The classic 'butterfly rash' of systemic lupus erythematosus (SLE)
In my days as an operational paramedic, I once had to move a 26 your old women to hospital because lupus had made her so ill her blood pressure was below the safe level to maintain her renal function.
It was so low I couldn't even sit her up to carry her down stairs without her losing consciousness, so I had to run a couple of units of IV fluid into her to bring it up enough to make it safe to move her. She really was profoundly ill and at death's door. But such was the nature of the profession that, having delivered her safely to hospital and handed her over to the care of doctors and nurses, that was the end of my role in her care, so I never heard the outcome.
The autoimmune condition, lupus erythematosus, is caused by a malfunction of the immune system in which something triggers it to turn against the sufferer's own body instead of the invasive pathogens from which it has evolved to protect us. Although, of course, a creationist would hotly dispute the idea that a system like our immune system evolved at all, and would insist that it was intelligently [sic] designed by their favourite, evidence-free, supernatural deity without whom nothing can be created, presumably because they believe chemistry and physics don't know how to behave without a magic god telling them.
But an intelligently-designed immune system would only malfunction and turn against the person it is supposedly designed to protect if it were either incompetently designed or malevolently designed and is doing what it was designed to do - randomly increasing the suffering in the world. The evidence is that lupus is far more common in women than in men by a ratio of 9:1, which begs the question, does the designer just hate women more than men or was he more diligent when designing men's immune system then when designing women's?
The answer, as anyone who understands anatomy and physiology and particularly, evolution, will tell you, is that as an evolved system, we can expect compromises and a lack of perfection because evolution is a utilitarian process with no foresight and no reverse gear, so we are stuck with a sub-optimal immune system that evolved in an ancient ancestor, maybe even a pre-vertebrate ancestor. Certainly, all known vertebrates have one, and some, like that of bats, is far superior to ours.
Now a team of researchers at Stanford University School of Medicine, Stanford, CA, USA have worked out why lupus is far more common in women than men. Ther results are published, open access, in Cell and explained in a Stanford Medical news release. But first, a little AI background:
What is systematic lupus erythematosus and what causes it? Systemic Lupus Erythematosus (SLE), commonly known as lupus, is a chronic autoimmune disease. In autoimmune diseases, the immune system, which is supposed to protect the body from infections and foreign invaders, mistakenly attacks its own tissues and organs.What the Stanford team discovered is that at least part of the story is the way our cells need to turn certain genes on and off, because, in another example of utilitarian evolution, but terrible design, if you insist on a 'design' explanation, all our cells inherit our entire genome, even the highly specialised cells that just need a small handful of them. So, to make cell specialisation work, a whole complex system is there to turn genes on and off, in a process of which William Heath Robinson would be proud, but for which any intelligent designer should have been sacked and forbidden from designing anything else. It's this switching process, or rather the proteins and lengths of long non-coding RNA (lncRNA) that do the switching, that sometimes go wrong and results in an autoimmune response, such as lupus.
In the case of lupus, the immune system can attack various parts of the body, including the joints, skin, kidneys, heart, lungs, brain, blood cells, and other organs. This can lead to inflammation, pain, and damage to affected organs.
The exact cause of lupus is not well understood, and it is likely to involve a combination of genetic, environmental, and hormonal factors. Some potential factors that may contribute to the development of lupus include:
It's important to note that lupus can vary widely in its presentation and severity. Symptoms may include fatigue, joint pain, skin rashes, fever, and organ involvement. Diagnosis typically involves a combination of clinical evaluation, blood tests, and other diagnostic procedures.
- Genetic Factors: There is a genetic predisposition to lupus, as it tends to run in families. Certain genes may increase the likelihood of developing the disease.
- Environmental Triggers: Various environmental factors may trigger lupus in genetically predisposed individuals. These triggers can include exposure to ultraviolet light, certain medications (such as hydralazine, procainamide, and others), infections, and hormonal changes.
- Hormonal Factors: Lupus is more common in women, particularly during childbearing years. Hormonal fluctuations, such as those that occur during puberty, pregnancy, and menopause, may influence the development of lupus.
- Immunological Factors: Abnormalities in the immune system, such as the production of autoantibodies (antibodies that target the body's own tissues), play a significant role in the development of lupus.
While there is no cure for lupus, medical management often focuses on controlling symptoms, preventing flares, and minimizing organ damage. Treatment may involve medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, and antimalarial drugs. Patients with lupus often work closely with healthcare professionals to manage their symptoms and improve their quality of life.
The Stanford University news release, by science writer, Jennie Dushek, explains the team's research:
A new technology for studying the human body’s vast system for toggling genes on and off reveals that genes associated with the immune system toggle more frequently, and those same genes operate differently in women and men.In the abstract and introduction to their open access paper incell, the team say:
Some genes are virtually always on, like the clock light on a microwave; others sit unused for years at a time, like some regrettable appliance you bought, stuffed into the back of the closet and forgotten. Some genes can be always on in one person and always off in another. A minority of genes switch on and off, like a favorite cell phone app. A new technology, which makes it possible to study the molecules that regulate all of that switching in living people as they go about their lives, has revealed some intriguing surprises, according to a study from the Stanford University School of Medicine.
One of those discoveries is that the genes that switch on and off differently from person to person are more likely to be associated with autoimmune diseases. Another is that women and men use different switches to turn on many immune system genes. It’s too soon to be sure, but that difference in activity might explain the much higher incidence in women of autoimmune diseases such as scleroderma, lupus and rheumatoid arthritis.
The new technique, called ATAC-seq and developed by Chang’s team, lets researchers sample living cells in real time to see what they are up to.Part of why this is possible is a new technology that was invented at Stanford for measuring the accessibility of the genome to regulatory elements. In the past, people needed a huge number of cells to do this kind of measurement. You’d actually need a pound of flesh to get certain rare cell types. So you can’t get that out of a live person — and certainly not more than once, right?
But now you are studying copies of copies; you aren’t studying the original cells anymore. Those months of being grown in the lab completely changes how the cells are behaving and so you are no longer looking at the personal. How the laboratory cells behave has nothing to do with what the person just ate, whether they had a fight with their girlfriend or whether they had an infection.
Professor Howard Chang, MD, PhD, senior author.
Center for Personal Dynamic Regulomes
Program in Epithelial Biology
Department of Dermatology
Stanford University School of Medicine, Stanford, CA, USA
Examining the source
Researchers coped by growing cells in the lab so they had enough cells to study. With lab-grown cells, the cells haven’t experienced any of those things, all of which can alter the regulation of individual genes.
The new study, published July 29 in the new journal Cell Systems, took ordinary blood samples from 12 healthy volunteers to measure how certain genes are switched on and off, and how that measure varied from individual to individual. Chang’s team also looked at how much change occurred at different times in the same volunteers. The researchers looked exclusively at specialized immune cells called T cells, which are easy to isolate from a standard blood test and easy for volunteers to supply and which are an important component of the immune system.
One goal of the study was to establish a baseline measure of how much this gene-switching activity varies among healthy people. That way, when other researchers make similar measures in people who are ill, they’ll have an idea of what is normal. Another goal was to refine the new technique for measuring gene activity in standard blood samples.
“We were interested in exploring the landscape of gene regulation directly from live people and look at differences,” said Chang. “We asked, ‘How different or similar are people?’ This is different from asking if they have the same genes.” Even in identical twins, he said, one twin could have an autoimmune disease and the other could be perfectly well. And, indeed, the team reported that over a third of the variation in gene activity was not connected to a genetic difference, suggesting a strong role for the environment. “I would say the majority of the difference is likely from a nongenetic source,” he said.
The sex factor
Across the 12 volunteers, 7 percent of the genes were switched on in different patterns from person to person. For each person, these patterns persisted over time, like a unique fingerprint.
When the team measured gene activity levels from 30 of the top 500 genes the researchers expected would show gender-influenced activity, they found that 20 of the 30 genes showed significant differential activity between men and women. Chang directs the Center for Personal Dynamic Regulomes at Stanford University, which aims to map the “regulome” — the complete set of all the switches that turn genes on and off in real time. Other Stanford-affiliated authors of the paper are Kun Qu, PhD, senior research associate; Lisa Zaba, MD, PhD, instructor of dermatology; Paul Giresi, PhD, former postdoctoral scholar; Rui Li, life science research assistant; Michelle Longmire, MD, clinical instructor of dermatology; Youn Kim, MD, the Joanne and Peter Haas Jr., Professor for Cutaneous Lymphoma Research; and William Greenleaf, PhD, assistant professor of genetics.But the single greatest predictor for genes’ tendency to turn on and off was the sex of the person. In terms of significance, sex was far more important than all the other things we looked at, perhaps even combined.
Professor Howard Chang, MD, PhD
And all because creationism's intelligent [sic] designer couldn't come up with anything better than that which mindless, unintelligent evolution would come up with as the solution to the problem of how to replicate cells in a multicellular organism so that the different specialised cells could function, and the outcome is of course vastly different to what a real intelligent, omnibenevolent designer worthy of the description would have designed, had there been such a thing.HighlightsGraphical abstract
- Transgenic mouse models inducibly express Xist in male animals
- Xist expression in males induces autoantibodies and autoimmune pathology
- Xist in males reprograms T and B cell populations to female-like patterns
- Autoantibodies to Xist RNP characterize female-biased autoimmune diseases in patients
Summary
Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
Introduction
Autoimmune diseases are the third most prevalent disease category, outpaced only by cancer and heart disease.1 Four out of five patients with autoimmune diseases are female. For instance, in systemic lupus erythematosus (SLE), the ratio of patient sex is 9:1 females to males; the ratio in Sjögren’s disease is 19:1 female to male patients.2,3 Although hormones have been extensively studied,4 the dosage of X chromosome appears to be a major driver of autoimmune risk irrespective of sex or hormonal status in humans and mice.5,6,7,8 Patients with Klinefelter syndrome (XXY) are phenotypically males, have male hormonal pattern, but have an elevated risk of autoimmune disease equivalent to females. Specific X-linked genes, such as TLR7, that can escape X inactivation have been nominated as contributors to specific autoimmune diseases.5,6,7,8 The genetic risk underlying autoimmune diseases from the second X chromosome in aggregate remains unresolved. In addition, identical twin studies have also shown varying degrees of autoimmune disease penetrance, suggesting a genetic disposition that is also reliant on environmental factors.9,10 Hence, adjuvant triggers11 in addition to genetic predisposition may be initiators of autoimmune disease development.
Mammalian females have a XX genotype and males have a XY genotype. To make the gene expression output roughly equivalent between females and males, every cell in a female’s body epigenetically silences one of two X chromosomes via the action of the long non-coding RNA (lncRNA) Xist. Xist is an ∼17-kb lncRNA (19 kb in human) that is transcribed only from the inactive X chromosome and thus not expressed in males. Xist is critical for the establishment of X chromosome inactivation (XCI) spreading from the X-inactivation center and coating the entire inactive X in association with its protein partners. During XCI establishment in mouse embryonic stem cells, Xist associates with 81 unique binding proteins to form an ribonucleoprotein (RNP) complex, 10 through direct RNA protein interaction and others through indirect protein-protein interaction.12,13 Xist is widely expressed in adult somatic tissues and associates with additional tissue-specific proteins.14 Several Xist binding proteins were previously noted to be autoantigens.12 Studies in SLE patients and mice demonstrated that DNA-autoantibody and RNA-autoantigen immune complexes, such as Sm/RNP and U1A, activate the TLR7, TLR8, and TLR9 pathways of the innate immune system.15,16,17 The XIST RNP, which comprised an lncRNA, bound RNA binding proteins, and tethered to pieces of genomic DNA, presents qualities resembling nucleic acid-autoantigen immune complexes.
To study the impact of the XIST RNP in autoimmune predilection independent of sex chromosome or hormonal background, we utilized an inducible and non-silencing allele of Xist introduced into an autosome in the autoimmune-resistant C57BL/6J and autoimmune-prone SJL/J strain backgrounds. Inducing transgenic Xist RNP formation in male animals allowed the study of this female-specific lncRNA in a male background, using a chemically induced SLE model. Both increased disease severity and elevated autoreactive lymphocyte pathway signatures were observed in the mouse models of pristane-induced SLE. Concurrently, we designed an antigen array to test autoimmune patient seroactivity to XIST-associating proteins and detected significant reactivity toward multiple components of the XIST RNP. Altogether, our data point to a significant role for the Xist RNP as a driver for autoimmunity that may underly the sex-biased female preponderance for developing autoimmune diseases.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
Lupus is another cruel, horrible disease and one of an infinite number of scourges the creator had to torture and kill His creation with. Cruelty and sadism on steroids describes the creator. I dont know how anyone could call this as loving and merciful when it's exactly the opposite of love and mercy.Creationists can't understand that all these diseases in Nature imply how bad and lousy the creator is. Why would anyone want to worship a being who creates and allows suffering, death, and evil? Fear of ending up in hell is one reason people worship this monstrosity. I prefer evolution any day than creationism.
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