William Heath Robinson
The more you learn of creationism's putative intelligent [sic] designer, the more like William Heath Robinson it becomes.
The main difference is that, no matter how ramshakled they were, William Heath Robinsons inventions actually worked, even if they didn't produce the required result. The same can't be said for creationism's god's designs. They resemble piecemeal designs where each part is designed in isolation in response to a problem, often a problem somewhere else in the design, where near enough is good enough and there is no joined up thinking.
Rather like a William Heath Robinson machine, conbbled together from disparate parts, but where when a knotted piece of string breaks, instead of replacing it with a new piece of string or tying the broken ends together, like Heath Robinson would, a different, weaker sort of string is designed and tied across the broken ends, but then that keeps breaking too.
An example of this inept design was discovered recently and found to be the cause of autoimmune diseases such as iritable bowel syndrome (IBS), type 1 diabetes, eczema and other chronic disorders. The problem is with a protein called DECTIN-1 (also known as CLEC7A) which is producd by the immune system in response to fungal infections. Researchers at The Australian National University (ANU) have discovered that a mutated form of DECTIN-1 limits the production of T regulatory cells or so-called ‘guardian’ cells in the immune system.
Mutations arise, of course, because of another poor design - the process for replicating DNA, which is so prone to errors that another mechanism for repairing it is needed. However this is also prone to errors, the result of which means that many of our cells carry mutations, some of which cause cancers.
The research is publshed in Science Advances and ex[lained in an Australian Nationa University News release:
A protein in the immune system programmed to protect the body from fungal infections is also responsible for exacerbating the severity of autoimmune diseases such as irritable bowel disease (IBS), type 1 diabetes, eczema and other chronic disorders, new research from The Australian National University (ANU) has found.The research is published in Science Advances. It was led by ANU in collaboration with The University of Queensland and the Francis Crick Institute.
The discovery could pave the way for new and more effective drugs, without the nasty side effects of existing treatments, offering new hope to more than one million Australians who suffer from some form of autoimmune disease.
In addition to helping to manage severe autoimmune conditions, the breakthrough could also help treat all types of cancer.
The scientists have discovered a previously unknown function of the protein, known as DECTIN-1, which in its mutated state limits the production of T regulatory cells or so-called ‘guardian’ cells in the immune system.
These guardian cells are crucial to preventing autoimmune disease because they suppress the effects of a hyperactive immune system, which can be extremely dangerous if not properly regulated.
The immune system is designed to protect the body from infection, but in severe cases it becomes overactivated and turns the body’s natural defences against itself.
The scientists believe they can control the immune system by turning the DECTIN-1 protein on and off, like a light switch.When this happens, the immune system wrongly perceives healthy cells as a threat, causing it to attack the body and promote the onset of autoimmune disease. Although the DECTIN-1 protein helps to fight fungal infections, in its mutated state it's also responsible for exacerbating severe autoimmune disease. Understanding how and why the mutated version of this protein causes autoimmunity in patients brings us a step closer to developing more effective drugs.
Dr Cynthia Turnbull, lead author
John Curtin School of Medical Research,
Australian National University, Canberra, ACT, Australia.
According to Dr Turnbull, this means DECTIN-1 could play a key role in treating cancer.Turning on the protein would lower the intensity of the immune system’s defensive response which would help to treat conditions such as autoimmune disease. On the other hand, turning off the protein could give the immune system a boost, sending its defensive mechanisms into overdrive and allowing the body to treat an entirely different set of diseases. The findings are exciting because there haven’t been many discoveries of so-called modifier proteins such as DECTIN-1, which can change the way the immune system behaves to the extent it can either cause a disease or prevent it.
Professor Carola G. Vinuesa, co-corresponding author
The Francis Crick Institute, London, UK. And John Curtin School of Medical Research,
Australian National University, Canberra, ACT, Australia.
Current treatments for autoimmune disease aren’t very effective and have a lot of damaging side effects. This is because the majority of existing treatments suppress the entire immune system rather than targeting a specific area.Cancer cells can disguise themselves by releasing certain proteins and chemicals into the body that essentially render them invisible from the immune system’s natural defences. We think that by using drugs to turn off the DECTIN-1 protein, in combination with existing therapies, we can activate the immune system and help it identify and attack the cancerous cells.
Dr Cynthia Turnbull.
By examining the DNA of a Spanish family, the researchers discovered the DECTIN-1 mutation was responsible for exacerbating the severity of a chronic autoimmune disease suffered by the family’s only child.That means it might not fix the exact problem behind the patient’s disease and could inadvertently make them vulnerable to infections. Many people on these kinds of treatments also get bacterial, fungal and viral infections which can make their autoimmunity worse.
Professor Carola G. VinuesaWe found the family was also carrying a mutated version of another immune system protein known as CTLA-4. The CTLA-4 mutation prevents guardian cells from working properly and is known to cause severe autoimmune disease in about 60 to 70 per cent of people who carry it in their DNA. Strangely, the remaining 30 to 40 per cent of the population who carry this mutated protein don’t develop disease.
We discovered the family’s only child had both the DECTIN-1 mutation and the CTLA-4 mutation, while his parents had only one of each. This helped us identify why the child, who is now in his twenties, was the only person in the family to develop severe autoimmunity, ending a 20-year-long mystery behind the cause of his disease. By discovering the existence of mutated versions of modifier proteins such as DECTIN-1, we finally have an explanation for why some people develop severe autoimmune diseases while others don’t, even if they inherit gene mutations passed down from family members.
Dr Pablo F. Canete, co-correspondin author
John Curtin School of Medical Research
Australian National University, Canberra, ACT, Australia
And the Frazer Institute
The University of Queensland, Woolloongabba, Queensland, Australia.
Abstract
Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor–β. Consistent with DECTIN-1’s Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.
INTRODUCTION
Inborn errors of immunity (IEIs) are a heterogeneous group of genetic abnormalities that lead to perturbations of the immune system. While these conditions were traditionally thought to encompass primary immune deficiencies, with susceptibility to infections as a major clinical hallmark, it is now clear that some IEIs exhibit autoimmune features or a combination of both, as seen in immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation (IDAIL). Although IDAIL is complex and heterogeneous in both genetic etiology and clinical phenotypes, most patients exhibit T cell hyperactivity. Not surprisingly, disruptions in genes that control T cell immune checkpoints, T cell tolerance, and regulatory T cells (Tregs), which use a variety of strategies to suppress effector T cells, often lead to immune dysregulation. Indeed, loss-of-function (LoF) variants in genes important for Treg differentiation, function, and maintenance, such as FOXP3, cytotoxic T-lymphocyte associated protein 4 (CTLA4), LPS Responsive Beige-Like Anchor Protein (LRBA), and CD25, result in various forms of IDAIL (1).
CTLA-4 haploinsufficiency (CTLA-4h) is a particularly severe but highly variable immune disorder characterized by the presence of damaging gene variants in CTLA4 (1–3). CTLA-4 is a transmembrane receptor predominantly expressed on Tregs, which is indispensable for maintaining immune tolerance and homeostasis (4). Being structurally similar to the T cell costimulatory molecule CD28, it restrains T cell responses predominantly by binding to and removing the CD28 ligands, CD80 and CD86, from the cell surface of antigen-presenting cells, thus precluding T cells from receiving adequate activation and proliferation signals (5, 6). Unlike homozygous Ctla4-deficient mice, which exhibit massive T cell lymphoproliferation, multi-organ damage, and premature death, heterozygous mice remain healthy (7). Selective elimination of CTLA-4 in the Treg compartment only delays onset of symptoms and mice eventually succumb to disease (8), thus highlighting the importance of Treg-expressed CTLA-4 for mediating immune tolerance. In contrast, human CTLA4 variants typically act in an autosomal dominant manner to cause complex IDAIL similar to that seen in mice (4). The presenting clinical manifestations include lymphoproliferation, autoimmune endocrinopathies, autoimmune cytopenias, lymphocytic infiltration of the gastrointestinal system, lungs, and brain, and combined variable immunodeficiency manifestations such as hypogammaglobulinemia and recurrent respiratory infections (1–3).
Incomplete penetrance and variable expressivity are the norm for CTLA-4h–mediated IDAIL, with 30 to 40% of carriers of pathogenic CTLA4 variants showing no clinical symptoms (1–3). This is despite both affected and unaffected mutation carriers showing comparable defects in CTLA-4 expression and function in vitro (1–3). Several studies have ruled out the contribution of genetic and environmental factors known to explain other incompletely penetrant IEIs such as biallelic genetic deficiencies of CTLA4 (e.g., frameshifts and deletions), somatic mutations, or past viral infections (1, 2, 9). Given that phenotypic manifestations of many gene variants depend on interactions and contributions of additional genetic elements, it is possible that aggravating genetic modifiers of CTLA-4 may explain the incomplete penetrance and variable expressivity. To date, there has been one report of functional epistasis where a rare variant in JAK3 (10) appeared to enable expressivity of a CTLA4 variant (10). This JAK3 variant was not found in a cohort of 52 unrelated CTLA-4h patients (10), suggesting that there are likely to be additional modifier genes.
Here, we report functional epistasis between DECTIN-1, a pattern recognition receptor (PRR) specific to fungal components, and CTLA-4 in a severe case of CTLA-4h. Whole genome sequencing (WGS) revealed a maternally inherited pathogenic CTLA4 variant together with a paternally inherited rare (MAF = 0.004) heterozygous variant in the gene encoding DECTIN-1, CLEC7A (L183F). Beyond its role in fungal immune surveillance, DECTIN-1 is also known to regulate gut microbial composition and functionality. Indeed, DECTIN-1–deficient mice (Clec7a−/−) exhibit heightened susceptibility to chemically induced colitis, while human polymorphisms in the DECTIN-1 gene (CLEC7A) are strongly associated with ulcerative colitis (11).
We report that DECTIN-1 L183F inhibited protein dimer formation, localization, and ligand binding. Importantly, DECTIN-1 stimulation increased peripheral Treg differentiation of human and mouse T cells in vitro and in vivo, suggesting that partial loss of DECTIN-1 function may explain the full IDAIL expressivity in the patient (12). Our data reveal a previously unappreciated epistatic interaction between CTLA-4 and DECTIN-1 that maintains immune homeostasis by respective control of Treg quality and quantity.
So, because creationism's putative intelligent designer designed some fungi to make us sick, then designed our immune system to protect us from these fungi, the 'solution' to the problem is caused in the first place has produced another problem that medical science is now trying to overcome.
And the reason this 'solution' to the problem is caused causes the next problem in the chain is because the method to replicate the gene that is a template for it sometimes fails and the resulting mutant gene produces a defective 'solution', which ends up turning the immune system against the person it was allegedly designed to protect.
It's only by remaining stoically ignorant of these details are in the detail below the superficial resemblance of design, that creationists are able to continue to believe a supremely intelligent designer designed these ramshackled, Heath Robinson systems.
No comments :
Post a Comment
Obscene, threatening or obnoxious messages, preaching, abuse and spam will be removed, as will anything by known Internet trolls and stalkers, by known sock-puppet accounts and anything not connected with the post,
A claim made without evidence can be dismissed without evidence. Remember: your opinion is not an established fact unless corroborated.