnosed with POI were nearly three times as likely to be diagnosed with an autoimmune disease in the following three years, with the risk decreasing but still significantly higher than in the control group during the follow-up period of at least 12 years. 

Dr Savukoski said: “These findings reflect the fact that the association between POI and severe autoimmune diseases is strong and that the women with POI have long-term risk for autoimmune conditions. As with POI, severe autoimmune diseases typically manifest with significant symptoms and can have very unfavourable effects on general health, functional ability and quality of life. Luckily, there are good medication options available for many of these conditions.

“It’s important to stress that most women with POI do not develop severe autoimmune conditions, and most women with severe autoimmune diseases do not develop POI. However, medical professionals should be aware of the increased risk, and patients should also be informed about it.

“It should be noted that the risk is not the same for all autoimmune conditions: the association between POI and some autoimmune conditions, such as polyglandular autoimmune syndrome, Addison’s disease and vasculitis, was very strong – a ten to 26-fold risk of having these diseases among women with POI preceding their POI diagnosis compared to the controls – while the risk of having rheumatoid arthritis or hyperthyroidism was about two-fold.

“As POI threatens fertility at a young age, this indicates that women with an increased risk of the condition should be encouraged to try to conceive when they are young. However, some autoimmune diseases can significantly increase the risk of pregnancy complications, especially if therapeutic control is not good enough, and this should be considered in discussions with patients. Unfortunately, so far, there are no treatments available to prevent the development of POI or autoimmune diseases.”

The biological mechanisms underlying the association between POI and autoimmune diseases are not fully understood, especially as the mechanisms may differ depending on the disease.

“Future research should focus on finding detailed mechanisms of how POI develops in different autoimmune conditions. That would enhance the development of preventive treatments against POI of autoimmune origin and other autoimmune conditions as well,” said Dr Savukoski. “We are investigating whether long-term use of HRT can prevent other conditions developing among women with POI.”

Posted on autoimmune conditions, Diet, Lupus, Sjögren’s Syndrome

Amazing Autoimmune Disease Breakthrough

Amazing Autoimmune Disease Breakthrough With This Diet! + 3 Important Foods! - YouTube

Is there a proven effective plant-based diet for autoimmune diseases like lupus and Sjogren’s syndrome? Are there specialists in plant-based medicine for autoimmune diseases? Can a plant-based diet help with autoimmune diseases like Hashimoto’s? Let’s find out.

Posted on Lupus

Impressive results against Lupus-no longer detectable after five injections

Blood samples

 © Charité | Arne Sattler

The team at Charité – Universitätsmedizin Berlin has observed a remarkable improvement in a female patient with severe systemic lupus erythematosus (SLE) after she was treated with the cancer medication teclistamab. Not long ago, the 23-year-old was confined to a wheelchair due to an autoimmune disease. Nearly six months after beginning the treatment, the patient is now completely symptom-free. It remains to be seen whether this improvement will last over the long term, but the case has been published in the New England Journal of Medicine*, marking a promising starting point for further studies.

Nothing was able to alleviate the symptoms of the 23-year-old patient from Berlin, not even cortisone and eight other therapies meant to control her overactive immune system. Her autoimmune disease, known as systemic lupus erythematosus, was very severe, affecting four of her organ systems. Her skin was blistered, her joints and kidneys were severely inflamed, and her red blood cell count, responsible for supplying oxygen to the body, was too low. “Due to the constant pain she was in, the patient could no longer walk, was confined to a wheelchair, and her kidneys were at risk of failing,” said Dr. Tobias Alexander, the physician treating her at the Department of Rheumatology and Clinical Immunology at Charité. As the Head of the Rheumatology Outpatient Clinic, he had “never seen a case this severe before.”

Because all of the established treatment options had been tried without success, the doctor suggested that the patient should try teclistamab, a bispecific antibody approved for treating multiple myeloma, a type of cancer affecting plasma cells in the bone marrow. In systemic lupus erythematosus, plasma cells produce autoantibodies that target the body’s own tissue. Alexander, a consultant rheumatologist, explained, “Teclistamab is highly effective at destroying the plasma cells and also works against their progenitor cells, which would otherwise rapidly produce new plasma cells. Therefore, we hypothesized that this cancer medication could eliminate the cause of the systemic lupus and provide long-term relief for the patient.”

Disease no longer detectable after five injections

The drug was prescribed “off-label” with the patient’s consent. The treatment took place at the Department of Hematology, Oncology, and Cancer Immunology on Charité Campus Benjamin Franklin and was successful. The patient received five injections of the cancer medication under the abdominal skin over a period of five weeks, which gradually relieved her symptoms. Within a few weeks, her kidney function and blood levels improved, and her skin and joint inflammation completely subsided. Since mid-April, no more autoantibodies have been detected in the 23-year-old’s blood, even though the treatment with immunosuppressants was stopped before the therapy began, and cortisone was no longer administered after six weeks.

“The patient is in full remission,” says Alexander. “This means she is no longer experiencing any symptoms of her disease, and we can no longer find any indication of systemic lupus, either clinically or in the laboratory. It’s too early to say she’s cured, but these powerful results are a rare exception in rheumatology. This is especially remarkable because none of the available treatment approaches had been sufficiently effective before. Most importantly, the success of the therapy signifies a significant improvement in the patient’s quality of life, which we are delighted about. However, we don’t know yet how long the positive effects will last. Since the results are provisional, the therapy is not yet suitable for wider use.”

Risks of the treatment

The drug’s significant impact on the immune system also comes with considerable risks. For instance, immune cells may release excessive amounts of inflammatory mediators. This type of cytokine release syndrome can be life-threatening, depending on its severity. At Charité, a patient undergoing teclistamab therapy experienced severe cytokine release syndrome, along with pneumonia and sinusitis, and a decrease in protective antibodies in her blood. Prof. Jan Krönke, who supervised the patient’s oncological treatment, stated that these side effects are more serious than those seen in traditional rheumatological therapies and sometimes necessitated inpatient care. However, they are consistent with the reactions that teclistamab induces in patients with multiple myeloma and were not unexpected.

The treatment team is closely monitoring the patient and her immune system’s activity to determine how long the positive effects of teclistamab last. If the effects prove to be long-term and are confirmed in further studies, Alexander believes that the cancer medication could have huge potential benefits in rheumatology. Teclistamab’s therapeutic results for the patient are currently comparable with the impact of CAR T-cell therapies. The difference is that the bispecific antibody is much easier to use and can be administered over a shorter period, which would be a considerable advantage. CAR T-cell therapies are new treatment methods that have been able to keep autoimmune diseases at bay for years in individual cases. However, they require chemotherapy and gene therapy, and are very time-consuming and resource-intensive.

Posted on autoimmune conditions, Cardiovascular disease, Lupus

“Tiny Killers: How Autoantibodies Attack the Heart in Lupus Patients”

Hand-drawn: Autoantibodies attacking the heart in lupus patients

Autoantibodies attacking the heart in lupus patients Credit Hand-drawn image by Xiaokan Zhang/Vunkak-Novakovic Lab

Cardiovascular disease is the primary cause of death in individuals with lupus, an autoimmune disease that occurs when the immune system attacks the body’s own tissues and organs, including the heart, blood, lungs, joints, brain, and skin. Lupus myocarditis, inflammation of the heart muscle, can be extremely serious as it can disrupt the normal rhythm and strength of the heartbeat. However, understanding the mechanisms of this complex disease is challenging and studying it is difficult.

A long-standing question about lupus is why some patients develop myocarditis while others remain unaffected, and why the clinical manifestations of affected patients range so dramatically, from no symptoms at all to severe heart failure. Lupus is characterized by a large number of autoantibodies, which are immune proteins that mistakenly target a person’s own tissues or organs, with different specificities for various molecules. These autoantibodies, similar to our genes, may explain why different individuals experience different symptoms.

Researchers have long suspected that certain autoantibody signatures may be the key to understanding the varied clinical presentations seen in lupus patients. Identifying the specific autoantibodies responsible for heart damage has been very difficult due to the lack of experimental models that accurately mimic the cardiac disease in lupus patients. The animal models currently used have limitations due to differences in cardiac physiology, and human cell cultures are unable to fully replicate the complexity and function of the human heart.

New study shows that autoantibodies can directly affect heart disease in lupus patient

The researchers created small cardiac tissues from healthy adult human stem cells, and then they matured the tissues using metabolic and electromechanical signals. Afterward, they exposed the tissues to the autoantibodies present in the blood of lupus patients who had myocarditis and those who did not. The team found that the way the patients’ autoantibodies attached to the heart tissue depended on the type and severity of their myocardial damage. Some patients with severe myocarditis had unique autoantibodies that mainly targeted dying cardiac cells, while those with weakened heart pump function had autoantibodies that mostly focused on the surface of live cells. Interestingly, the team also found that the autoantibodies binding to live cardiac cells could have powerful biological effects on the tissues without the presence of immune cells, potentially revealing new mechanisms that could lead to heart failure in lupus patients.

The study also identified four autoantibodies that may directly affect the heart muscle. These findings could assist in identifying lupus patients with the highest risk of developing heart disease, informing the development of new therapeutic strategies, and potentially extending to other autoimmune diseases.

“This study is the first to show that autoantibodies can directly cause injury to the heart in this complicated autoimmune disease,” said Gordana Vunjak-Novakovic, the leader of the team. She is the University Professor and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine at Columbia. “It’s astonishing that the miniature heart tissues we’ve created using human stem cells and ‘organs-on-chip’ technology can replicate organ-level functions in a way that is specific to each patient, particularly for such a complex disease. We are now in an era where we can examine the progression and treatment of diseases using seemingly simple yet highly controllable and predictive models of human organs. It feels like we are living in the future.”