Lupus is a chronic inflammatory disease that occurs when your body’s immune system attacks your own tissues and organs. Inflammation caused by lupus can affect many different body systems including your joints, skin, kidneys, blood cells, brain, heart and lungs. Lupus can be difficult to diagnose because its signs and symptoms often mimic those of other ailments.
From Visually.
Time of day affects severity of autoimmune disease
Insights into how the body clock and time of day influence immune responses are revealed today in a study published in leading international journal Nature Communications. Understanding the effect of the interplay between 24-hour day-night cycles and the immune system may help inform drug-targeting strategies to alleviate autoimmune disease.
Circadian rhythms or 24-hour rhythms are generated by the body clock, allowing us to anticipate and respond to the 24-hour cycle of our planet. Maintaining a good body clock is generally believed to lead to good health for humans, and disrupting the circadian rhythm (for example, working night shifts) has been associated with immune diseases such as multiple sclerosis; however, the underlying molecular links have been unclear.
In the new study, Professor Kingston Mills and Dr Caroline Sutton of Trinity College Dublin, and Dr Annie Curtis of RCSI (Royal College of Surgeons Ireland), and colleagues show that immune responses and regulation of autoimmunity are affected by the time of the day when the immune response is activated.
Using mice as a model organism, they show that a master circadian gene, BMAL1, is responsible for sensing and acting on time-of-the-day cues to suppress inflammation. Loss of BMAL1, or induction of autoimmunity at midday instead of midnight, causes more severe experimental autoimmune encephalomyelitis, which is essentially an analogue of multiple sclerosis in mice.
Professor of Experimental Immunology at Trinity, Kingston Mills, said: “In the year that the Nobel Prize in Medicine was awarded for discoveries on the molecular mechanisms controlling the circadian rhythm, our exciting findings suggest that our immune system is programmed to respond better to infection and insults encountered at different times in the 24-hour clock. This has significant implications for the treatment of immune-mediated diseases and suggests there may be important differences in time of day response to drugs used to treat autoimmune diseases such as multiple sclerosis.”
Although further investigations are needed to understand how to precisely modulate circadian rhythm or time-of-the-day cues for beneficial immunity, the findings in this article serve well to remind us the importance of ‘keeping the time’ when dealing with the immune system.
Research Lecturer in the Department of Molecular and Cellular Therapeutics at RCSI, Dr Annie Curtis, said: “Our study also shows how disruption of our body clocks, which is quite common now given our 24/7 lifestyle and erratic eating and sleeping patterns, may have an impact on autoimmune conditions.”
“We are really beginning to uncover exactly how important our body clocks are for health and wellbeing.”
Infection with Epstein-Barr virus (EBV), the cause of infectious mononucleosis, has been associated with subsequent development of systemic lupus erythematosus and other chronic autoimmune illnesses, but the mechanisms behind this association have been unclear. Now, a novel computational method shows that a viral protein found in EBV-infected human cells may activate genes associated with increased risk for autoimmunity. Scientists supported by the National Institute of Allergy and Infectious Diseases report their findings today in Nature Genetics.
“Many cases of autoimmune illness are difficult to treat and can result in debilitating symptoms. Studies like this are allowing us to untangle environmental and genetic factors that may cause the body’s immune system to attack its own tissues,” said NIAID Director Anthony S. Fauci, M.D. “A better understanding of the complex causes of autoimmunity promises to lead to better treatment and prevention options.”
EBV infection is nearly ubiquitous in the human population worldwide. Most people acquire EBV in early childhood, experience no symptoms or only a brief, mild cold-like illness, and remain infected throughout their lives while remaining asymptomatic. When infection first occurs in adolescence or young adulthood, EBV can lead to a syndrome of infectious mononucleosis characterized by prolonged fever, sore throat, swollen lymph nodes and fatigue. This syndrome, also known as “mono” or the “kissing disease,” generally resolves with rest and only rarely causes serious complications.
When EBV infects human immune cells, a protein produced by the virus–EBNA2–recruits human proteins called transcription factors to bind to regions of both the EBV genome and the cell’s own genome. Together, EBNA2 and the human transcription factors change the expression of neighboring viral genes.
In the current study, the researchers found that EBNA2 and its related transcription factors activate some of the human genes associated with the risk for lupus and several other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.
Previous studies suggested that EBV infection may result in autoimmune diseases, particularly lupus. In the current work, researchers led by John B. Harley, M.D., Ph.D., director of the Center for Autoimmune Genomics and Etiology (CAGE) at Cincinnati Children’s Hospital Medical Center, with his colleagues Matthew T. Weirauch, Ph.D., and Leah C. Kottyan, Ph.D., also of CAGE, wondered whether genetic analysis could further explain the relationship between EBV infection and lupus. Their team developed a new computational and biochemical technique known as the Regulatory Element Locus Intersection algorithm, or RELI. Sifting through and comparing a large collection of genetic and protein data from healthy individuals and those with autoimmune diseases, the team used RELI to identify regulatory regions in genes associated with the risk of developing lupus that also bound EBNA2 and its related transcription factors.
“We were surprised to see that nearly half of the locations on the human genome known to contribute to lupus risk were also binding sites for EBNA2,” said Dr. Harley. “These findings suggest that EBV infection in cells can actually drive the activation of these genes and contribute to an individual’s risk of developing the disease.”
In follow-up analyses, the investigators used RELI to probe regulatory genes associated with other autoimmune diseases and found that EBNA2 bound to genes associated with the risk for multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.
“Because EBV is most often encountered in early childhood, avoiding infection is practically impossible,” said Daniel Rotrosen, M.D., director of the Division of Allergy, Immunology and Transplantation at NIAID. “However, now that we understand how EBV infection may contribute to autoimmune diseases in some people, researchers may be able to develop therapies that interrupt or reverse this process.”
Researchers note that EBV infection is not the only factor that contributes to the development of the seven autoimmune conditions discussed in the paper. Many of the regulatory genes that contribute to lupus and other autoimmune disorders did not interact with EBNA2, and some individuals with activated regulatory genes associated with disease risk do not develop disease.
Autoimmune disease awareness
Living with an autoimmune disease can feel like an insider is attacking your body. An estimated 24 million people in the United States are affected by autoimmune diseases, a group of diseases in which the person’s immune system attacks part of the person’s own body.
Now, Purdue University researchers have developed a series of molecules that may provide more reliable relief with fewer side effects for people with any of several autoimmune diseases. The new molecules overcome difficulties with current drugs in targeting, for purposes of inhibiting, the appropriate form of Janus kinase, which has four forms affecting cell signaling and gene expression.
The new inhibitors may provide relief for people suffering from rheumatoid arthritis, psoriasis, myelofibrosis and other autoimmune diseases with a reduction in side effects compared with current therapies. The research appears in the November edition of the Journal of Medicinal Chemistry.
“Our new molecules fit within the emerging field of therapeutically useful Janus kinase inhibitors that have attracted a lot of attention and excitement within the medicinal chemistry community and the general field of medicine,” said Mark Cushman, a distinguished professor of medicinal chemistry in Purdue’s College of Pharmacy, who leads the research team. “Our compounds contribute a new structural chemotype that is expected to have unique pharmacological properties relative to the other known Janus kinase inhibitors.”
Cushman, a member of the Purdue University Center for Cancer Research, said the new molecules also show potential to allow for more treatment options for people with autoimmune diseases. Abnormalities of the immune system often lead to autoimmune diseases or cancer.
The work aligns with Purdue’s Giant Leaps celebration, celebrating the university’s global advancements in health as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.
Researchers filed a patent with the Purdue Office of Technology Commercialization and the technology is available for licensing.
##
This video is an overview of autoimmune disease. Autoimmune disease causes your immune system to attack healthy tissue and cells instead of harmful substances. Harmful substances contain antigens that allow the immune system to recognize these substances and destroy them. Sometimes these substances can confuse the immune system, as the immune system may not be able to distinguish between healthy tissue and antigens. This video was created by high-school students Hamza Khan (Hillfield Strathallan College), Kate Kim and Chris Chois (Notre Dame High School) in collaboration with the McMaster Demystifying Medicine Program and Khatija Anum.
