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Lupus: 3 Things to Know Mark L. Fuerst Dec 3, 2018 Lupus Three new studies in systemic lupus erythematosus (SLE) reveal that a gut bacterium may be linked to autoimmune diseases, including SLE; pregnancy complications in women with lupus have decreased over the past 2 decades; and physical or emotional abuse in childhood raises the risk of lupus.1-3Scroll through the slides for the latest findings and their clinical implications. http://www.rheumatologynetwork.com/lupus/lupus-3-things-know
Multiple sclerosis study reveals possible trigger Israeli scientists discover an abnormality in neurons’ protective membrane may enable the immune system to launch a mistaken attack. By ISRAEL21c Staff June 20, 2017, 9:00 am Multiple sclerosis, one of the most devastating neurodegenerative diseases, affects some 2.5 million people worldwide and has no known cure. Researchers have long speculated that MS is triggered by the body’s own immune system unleashing an uncontrolled attack on myelin sheaths that protect nerve cells (neurons). A study published by Israeli scientists in the Journal of the American Chemical Society (JACS) pinpoints a structural instability in the myelin membranes, the “insulating tape” surrounding neurons. This vulnerability seems to be what gives the immune system access to otherwise protected regions. “We found that small modifications in the myelin sheaths create structural instabilities that may help the immune system to enter and attack neurons,” said principal investigator Prof. Roy Beck of Tel Aviv University’s School of Physics and Astronomy and Sagol School of Neurosciences. “Current therapeutic approaches have focused on the autoimmune response without identifying a clear mechanism. Our research suggests a new avenue for multiple sclerosis therapies and diagnostics,” Beck said. Breaking down the insulation Axons, which carry electrical impulses in neurons, are surrounded by protective myelin sheaths. In MS, an autoimmune “error” mistakenly identifies these sheaths as hostile foreign entities and breaks them down. The research, conducted by Rona Shaharabani, a doctoral student in Prof. Beck’s lab, pinpoints the precise alterations to the myelin sheaths that result in structural instabilities, creating “easy access” for autoimmune attacks. “After years of research, we were amazed to discover that a possible trigger for the outbreak of the disease could be found in the membrane’s physical structure,” said Beck. Cylindrical instead of flat He explained that the lipid-and-protein building blocks of the myelin sheaths give the membrane a shape that is critical to their functioning. “If the basic building blocks are straight, the membrane will be flat, which is the preferred structure for a neuron’s ‘insulating tape,’” said Beck. “However, if they exhibit a more cone-like shape, the membrane will tend to form closed round cylinders. These produce spontaneous holes in the surface of the sheath, rendering it vulnerable to attack.” For the purpose of the research, the scientists harnessed X-ray light to examine hundreds of membrane model systems that mimicked those of healthy and diseased animal models. In collaboration with Prof. Ruth Arnon of the Weizmann Institute of Science in Rehovot, co-developer of the leading MS drug Copaxone, and Prof. Yeshayahu Talmon of the Technion-Israel Institute of Technology in Haifa, the team also used electron microscopy to determine the different nanoscopic structures of both natural myelin sheaths and model system membranes. “The next step is to find a way to reverse the disease progression and find new techniques for early detection,” said Beck. MS is "lupus of the myelin sheath." In SLE, the autommune system causes the body to attack itself via inflammation. In SLE, every body system, not just the myelin sheath, can be attacked, including body organs.
Overactive Immune System in Lupus Linked to Specific Triggers The little-understood antibody immunoglobulin E (IgE) plays a previously unknown role in systemic lupus erythematosus, new research finds. IgE is known to protect against parasitic worms and can also trigger intense allergic reactions. Now, a new study in Nature Immunology reveals a link between the antibody and the release of interferon-a, which in turn causes tissue damage in lupus. "This research has led to a groundbreaking discovery that IgE leads a double life as a trigger of allergy symptoms and a self-destructive agent in SLE. These findings could have tremendous implications for the lupus community," study senior author Miguel Sanjuan, a senior scientist at MedImmune, said in a statement. "In addition to the potential of targeting IgE in lupus patients, these findings show the scientific research community that there is a new realm of previously unknown activity of IgE that unleashes its pathogenic potential beyond orchestrating allergy symptoms, which may also be responsible for other autoimmune conditions." In a systemic lupus erythematosus cohort of 180 patients, 54.4 percent had double-strand DNA-specific IgE, compared to zero percent in healthy controls or patients with atopic dermatitis. Of patients with lupus nephritis, 70 percent exhibited dsDNA-specific IgE, a number that rose to 82 percent in those with the most-severe lupus nephritis class IV. ©Aysezgicmeli/Shutterstock.com Circulating dsDNA-specific IgE levels were correlated with the marker of disease activity C3, and patients with greater disease activity had higher levels of dsDNA-specific IgE, Sanjuan and his collagues found. A multivariate analysis using SLEDAI to measure disease activity found the following effects for dsDNA-specific IgE an IgG as risk factors, with a confidence interval of 95 percent: · Anti-dsDNA IgG: 0.00426 (0.000453-0.00807), p=0.029 · Anti-dsDNA IgE: 0.157 (0.0583-0.256) p=0.0020 · Anti-dsDNA IgG x anti-dsDNA IgE: -0.000232 (-0.000681-0.000218) p=0.31 To uncover the mechanisms behind the IgE link, the researchers exposed peripheral blood mononuclear cells to dsDNA-IgE-positive serum from lupus patients while blocking IgE from binding to its receptor. To their surprise, this blockade reduced the production of IFN-a, suggesting that IgE itself plays a role in abnormal interferon-a secretion in systemic lupus erythematosus. Further experimentation revealed the immunocomplexes of DNA and IgE induced IFN-a secretion, as complexes of DNA and IgG were previously known to do — and at similar levels. The dsDNA-IgE immunocomplexes are recognized at the cell surface by FcεRI receptors, which deliver them into intracellular compartments to be recognized by the toll-like receptor TLR9. TLR9, in turn, triggers the production of IFN-a and other proinflammatory cytokines, the researchers wrote. The dsDNA-IgE immunocomplexes were also found to induce plasmacytoid dendritic cell-dependent B cell responses, the researchers wrote, and to prompt B cells to differentiate into plasma cells. No patient was found to have IgE alone without IgG, the researchers found, likely because exposed DNA is snapped up by both immunoglobulins to form the disastrous immunocomplexes that trigger the autoimmune response. In combination, the two immunoglobulins elicited larger amounts of IFN-a secretion than either alone. This increased secretion resulted from more cells responding rather than the same amount of cells excreting more of the interferon, the researchers found, suggesting that IgE lowers the cellular threshold for response. In the healthy immune system, IgE may work with IgG to improve the sensing of viruses, Sanjuan and his colleagues wrote. In that sense, the study helps illuminate the a wider role for this immunoglobulin than parasite defense. In the context of autoimmune disease, IgE's newly discovered role may make it particularly harmful — but also a potentially promising target for treatment. "The previously unrecognized link between IgE and the interferon pathway that we have reported here provides additional insight into the pathological mechanisms underlying autoimmunity and might be useful in the rational design of therapies for the treatment of diseases such as SLE," Sanjuan and his colleagues wrote.
When gender makes a difference Men and women tend to have different diseases and are affected differently when treated, largely because of hormones. DR. AVITAL Porter and patient. (photo credit:BINYAMIN ADAM) By JUDY SIEGEL-ITZKOVICH When neurobiologist Anat Biegon was studying depression in females 40 years ago at the Weizmann Institute of Science in Rehovot, she asked a colleague what drug dosage was needed to safely anesthetize rats before experimenting on them. Biegon recognized than that women were much more likely than men to suffer from chronically low moods. She gave the female rodents the recommended amount – and all of them died. The colleague had given the dosage accepted for use on male rats; no special dose had been calculated for female rats because they were considered to be the same as the male gender. Today, as a professor of neurology and radiology at Stony Brook University in New York (part of the State University of New York), Biegon has established a center for the study of gender, hormones and health at her university. She delivered a solo lecture last month at Hadassah University Medical Center in Jerusalem’s Ein Kerem on “Sex Differences in Medicine? Why Should We Care?,” and has gone far to study the implications of differences between females in males. Biegon, who at Tel Aviv University studied chemistry for a bachelor’s degree and biochemistry for her master’s degree, branched out into neurobiology in Rehovot and then completed post-doctoral work at Rockefeller University in Manhattan. Since 1990, she has remained in the US, and her main research interests have included brain response to traumatic, ischemic or inflammatory insults; gonadal hormone modulation of brain function in health and disease; and radiopharmaceuticals for non-invasive imaging of neurotransmitter and hormone markers in the brain – all the while keeping an eye on gender differences in these subjects. “Gender, biological sex and sex hormones affect everything in medicine, including prevalence, disease presentation and outcome, the safety of medical devices and procedures, drug response, metabolism and safety and efficacy,” she said in the English-language speech. Her lecture was based on American statistics but, she said, “the situation in Israel shouldn’t be much different.” “As many as 66 percent of visits to doctors are by women,” she noted. This is not because women are more fearful of being ill or like to spend their time in health fund clinics. “It’s due to the fact that women live considerably more years than men and they are thus more likely to suffer from age-related, chronic and incurable diseases. In addition, pregnancy, birth, breastfeeding and taking care of children can have adverse effects on women’s health.” While victims of attention-deficit/hyperactivity disorder (ADHD), autism and traumatic brain injury are predominantly boys/men (75 percent versus 25% in females), autoimmune diseases (in which the immune system attacks bodily tissue or cells because it mistakenly regards them as “foreign”) and others affect mostly females. While ADHD is more common in boys, and girls have lower ratings on hyperactivity inattention and impulsivity, they tend to have more intellectual impairment in this condition. “About 90% of sufferers of lupus erythematosus [a complex inflammatory disease causing scaly red patches on the skin, and sometimes affecting connective tissue in the internal organs] are women,” said Biegon. In addition to depression, women suffer more from Alzheimer’s disease, multiple sclerosis, cluster headaches, osteoporosis, fibromyalgia and osteoarthritis. Hip, forearm, spinal and humerus bone fractures occur more in women. “These are generally not killer diseases, but they make life miserable for a long time,” she noted. “During the course of a woman’s life, affected by reproductive hormones the risk of disease can rise and ebb: For example, during her fertile years a woman is at higher risk of depression; this declines at menopause and then increases when she becomes old-old.” Even when a woman undergoes a sex change operation, the “liability” of disease can follow her on her path through the other gender. “Robert Eads, a twice-divorced man with two children who became a transsexual at the age of 45, died of ovarian cancer,” Biegon reported, showing her/his photo. She/he had her breasts removed and took testosterone supplements, but the ovaries were never removed because they were not functional at that age. But he nevertheless succumbed to ovarian cancer at 53. Transgender women who become men take testosterone, which is a precursor of estrogen. So this hormone treatment can also increase the risk of estrogen- linked diseases.” SYMPTOMS OF the same acute conditions can present themselves differently in men and women, Biegon continued. In men, the first signs of a myocardial infarction (heart attack) in men include sharp pain in the left part of the chest, possibly with the pain radiating down the arm on that side. In women, they could be very different. “Often, there is no chest pain. There could instead be a cough, feeling tired or pain in the jaw or back. So many women may not know they are having a heart attack, and many physicians in the emergency room may not take their symptoms seriously,” Biegon said. The emergency room doctor could think a woman was “hysterical” and just give her a Valium pill and send her home. “This situation costs a large number of women’s lives.” A few weeks ago, the American Heart Association issued an official statement on the matter. “Cardiovascular disease is the leading cause of mortality in American women. Since 1984, the annual cardiovascular disease mortality rate has remained greater for women than men; however, over the last decade, there have been marked reductions in cardiovascular disease mortality in women. The dramatic decline in mortality rates for women is attributed partly to an increase in awareness, a greater focus on women and cardiovascular disease risk and the increased application of evidence-based treatments for established coronary heart disease. This is our first scientific statement from the American Heart Association on acute myocardial infarction in women,” the association declared. “Sex-specific differences exist in the presentation, pathophysiological mechanisms and outcomes in patients with acute myocardial infarction. This statement provides a comprehensive review of the current evidence of the clinical presentation, pathophysiology, treatment, and outcomes of women with acute myocardial infarction.” BIEGON said that although traumatic brain injury is more common in men, the results are usually different in women and men. The injury usually causes the brain to swell. The victim undergoes a CT (computerized tomography) scan and is tested with intracranial pressure-measuring devices. The swelling alone can kill. “But in people with severe brain injury, a quarter of men have swelling that is reduced. In women, the brain swells much more from the same injury. In women in their reproductive years, under the age of 51, swelling in various female organs – the breasts and abdomen – is common during and after menstruation. So brain swelling in such women is also greater due to hormones. Post-menopausal women suffer much less brain swelling after traumatic injury to the head. One can’t ignore age in this matter.” Mortality rates of young girls who suffered traumatic brain injury are more than twice as high as that of boys, she says. “But when they reach puberty, the ratio stabilizes and becomes equal until age 30, but at age 50, men have higher death rates.” Biegon stressed: “The absence of evidence doesn’t mean evidence of absence. If a study shows no sex difference, it doesn’t mean it is true. One always has to look at the interaction with age. One needs large numbers of women to say something about a gender effect, but often many women are not included. Researchers compare older and younger men, but not women to men. When you survive brain injury, you are alive. The question is if life is worth living; one might need constant care for disability and even be in a vegetative state.” AS FOR the safety of medical devices and procedures, coronary angioplasty is claimed to be very safe and effective when arteries in the heart are found to be clogged. “But this is true for men! Death after angioplasty is less than 1% for men but close to 2% in women. This is a significant difference,” Biegon asserted. “This means more hospitalization and complications in women. The female gender is and independent predictor of lower success for angioplasty and a higher risk of death.” Drug response also varies according to whether the patient is male or female. “Women are more likely to suffer adverse effects of drugs than men, and not only because of their average smaller size. ACE inhibitors for treating hypertension have been found to be less effective in women than in men. The use of digitalis, found to be not effective in women in some major studies, has more side effects.” Digitalis, a natural medicine that strengthens the force of the heartbeat by increasing the amount of calcium in the heart’s cells and controls irregular heart rhythms has been found to cause more deaths in women than in men. Aspirin has been recommended for preventing myocardial infarction in older people. “Almost everyone over 60 takes baby aspirin,” said Biegon. “But 32,000 participants studied for the effects of aspirin in preventing the risk of heart attacks were all men. When a different study tested 40,000 women for the same purpose, aspirin made absolutely no difference in preventing MI. Aspirin is Man’s Best Friend but not that of women, who developed only side effects from taking it. Women are often overdosed with medications, and as they tend to suffer from more chronic illnesses at older ages, they are prescribed multiple mediations and suffer from drug-drug interactions.” Liver enzymes, the lecturer continued, “are induced by testosterone and inhibited by estrogen, so men have a faster oxidating metabolism than women. The effects of barbiturates, for example, are modulated by age and gender. Before puberty, boys and girls spend the same amount of time sleeping. After puberty, girls and women receiving barbiturate pills sleep significantly more than men, depending on where they are in their menstrual cycle and the involvement of their sex hormones.” The US Food and Drug Administration, she said, forced a pharmaceutical company to lower the recommended doses of zolpidem (brand names include Ambien, Zonadin, Sanval, Zolsana and Zolfresh), a prescription medication used for the treatment of insomnia and some brain disorders. Younger women need only half the dose as that given to males, as their estrogen affects it, Biegon said. GENDER DISCRIMINATION in the medical establishment has been quite ludicrous for centuries. In 1859, the American Medical Association said that women’s “psychological condition during part of the month disqualifies them from being doctors.” Only in 1945 did the Harvard Medical School remove a ban on accepting female medical students. In 1977, FDA guidelines excluded “women of childbearing potential” (meaning the ability to become pregnant) from taking part in Phase 1 and Phase 2 clinical trials. Sixteen years later, the US National Institutes of Health issued a requirement to include women in all 93, NIH issues requirement to NIH-sponsored clinical trials, but, said Biegon, “many drug companies ignore this. But things are changing: Last year, the NIH issued a mandate to consider sex as a ‘biological variable’ in all research it funds.” Today, there are a growing number of organizations, professional societies, journals and hospital-based centers dedicated to research and sex differences in medicine. Still, said Biegon, the “vast majority of medical research today is on males, except for breast cancer and some multiple sclerosis trials. We still don’t know how various drugs affect the fetus and women in pregnancy. Fertile women suffer from allergic, cardiovascular system, skin, endocrine, immune, infectious, respiratory, pain, urogenital and many other conditions, and automatically, doctors say they are not considered safe in pregnancy. “The drug packages say: ‘Consult your doctor about use in pregnancy,’ but what does the doctor know if there are no clinical trials? Sick women do get pregnant, and pregnant women do get sick. They have no access to evidence-based medical care.” Such women, she continued, “need medications, but they can hardly be given to them due to lack of study. A sick mother is not good for a fetus. If you’re taken off medication because it may harm fetus and then have epileptic seizures, your fetus can suffer from fetal bradycardia [very slow heartbeat] and other serious problems.” But “many women who are pregnant and have epilepsy are, despite warnings, still taking drugs for the condition, so they should be included in randomized clinical trials to compare them with men. One can do MRI scans of infants and see any effects of the drugs on the fetus and identify blood in the brain. You don’t have to wait for the birth to see any effects. If you see a problem, you can deal with it in utero in prenatal surgery; for example, one can operate in the uterus on fetuses with spina bifida, for example.” Biegon concluded that medical schools have to teach students differently so they can appreciate sex differences in medicine. “At my school, we will soon start a course on gender- based medicine for fourth-year students.” http://www.jpost.com/Business-and-Innovation/Health-and-Science/When-gender-makes-a-difference-444090