Tag: autoimmune disease

Categories : Immune SystemTags :

Immune ‘Brake’ Reveals Drug Targets for Cancer and Autoimmune Disease

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Killer T cells about to destroy a cancer cell. Credit: NIH

Researchers have discovered a genomic ‘brake’ in a subset of immune cells that could help advance immunotherapy for cancer and autoimmune disease. The findings, led by a team at the Peter MacCallum Cancer Centre in collaboration with researchers at the Garvan Institute and Kirby Institute, provide new insights into how the body’s immune defence mechanisms can go awry in these diseases and open a new class of potential drug targets that could activate immune cells in tumour tissue.

The research was published in the journal Immunity.

Discovering an immune brake

Specialised killer T cells are released during an infection, trained to recognise and destroy the threat. When unchecked, these cells can cause autoimmune diseases such as type 1 diabetes or rheumatoid arthritis if they mistakenly attack the body’s own healthy tissues.

The immune system employs a mechanism to prevent autoimmune attacks called ‘tolerance’ – a process that can be exploited by cancer cells to shield them from the body’s natural defences.

“Until now, it was not fully understood how tolerance works at a molecular level. We used advanced sequencing techniques to identify a unique genomic signature in ‘tolerant’ T cells that differentiated them from killer T cells that were activated in response to viral infection,” says Dr Timothy Peters, co-first author from Garvan.

“These precise genome locations have never before been observed and allowed us to track precisely how killer T cells progress through the tolerance pathway, and how specific gene networks enable tolerance to be abused.”

Breakthrough for cancer and autoimmune disease

Dr Ian Parish, who led the research at the Peter MacCallum Cancer Centre said this breakthrough helps to understand why cancer treatments fail and opens the door to developing new treatments in the future.

“Current cancer immunotherapy treatments target the exhaustion phase of the immune response,” he said. “Our research suggests that a second, earlier ‘off-switch’ called tolerance may explain how many cancers resist current immunotherapies by blocking anti-cancer immunity from getting off the ground. We’re excited as these findings can be exploited for new treatments. Our next step is to understand if we can disrupt tolerance and engage the immune system to restart and attack those cancers resistant to treatment.”

Professor Chris Goodnow, Head of the Immunogenomics Lab at Garvan, says this new understanding of T cell tolerance opens up opportunities to develop new drugs that could selectively alter this pathway.

“The discovery of these gene locations provides us with a roadmap for developing future drugs, which could block the tolerance mechanisms to boost cancer-killing ability for immunotherapies. Conversely, for autoimmune diseases, enhancing tolerance could prevent harmful autoimmune attack,” he says.

In next steps, the researchers will focus on understanding how to disrupt the tolerance mechanism and engage the immune system to restart.

“These findings have revealed around 100 new potential targets for drugs to target the tolerance mechanism in T cells, which have until now been largely developed by trial and error,” says Professor Goodnow. “This could lead to a whole new class of treatments for autoimmunity and cancer.”

Professor Chris Goodnow is The Bill and Patricia Ritchie Foundation Chair and Director of the Cellular Genomics Futures Institute, UNSW Sydney. Dr Tim Peters is a Conjoint Lecturer at St Vincent’s Clinical School, UNSW Medicine and Health.

Source: Garvan Institute of Medical Research

Categories : Diseases, Syndromes and ConditionsTags :

Kidney Damage in Lupus Comes from an Unexpected Source

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When the NKp46 receptor of the ILCs is blocked (right), the lupus nephritis recedes. Blue: cell nuclei.
Credit: Charité | Frauke Schreiber

A Berlin-led research team has uncovered critical regulators of severe kidney damage in patients with the autoimmune disorder lupus. A small, specialised population of immune cells – called innate lymphoid cells (ILCs) – trigger an avalanche of effects that cause harmful kidney inflammation, also known as lupus nephritis.

The research, published this week in Nature, upends conventional wisdom that autoantibodies are primarily responsible for lupus nephritis.

“While autoantibodies are required for tissue damage, they are by themselves not sufficient. Our work reveals that ILCs are required to amplify the organ damage,” says Dr Masatoshi Kanda, a senior paper author who was a Humboldt Fellow at Max Delbrück Center and is now at the Department of Rheumatology and Clinical Immunology, Sapporo Medical University in Japan.

Lupus, or systemic lupus erythematosus, is most often diagnosed between the ages of 15 and 45. Symptoms can range from mild to severe. But what causes kidney damage in some patients – some to the point of requiring dialysis – has been unclear.

“The role of ILCs in lupus or lupus nephritis was entirely unknown,” says Professor Antigoni Triantafyllopoulou, a senior paper author at the German Rheumatology Research Center (DRFZ), an institute of the Leibniz Association, and at the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin. “We have now identified most of the circuit controlled by ILCs by looking at the whole kidney at single-cell resolution.”

Unusual immune cells

ILCs are a small group of immune cells that – unlike most other immune cells that circulate throughout the body – live in a specific tissue or organ.

“They are in the tissue all the time, from the time of embryonic development, which makes them very different from other immune cells,” says Professor Andreas Diefenbach, a senior paper author and director of the Institute of Microbiology, Infectious Diseases and Immunology at Charité – Universitätsmedizin Berlin.

Diefenbach’s lab was among those that discovered ILCs in the mid-2000s. Most of his research is focused on ILCs in the gut and how they modify tissue function. In this study, Triantafyllopoulou and Kanda teamed up with his group and Dr Mir-Farzin Mashreghi at the DRFZ to find out whether ILCs were present in the kidney and what role they might play in lupus nephritis.

The whole single-cell picture

To unravel this mystery, the team turned to single-cell RNA sequencing, which identifies genes that are active, or “switched on,” in individual cells and helps researchers understand the cell’s identity and function.

Kanda, a rheumatologist who was studying bioinformatics in Professor Norbert Hübner’s lab at the Max Delbrück Center at the time, developed a specialized protocol for single-cell RNA sequencing of mouse and human kidneys. “Masatoshi’s protocol was very good at pulling out and preserving multiple types of kidney cells, which gave us a much more complete overview of how lupus affects the whole kidney,” explains Triantafyllopoulou. The team sequenced nearly 100 000 individual kidney and immune cells of various types and functions.

The key receptor

Through experiments in mice, the team learned that a subgroup of ILCs with a receptor called NKp46 must be present and activated to cause lupus nephritis. When NKp46 is activated, this subgroup of cells ramped up production of a protein called GM-CSF, which stimulates invading macrophages to multiply. In the kidney, a flood of incoming macrophages caused severe tissue damage and fibrosis.

“These ILCs are really amplifiers in this system,” Diefenbach says. “They are small in population, but they seem to fertilise the whole process.”

When the team blocked NKp46 with antibodies or the receptor was genetically removed, kidney tissue damage was minimal. They also blocked GM-CSF with similar anti-inflammatory effects.

“Critically, autoantibody levels did not change when NKp46 was inhibited, but kidney tissue damage was reduced, which shows autoantibodies are not directly responsible for kidney inflammation,” Triantafyllopoulou explains.

The team also compared the results to sequencing data from tissue taken from human patients with lupus and found ILCs present, though more work is required to fully understand how to target ILCs in human kidneys. Nevertheless, the insights gained through these detailed studies point to new antibody therapies for patients with severe forms of lupus. The hope is to prevent the need for kidney dialysis in these patients.

Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Categories : Diseases, Syndromes and Conditions Environmental EffectsTags :

Does Air Pollution Affect Lupus Risk?

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Photo by Kouji Tsuru on Pexels

New research published in Arthritis & Rheumatology indicates that chronic exposure to air pollutants may increase the risk of developing lupus, an autoimmune disease that affects multiple organs.

For the study, investigators analysed data on 459 815 participants from the UK Biobank. A total of 399 lupus cases were identified during a median follow-up of 11.77 years. Air pollutant exposure was linked with a greater likelihood of developing lupus. Individuals with a high genetic risk and high air pollution exposure had the highest risk of developing lupus compared with those with low genetic risk and low air pollution exposure.

“Our study provides crucial insights into the air pollution contributing to autoimmune diseases. The findings can inform the development of stricter air quality regulations to mitigate exposure to harmful pollutants, thereby reducing the risk of lupus,” said co–corresponding author Yaohua Tian, PhD, of the Huazhong University of Science and Technology, in China.

Source: Wiley

Categories : Diseases, Syndromes and Conditions Obstetrics & GynaecologyTags :

Clear Link between Autoimmune Disease and Perinatal Depression

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This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Women with autoimmune disease are more likely to suffer from depression during pregnancy and after childbirth; conversely, women with a history of perinatal depression are at higher risk of developing autoimmune disease, according to a new study from Karolinska Institutet which is published in the journal Molecular Psychiatry.

Some of the most common autoimmune diseases are gluten intolerance (coeliac disease), autoimmune thyroiditis, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis (MS). 

In the present study, researchers used data from the Swedish Medical Birth Register and identified all women who had given birth in Sweden between 2001 and 2013. Out of the resulting group of approximately 815 000 women and 1.3 million pregnancies, just over 55 000 women had been diagnosed with depression during their pregnancy or within a year after delivery. 

The researchers then compared the incidence of 41 autoimmune diseases in women with and without perinatal depression, controlling for familial factors such as genes and childhood environment by also including the affected women’s sisters.

Strongest association for MS

The results reveal a bidirectional association between perinatal depression and autoimmune thyroiditis, psoriasis, MS, ulcerative colitis, and coeliac disease. Overall, women with autoimmune disease were 30 per cent more likely to suffer perinatal depression. Conversely, women with perinatal depression were 30 per cent more likely to develop a subsequent autoimmune disease.

The association was strongest for the neurological disease MS, for which the risk was double in both directions. It was also strongest in women who had not had a previous psychiatric diagnosis.

“Our study suggests that there’s an immunological mechanism behind perinatal depression and that autoimmune diseases should be seen as a risk factor for this kind of depression,” says the study’s first author Emma Bränn, researcher at the Institute of Environmental Medicine at Karolinska Institutet.

Can have serious consequences

The researchers will now continue to examine the long-term effects of depression during pregnancy and in the first year following childbirth.

“Depression during this sensitive period can have serious consequences for both the mother and the baby,” says Dr Bränn. “We hope that our results will help decision-makers to steer funding towards maternal healthcare so that more women can get help and support in time.”

Since this was an observational study, no conclusions on causality can be drawn.

The study was financed by Karolinska Institutet, Forte (the Swedish Research Council for Health, Working Life and Welfare), the Swedish Research Councill and the Icelandic Research Fund. The researchers report no conflicts of interest.

Source: Karolinska Institutet

Categories : Dentistry Immune SystemTags :

Clues from Autoimmune Disorder on Disrupted Tooth Enamel Development

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Photo by Caroline Lm on Unsplash

In one of every 10 people, and in one third of children with celiac disease, the enamel coating of the teeth appears defective, failing to protect the teeth properly. As a result, teeth become more sensitive to heat, cold and sour food, and they may decay faster. In most cases, the cause of the faulty enamel production is unknown.

Now, a study by Prof Jakub Abramson and his team at the Weizmann Institute of Science, published recently in Nature, may shed light on this problem by revealing a new children’s autoimmune disorder that hinders proper tooth enamel development. The disorder is common in people with a rare genetic syndrome and in children with celiac disease. These findings could help develop strategies for early detection and prevention of the disorder.

Tooth enamel is made up primarily of mineral crystals that are gradually deposited on protein scaffolds during enamel development. Once the crystals are in place, the protein scaffold is dismantled, leaving behind a thin, exceptionally hard layer of enamel. A strange phenomenon was identified in people with a rare genetic disorder known as APS-1: although the enamel layer of their milk teeth forms perfectly normally, something causes its faulty development in their permanent teeth. Since people with APS-1 suffer from a variety of autoimmune diseases, Abramson and his team hypothesised that the observed enamel defects may also be of an autoimmune nature

In autoimmune disease, to prevent T cells from triggering the immune system to attack body tissues, T cells developing in the thymus gland must be educated’ to discriminate between the body’s own proteins and those of foreign origin. To this end, T cells are presented with short segments of self-proteins that make up various tissues and organs in the body. When a ‘poorly educated’ T cell erroneously identifies a self-protein in the thymus as a target for attack, that T cell is labelled as dangerous and destroyed, so that it could not cause any damage after being released from the thymus.

This critical education step is impaired in APS-1 patients as a result of a mutation in a gene known as the autoimmune regulator (Aire). This gene is essential for the T cell education process: It produces a protein that is responsible for the collection of self-proteins presented to the T cells in the thymus. In their new study, scientists from Abramson’s lab in Weizmann’s Immunology and Regenerative Biology Department, led by research student Yael Gruper, sought to work out how mutations in the Aire gene lead to deficient tooth enamel production. The researchers discovered that, in the absence of Aire, proteins that play a key role in the development of enamel are not presented to the T cells in the thymus gland. As a result, T cells that are liable to identify these proteins as targets are released from the thymus, and they encourage the production of antibodies to the enamel proteins. But why do these autoantibodies damage permanent teeth and not baby teeth?

The answer to this question lies in the fact that milk teeth develop in the embryonic stage, when the immune system is not yet fully formed and cannot create autoantibodies. In contrast, the development of enamel on permanent teeth starts at birth and continues until around the age of six, when the immune system is sufficiently mature to thwart enamel development. Furthermore, the researchers found a correlation between high levels of antibodies to enamel proteins and the severity of the harm to enamel development in children with APS-1. This strengthens the assumption that the presence of enamel-specific autoantibodies in childhood can potentially lead to dental problems.

When the researchers looked into deficiencies in enamel development in people with other autoimmune diseases, they found a very similar phenomenon in children with celiac disease, a relatively common autoimmune disorder that affects around 1% of people in the West. When people with this disease are exposed to gluten, their immune system attacks and destroys the cellular layer lining the small intestine, leading to attacks on other self-proteins in the intestine.

In an attempt to understand how celiac disease, known to cause intestinal damage, may also cause damage to tooth enamel, the researchers first examined whether people with this disease have autoantibodies against enamel. They found that a large proportion of celiac patients have these autoantibodies, just as do people with APS-1. But the ‘education’ in the thymus gland of these patients seems normal, so why do they develop these antibodies? The researchers hypothesised that some proteins are found in both the intestine and the dental tissue and that these proteins play an important role in the development of tooth enamel. In this case, the antibodies that identify proteins in the intestine might move through the bloodstream to the dental tissue, where they could start to disrupt the enamel production process.

Since many celiac patients had previously been found to develop sensitivity to cow’s milk, the researchers decided to focus on the k-casein protein, a major component of dairy products. Strikingly, they found that the human equivalent of k-casein is one of the main components of the scaffold necessary for enamel formation. This led them to hypothesise that antibodies produced in the intestines of celiac patients in response to certain food antigens, such k-casein, may subsequently cause collateral damage to the development of enamel in the teeth, similarly to the way in which antibodies against gluten can eventually trigger autoimmunity against the intestine.

Indeed, they discovered that most of the children diagnosed with celiac had high levels of antibodies against k-casein from cows’ milk, which in many cases can also react against k-casein’s human equivalent expressed in the enamel matrix. This means that in theory, the same antibodies that are produced in the intestine against the milk protein could act against the human k-casein in the teeth.

These findings could have implications for the food industry. “Similarly to the lessons learned from gluten, we can assume that the consumption of large quantities of dairy products could lead to the production of antibodies against k-casein,” Abramson explains. “This protein increases the amount of cheese that can be produced from milk, so the dairy industry deliberately raises its concentration in cow’s milk. Our study, however, found that the milk k-casein is a potent immunogen, which may potentially trigger an immune response that can harm the body itself.”

Tooth enamel flaws are common, not just among people with celiac disease or APS-1. “Many people suffer from impaired tooth enamel development for unknown reasons,” Abramson says. “It is possible that the new disorder we discovered, along with the possibility of diagnosing it in a blood or saliva test, will give their condition a name. Most important, early diagnosis in children may enable preventive treatment in the future.”

Source: Weizmann Institute of Science

Categories : Immune System Neurodegenerative DiseasesTags :

Scientists Strengthen Evidence Linking Autoimmunity and Schizophrenia

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Links have been reported between schizophrenia and autoimmunity. In a study published in Brain Behavior and Immunity, Japanese researchers identified autoantibodies that target a ‘synaptic adhesion protein’, neurexin 1α, in a subset of patients with schizophrenia. When injected into mice, the autoantibodies caused many schizophrenia-related changes.

What is a synaptic protein, and why might it be linked to schizophrenia? Synaptic adhesion proteins are specialised proteins that bind to create physical connections between brain cells. These connections, called synapses, allow the cells to communicate by passing molecules back and forth. Both synapses and autoimmunity are known to be associated with schizophrenia, so the research team from Tokyo Medical and Dental University (TMDU) decided to investigate autoantibodies that target synaptic proteins in patients with schizophrenia.

“In around 2% of our patient population, we identified autoantibodies against the synaptic protein neurexin 1α, which is expressed by one cell in the synapse and binds to proteins known as neuroligins on the other cell in the synapse,” says lead author of the study Hiroki Shiwaku. “Once we had identified these autoantibodies, we wanted to see if they were able to cause schizophrenia-related changes.”

To do this, the researchers isolated autoantibodies from some of the patients with schizophrenia and injected them into the cerebrospinal fluid of mice, so that the autoantibodies would travel into the brain. In these mice, the autoantibodies blocked neurexin 1α and neuroligin binding and altered some related synaptic properties. The administration of these autoantibodies also resulted in fewer synapses in the brains of mice and schizophrenia-related behaviours, such as reduced social behaviour toward unfamiliar mice and reduced cognitive function.

“Together, our results strongly suggest that autoantibodies against neurexin 1α can cause schizophrenia-related changes, at least in mice,” explains Hiroki Shiwaku. “These autoantibodies may therefore represent a therapeutic target for a subset of patients with schizophrenia.”

Schizophrenia has a wide variety of both symptoms and treatment responses, and many patients have symptoms that are resistant to currently available treatment options. Therefore, the identification of possible disease-causing autoantibodies is important for improving symptom control in patients with schizophrenia. It is hoped that the results of this investigation will allow patients with autoantibodies that target neurexin 1α – all of whom were resistant to antipsychotic treatment in the present study — to better control their symptoms in the future.

Source: Tokyo Medical and Dental University

Categories : Diseases, Syndromes and Conditions Immune SystemTags :

Autoimmune Disorders Now Affect Roughly One in Ten Individuals

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A population-based study of 22 million people in the UK estimates that around one in ten individuals in the UK now live with an autoimmune disorder. The findings, published in The Lancet, also highlight important socioeconomic, seasonal and regional differences for several autoimmune disorders, providing new clues as to what factors may be involved in these conditions.

There are more than 80 known autoimmune diseases, including conditions like rheumatoid arthritis, type 1 diabetes and multiple sclerosis, some of which have been increasing in the last few decades.

This has raised the question whether overall incidence of autoimmune disorders is on the rise and what factors are involved, such as environmental factors or behavioural changes in society. The exact causes of autoimmune diseases remain largely unknown, including how much can be attributed to a genetic predisposition to disease and how much is down to exposure to environmental factors.

The study used anonymised electronic health data from 22 million individuals in the UK to investigate 19 of the most common autoimmune diseases. The authors examined whether incidence of autoimmune diseases is rising over time, who is most affected by these conditions and how different autoimmune diseases may co-exist with each other.

They found that the 19 autoimmune diseases studied affect around 10% of the population. This is higher than previous estimates, which ranged from 3–9% and often relied on smaller sample sizes and included fewer autoimmune conditions. The analysis also highlighted a higher incidence in women (13%) than men (7%).

The research discovered evidence of socioeconomic, seasonal and regional disparities for several autoimmune disorders, suggesting that these conditions are unlikely to be caused by genetic differences alone. This observation may point to the involvement of potentially modifiable risk factors such as smoking, obesity or stress. It was also found that in some cases a person with one autoimmune disease is more likely to develop a second, compared to someone without an autoimmune disease.

Dr Nathalie Conrad at the University of Oxford said: “We observed that some autoimmune diseases tended to co-occur with one another more commonly than would be expected by chance or increased surveillance alone. This could mean that some autoimmune diseases share common risk factors, such as genetic predispositions or environmental triggers. This was particularly visible among rheumatic diseases and among endocrine diseases. But this phenomenon was not generalised across all autoimmune diseases. Multiple sclerosis, for example, stood out as having low rates of co-occurrence with other autoimmune diseases, suggesting a distinct pathophysiology.”

These findings reveal novel patterns that will inform the design of further research into the possible common causes of different autoimmune diseases.

Professor Geraldine Cambridge at UCL Medicine said: “Our study highlights the considerable burden that autoimmune diseases place upon individuals and the wider population. Disentangling the commonalities and differences within this large and varied set of conditions is a complex task. There is a crucial need, therefore, to increase research efforts aimed at understanding the underlying causes of these conditions, which will support the development of targeted interventions to reduce the contribution of environmental and social risk factors.”

Source: University College London

Categories : COVID Diseases, Syndromes and ConditionsTags :

Prior COVID Infection Linked to New Autoimmune Conditions

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In a new entry to the growing list of lasting complications from COVID infection, a large German cohort study of over 600 000 COVID patients indicates that new autoimmune conditions may result from previous COVID infection. The findings, which are awaiting peer review on the MedRxiv preprint server, show that the odds of new autoimmune conditions appear to increase in line with the severity of COVID infection.

After the acute phase of infection, some people may develop long-lasting symptoms, known as post-COVID, which are consistent with COVID infection and last more than 12 weeks. Most studies to date have focused on symptoms that partly wane over time. Many studies examined a small selective sample of patients, and only a few studies included a control group or information on chronic health conditions, such as SARS-CoV-2 infection.

Compared to post-COVID emergence of cardiovascular and other diseases, autoimmune diseases are less discussed in the literature, although autoantibodies could be found in patients after SARS-CoV-2 infection. So far there is limited evidence on newly manifested autoimmune diseases after an infection based on several case reports and one recent cohort study using UK health record data. In addition, COVID itself has some similarities with systemic autoimmune rheumatic diseases, which could make diagnosis difficult.

The researchers selected a cohort from German routine health care data, identifying individuals with polymerase chain reaction (PCR)-confirmed COVID through December 31, 2020. Patients were matched 1:3 to control patients without COVID. Both groups were followed up until June 30, 2021. We used the four quarters preceding the index date until the end of follow-up to analyse the onset of autoimmune diseases during the post-acute period. The researchers calculated the incidence rates (IR) per 1000 person-years for each outcome and patient group, and estimated incidence rate ratios (IRRs) of developing an autoimmune disease conditional on a preceding COVID.

In total, 641 704 patients with COVID were included. When comparing the incidence rates in the COVID and matched control groups, the researchers found a 42.63% higher likelihood of acquiring autoimmunity for patients who had suffered from COVID. This estimate was similar for common autoimmune diseases, such as Hashimoto thyroiditis, rheumatoid arthritis, or Sjögren syndrome. The highest IRR was observed for autoimmune disease of the vasculitis group. Patients with a more severe course of COVID were at a greater risk for incident autoimmune diseases. These risk increases were as follows:

  • 41% higher risk of Grave’s disease
  • 42–45% higher risk of rheumatoid arthritis
  • 25% higher risk of type 1 diabetes
  • 27-29% higher risk of Crohn’s disease

The researchers concluded that SARS-CoV-2 infection is associated with an increased risk of developing new-onset autoimmune diseases after the acute phase of infection.

Categories : Mental Health Metabolic DisordersTags :

Genes and Environment Bridge Depression and Endocrine-metabolic Disorders

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While endocrine-metabolic disorders and depression are known to co-occur, genetic and environmental factors are known to underlie both. In a study examining the link, published in the American Journal of Psychiatry, analysis revealed the balance of genetic and environmental influences underlying the co-occurrence of depression for a range of endocrine-metabolic disorders.

It is known that there is elevated co-occurrence between endocrine-metabolic disorders and depression, but the relationship between them is still not well understood.

Familial aggregation

The authors identified 2.2 million individuals born in Sweden between 1973 and 1996, as well as their full and half siblings, and followed them up to age 40. A number of medical conditions were studied; depression and various endocrine-metabolic disorders, including three autoimmune diseases (autoimmune hypothyroidism, Graves’ disease, and type 1 diabetes) and three non-autoimmune disorders (type 2 diabetes, obesity, and polycystic ovary syndrome).

Individuals with endocrine-metabolic disorders had 1.4 to 3.5 times the risk of depression compared to people without these diagnoses. Full and half siblings of these individuals also showed some elevated risk for depression, suggesting that genetic and/or environmental risk factors shared between family members play a role in the co-occurrence of these mental and physical disorders.

Genetic and environmental contributions

By comparing pairs of full sibling (who share about half of their genes) to pairs of half siblings (who share about a quarter of their genes), it was possible to calculate the relative contribution of genetic and environmental factors to the co-occurrence of depression and various endocrine-metabolic disorders. 

The results were a mix of these possibilities; the overlap between depression and non-autoimmune conditions was mainly explained by shared genetic influences, while environmental factors were predominantly involved in the association between depression and autoimmune disorders, particularly type 1 diabetes.

This indicates that the link between depression and different endocrine-metabolic disorders may be driven by different mechanisms. For example, shared biological mechanisms, such as immuno-inflammatory and metabolic dysregulations, may underlie the co-occurrence of depression and type 2 diabetes, obesity, and polycystic ovarian syndrome. In contrast, the absence of shared genetics in the association between type 1 diabetes and depression may reflect the existence of environmental factors influencing the risk of both conditions and/or a direct link between these conditions through mediating factors – eg, biological and psychosocial mechanisms connected to type 1 diabetes, including inflammation, cerebral damage, as well as stress of this lifelong condition that is often diagnosed early in life and that requires a complex management regime for both patients and their families.

“Our results underscore that clinicians should be aware of increased risks of depression in individuals with endocrine-metabolic disorders, and vice versa, and be vigilant for shared symptoms. This study also provides a useful foundation for future research aimed at identifying and targeting the biological mechanisms and modifiable risk factors underlying the co-presentation of endocrine-metabolic disorders and depression”, said Marica Leone, first author for the study.

Source: Karolinska Institutet

Categories : Cardiovascular Disease Diseases, Syndromes and ConditionsTags :

Array of Autoimmune Disorders Linked to Cardiovascular Disease

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Source: Wikimedia Commons CC0

A new epidemiological study published in The Lancet shows that patients with autoimmune disease have a substantially higher risk (between 1.4 and 3.6 times depending on which autoimmune condition) of developing cardiovascular disease (CVD) than people without an autoimmune disorder. This excess risk is comparable to that of type 2 diabetes, a well-known risk factor for cardiovascular disease.

Although earlier research has suggested associations between various different autoimmune disorders and a higher risk of cardiovascular disease, these studies were often too small and limited to selected autoimmune or selected cardiovascular conditions to draw conclusive evidence on the necessity of CVD prevention among patients with autoimmune disease.

At the annual congress of the European Society of Cardiology, researchers presented the outcome of a thorough epidemiological investigation into possible links between 19 of the most common autoimmune disorders and CVD. The research shows for the first time that cardiovascular risks affect autoimmune disease as a group of disorders, rather than selected disorders individually.

The whole cardiovascular disease spectrum

In the study, the authors show that the group of 19 autoimmune disorders they have studied accounts for about 6% of cardiovascular events. Importantly, excess cardiovascular risk was visible across the whole cardiovascular disease spectrum, beyond classical coronary heart disease, including infection-related heart disorders, heart inflammation, as well as thromboembolic and degenerative heart disorders, suggesting the implications of autoimmunity on cardiovascular health are likely to be much broader than originally thought. Furthermore, the excess risk was not explained by traditional cardiovascular risk factors such as age, sex or smoking. Another noteworthy finding: the excess risk is particularly high among patients with autoimmune disorders under 55 years and suggests that autoimmune disease is particularly important in causing premature cardiovascular disease, with the potential to result in a disproportionate loss of life years and disability.

The study was based on UK electronic health with data from about one-fifth of the current UK population. The researchers assembled a cohort of patients newly diagnosed with any of the nineteen autoimmune disorders. They then looked at the incidence of twelve cardiovascular outcomes – an unprecedented granularity that was made possible by the very large size of the dataset – in the following years, and they compared it to a matched control group. The risk of developing CVD for patients with one or more autoimmune disorders was on average 1.56 times higher than in those without autoimmune disease. The excess risk also rose with the number of different autoimmune disorders in individual patients. Among the disorders with the highest excess risk were systemic sclerosis, Addison’s disease, lupus and type I diabetes.

Need for targeted prevention measures

The results show that action is needed, said Nathalie Conrad, lead author of the study. “We see that the excess risk is comparable to that of type 2 diabetes. But although we have specific measures targeted at diabetes patients to lower their risk of developing cardiovascular disease (in terms of prevention and follow-up), we don’t have any similar measures for patients with autoimmune disorders.” Conrad also noted that the European Society of Cardiology guidelines on the prevention of cardiovascular diseases, do not yet mention autoimmunity as a cardiovascular risk factor, only mentioning specific disorders such as lupus, nor do they list any specific prevention measures for patients with autoimmune disease.

Conrad hopes the study will raise awareness among patients with autoimmune disease and clinicians involved in the care of these patients, which will include many different specialties such as cardiologists, rheumatologists, or general practitioners. ‘We need to develop targeted prevention measures for these patients. And we need to do further research that helps us understand why patients with an autoimmune disorder develop more cardiovascular diseases than others, and how we can prevent this from happening.’

The underlying mechanisms are still poorly understood. Conrad said: “The general hypothesis is that chronic and systemic inflammation, which is a common denominator in autoimmune disorders, can trigger all sorts of cardiovascular disease. Effects of autoimmune disease on connective tissues, small vessels, and cardiomyocytes, and possibly some of the treatments commonly used to treat autoimmunity are also likely to contribute to patients’ cardiovascular risk. This really needs to be investigated thoroughly.”

Source: KU Leuven