https://www.the-scientist.com/the-innate-immune-system-s-secret-weapon-73061

"When a pathogen enters the body and begins multiplying, the immune system has to respond with haste. However, adaptive immune cells—so-named because they can recognize, respond to, and remember specific microbes—require four to seven days to mount a tailor-made defensive.1 Meanwhile, innate immune cells, which recognize general signs of a threat, such as common bacterial lipids, strike immediately and buy time for the adaptive immune system to prepare its attack. Immunologists have long accepted the “innate-first, adaptive-second” model of the immune response, but following an odd discovery 15 years ago, the line separating the innate and adaptive axes began to blur.2 Scientists uncovered a new group of immune cells called innate lymphoid cells that elicit similar responses to the adaptive arm’s T cells, mainly by triggering inflammation through the secretion of chemical signals called cytokines. However, like other innate cells, they are unable to recognize specific antigens.

***

"These novel cells didn’t possess any antigen-specific receptors, indicating that they belonged to the innate immune system...Today, scientists call them type-2 innate lymphoid cells (ILC2s).

"In the years that followed, other groups identified more types of innate lymphoid cells and noticed a peculiar pattern: For every class of T cell, an ILC counterpart exists that resembles it. For example, both type-1 helper T cells (Th1s) and ILC1s mount a similar immune response against viruses and other intracellular parasites by secreting a signature set of cytokines.

***

"Despite their many similarities to T cells, ILCs lack a key feature that make T cells adaptive. They cannot recognize specific antigens, which means they lack the marksmanship to attack diseased cells while leaving healthy bystanders unharmed.7 They also make their appearance during the immediate, innate phase of the immune response rather than during the delayed, adaptive phase.

***

"Even after T cells are activated, ILCs continue to play an important role in the immune response by recruiting T cells to threats, and producing cytokines that keep them active.

***

"...Jefferies’s team found that the cytokine IL-33 plays an important role in helping T cells to fight solid lung tumors. “We were interested in what IL-33 actually regulates,” Jefferies said. Other researchers had previously shown that this cytokine activates ILC2s, so Jefferies transferred a small number of these cells into mice with lung cancer.16 They found that these innate immune fighters significantly shrank the tumors by recruiting T cells to the cancer, narrowing the focus of the T cells to the tumor.

***

"The innate-then-adaptive model of immunity implies that each axis employs distinct tactics depending on whether they indiscriminately target whole tissues or pinpoint strikes on diseased cells. ILCs obscure the distinction by eliciting a general, imprecise reaction using functions typically associated with the antigen-specific adaptive response. Beyond serving as a potential therapeutic against cancers, these elusive cells force immunologists to question the tidy separation between innate and adaptive immunity."

Comment: the concluding paragraph Tells us where new current research is needed. The interplay between innate and adaptive cells is fascinating and suggests a designer at work creating a very flexible response to all challenges. dhw will be pleased at the automatic intelligent interplay between the cell types.

https://www.the-scientist.com/how-does-the-gut-immune-system-distinguish-between-friend...

"From cholera to norovirus, Giardia to hookworms, the gut is vulnerable to an impressive array of pathogens. To keep us alive in the face of this onslaught, the intestinal immune system must be constantly on the lookout for antigens that signal danger. However, the gut is also chock-full of other antigens that originate from the foods that we consume, posing a dilemma for these surveillance systems.

***

"In the intestinal immune system, specialized antigen-presenting cells (APCs) gather antigens from both food and pathogens in the gut contents and present them to T cells, causing them to differentiate into regulatory T cells (Tregs) or inflammatory T cells. In a study published in Science, Canesso and her colleagues used a recently-developed labeling technique to identify APC subtypes that present food antigens and aid in Treg induction.1 They also showed that certain kinds of parasitic worm infections alter the balance of APCs that promote food tolerance and those that trigger inflammation, disrupting the development of tolerance to food antigens.

***

"In this experiment, the researchers expressed this enzyme in OVA-specific naïve T cells—T cells with receptors capable of recognizing the OVA antigen that had not yet “decided” whether they would become regulatory or inflammatory. These T cells would then mark any OVA-presenting APCs they connected with, enabling the scientists to isolate these APCs for further study.

***

"Twenty-four hours after the mice received the OVA protein, identifying two conventional dendritic cell subsets, cDC1s and cDC2s, in approximately equal numbers. When they cocultured both types of APCs with naïve T cells, they found that only the cDC1s increased the number of Tregs present in the culture, suggesting that this cell type is important for promoting tolerance to food antigens.

"To explore the role of cDC1s in vivo, the researchers utilized a mouse model in which cDCs were unable to present antigens. They found that Treg numbers dropped by about 50 percent compared to mice with functional APCs. However, the fact that there were still Tregs present suggests that other cell types are also involved in this tolerization process.

***

"Littman said these experiments clearly show that cDC1s do ultimately influence the final proportion of OVA-specific Tregs. However, he added, “The function that they demonstrate is not necessarily an inducing function. It may be a role in expansion or maintenance of the Tregs. It could be some kind of positioning of the Tregs so that they can carry out their appropriate function.” Indeed, preprints from Littman’s laboratory suggest that another subset of APCs that express the transcription factor RORγt are necessary for the induction of food antigen-specific Tregs, whereas cDC1s may be dispensible.

***

"Indeed, this study by Canesso and her colleagues supports the involvement of multiple APC types in the cascade of events leading to long-term tolerance of food antigens. At 24 hours after OVA administration, most of the LIPSTIC-labelled APCs—the APCs interacting with the OVA-specific T cells—were cDCs. However, at four hours, RORγt-expressing APCs made up a substantial portion of the cells marked with LIPSTIC. The authors proposed that these RORγt-expressing cells played an important part in tolerance induction immediately following food antigen exposure, while cDCs took on a larger role at slightly later time points.

"...They had previously shown that mice infected with a specific type of intestinal parasite—the helminth Strongyloides venezuelensis—did not develop tolerance when they were exposed to novel food antigens.5

"In the present study, they found that helminth-infected mice did not develop OVA-specific Tregs when they were exposed to this food protein. As a potential mechanism to explain this difference, they found that infection nearly abolished food antigen presentation by RORγt-expressing cells and cDC1s.

"The researchers also analyzed gene expression in the unlabelled APCs—those that didn’t interact with the OVA-specific T cells—in the healthy mice and the infected mice. When they grouped the cells using these transcriptional profiles, they identified different subtypes of cDC2s present in the different groups of mice: Cells from infected mice contained a subset of inflammation-promoting cDC2s that were virtually absent in the healthy mice.

“'This was surprising for us: You have tons of these other cells that induce an inflammatory response to the [parasite], but [they’re] not presenting dietary antigens,” said Canesso. “So, it's a compartmentalization of dietary versus pathogen-derived antigens by different antigen-presenting cells.'”

Comment: this cascade of cellular responses is reminiscent of the blood clot cascading controls. This could not develop by chance since it manages the diet of hominins from early Erectus to sapiens over millions of years, constantly changing antigens to handle.

https://www.sciencedaily.com/releases/2025/01/250131194428.htm

"...the study revealed that the endurance of these stem-like T cells is fuelled by a protein called ID3, expressed by a gene of the same name. These ID3+ T cells have a unique ability to self-renew and resist exhaustion, giving them the power to sustain immune responses far longer than other T cells that don't express ID3.

***

"'ID3+ T cells have the remarkable ability to resist burnout and maintain a powerful immune response over time, making them particularly effective in the face of chronic infections or cancer," said and co-first author Gago da Graça.

The research also found that certain signals in the body could increase the number of ID3+ T cells, paving the way for improved treatments like CAR T cell therapy. While CAR T therapy has been transformative in treating certain cancers, its effectiveness can wane over time due to T cell exhaustion.

***

"'We discovered that ID3+ T cell formation could be promoted by specific inflammatory cues, potentially offering new strategies to boost the number of immune cells that excel at fighting cancer in patients," said Professor Johnstone.

***

"'Exhausted immune cells remain one of the biggest challenges in treating chronic diseases," said Dr Utzschneider.

"'This research provides a roadmap for how we might reinvigorate the immune system to improve health outcomes for people living with cancer or chronic infections like HIV or hepatitis B and C, thanks to these stem-like T cells, the immune system's secret power.'"

Comment: a necessary fighter in the immune system, allowing for a long term resistance. It demonstrates 'purpose' as do all evolutionary processes like it. It supports a designer theory.

https://www.sciencenews.org/article/fever-adaptive-immunity-fish-ancient

"Cold-blooded creatures like fish typically move to warmer environments to help fight infections. In one fish species, Nile tilapia, that behavioral — or sought-out — fever triggers the adaptive immune system, known for its acquired memory of specific bodily invaders, researchers report in the Dec. 24 Proceedings of the National Academy of Sciences. The finding hints that the link between fever and adaptive immunity arose long ago in animals’ evolutionary history, with a truly archaic common ancestor.

“'It was really exciting to see a concrete link between fever and adaptive immunity [in fish]. That’s something that hadn’t been solidified before,” says comparative immunologist Daniel Barreda of the University of Alberta in Edmonton, Canada, who was not involved in the study. The results, he says, nicely show that this is something that had evolved before our ancestors went through the transition from water to land.

***

"...comparative immunologist Jialong Yang of East China Normal University in Shanghai and colleagues investigated immune responses in Nile tilapia (Oreochromis niloticus). Fish are special because they’re the evolutionarily oldest living animals with T cells — key players in the adaptive immune system, Yang says.

"After tilapia were infected with the bacterium Edwardsiella piscicida, they preferred to swim in a water chamber kept at 34° Celsius, about 5 degrees above their typical temperature, for five days. Compared with sick fish kept at their usual temperature, those that sought warmer water had less bacteria in their livers four to six days after infection, and more of them survived.

"Unlike fevers in warm-blooded animals, fish fevers did not cause T cells to multiply into a large number of cells that recognize and attack the specific invader.

"But examining fish spleens five days after infection revealed that fever improved T cell survival and ability to kill infected cells. The researchers found the survival benefit comes from upping T cells’ production of a protein that stops programmed cell death, a response not found in animals before. This effect disappeared eight days after infection, suggesting that disease-fighting T cells were dying off to maintain immune homeostasis.

“'It is becoming increasingly clear that fever is not simply a symptom of infection … it actually plays an important role in the protection against infection,” Barreda says. “We might take Tylenol or fever [reducers] to make us feel better when we have an infection. The question is, what are we giving up?'”

Comment: I always told my patients to allow as much fever as they were comfortable with as fever had an obvious role in immunity.

https://www.newscientist.com/article/2458812-killer-cells-explain-differences-in-immuni...

"As women age, they produce an increasing number of “killer” immune cells, which hunt down and destroy infected cells. This discovery, and the fact that the same isn’t true of men, could help to explain why women are less likely to catch infections but have higher rates of autoimmune conditions.

"We already know that women tend to have stronger immune systems than men, but because studies tend to focus on men or male animals, we lack a detailed understanding of how immunity really differs between the sexes.

***

"Maria Sopena Rios at the Barcelona Supercomputing Center in Spain and her colleagues analysed data on nearly 1.3 million immune cells collected as part of a previous research project. The cells came from blood samples collected from more than 500 female and around 400 male participants, making this the largest study of its kind so far. They were aged from 19 to 97 and all were living in Australia. There were no transgender or non-binary people in the study.

"The researchers found that the number of a subset of CD8 T-cells, which form part of the immune system by killing other cells, increased with age in the female participants, but the same pattern wasn’t seen in the male volunteers.

"This may be why women have a reduced risk of infections, as these T-cells target infected cells. It could also explain why women are more likely to have an autoimmune condition, if the same T-cells mistakenly attack healthy cells.

"For instance, these T-cells also showed genetic changes that have previously been linked to Crohn’s disease, when immune cells attack the gut, and, again, these changes were only seen in the female participants.

"This suggests that differing numbers of these T-cells could partly account for sex-based differences in infections and autoimmunity, though the study didn’t demonstrate a causal link."

Comment: in a sexual species the female is more important than the male. The male fertilizes eggs, but it is the female who carries the forming fetus. This is pure evidence of design while in purposeless evolution this need would not be recognized.

https://www.the-scientist.com/pseudomonas-bacteria-escape-immunity-by-disrupting-energy...

"In a recent publication in eLife, Harvard University molecular microbiologists Laurence Rahme and Arijit Chakraborty found that these bacteria release a chemical that inhibits energy generation in the mitochondria of macrophages, thus dampening the immune response.4 This work identified a new tactic that P. aeruginosa uses to subvert host immunity, and it intimated a new approach for treating the recalcitrant infection.

"One of the chemicals produced by Pseudomonas, called 2-aminoacetophenone (2-AA), is a useful biomarker for Pseudomonas infections in the clinic, but many of its functions, including its effects on innate immune cells, remain unexplored. Previously, the Harvard researchers found that macrophages don’t engulf and dispose of P. aeruginosa—an energy intensive process—in the presence of 2-AA.6 In the present study, they explored which mechanisms 2-AA might use to interfere with macrophage functions, focusing on how this molecule dampens macrophage bioenergetics.

"The team discovered that laboratory cultures of mouse macrophages inoculated with 2-AA produced less adenosine triphosphate (ATP), the molecule that cells use as an “energy currency” to fund energy-demanding biochemical reactions. This confirmed their suspicion that 2-AA dampens energy production in the cell. However, multiple pathways produce ATP. Since some pathways produce more ATP than others, they had to pinpoint the one 2-AA blocks to work out the magnitude of its impact.

"There are two main pathways that cells use to convert glucose into energy. The first is glycolysis, which occurs in the cytoplasm and produces two molecules of ATP per molecule of glucose. Pyruvate, the breakdown product of glycolysis, is then imported into the mitochondria where it fuels other energy-generating pathways, namely the Krebs cycle and oxidative phosphorylation. These produce approximately 30 additional ATP copies. Since only oxidative phosphorylation consumes oxygen, the researchers conducted a Seahorse assay to measure oxygen uptake by the cells using a probe that fluoresces in the presence of this gas molecule.9 Oxygen consumption dropped in cells exposed to 2-AA, revealing that the more-profitable energy-generating pathway crashed.

***

"As Pseudomonas bacteria grow increasingly resistant to antibiotics, researchers need to develop different types of therapeutics to treat them. Kayeen Vadakkan, a microbiologist at St. Mary’s College, Thrissur who was not involved with the work, suggested that 2-AA could serve as a new bull’s eye that drugs could target. “We can complement our immune system,” he said, proposing that drugs that block 2-AA’s effects could give macrophages a boost. Rahme’s laboratory is working on this therapeutic approach. “We’re very excited because the inhibitor of MvfR that we developed is working pretty well,” she said, referring to further research not included in this study. However, more research must take place to assess its efficacy and safety before it can be used in the clinic.

"Besides blocking 2-AA to fight bacteria, researchers could theoretically harness it to stave off autoimmune diseases. In some disorders, such as rheumatoid arthritis and lupus, overactive macrophages exacerbate inflammation.12 “2-AA is a molecule which is anti-inflammatory in nature,” Chakraborty said, suggesting that it may have potential as an immunosuppressive drug."

Comment: Pseudomonas is a tough nasty bug. This exciting research in finding ways to fight it. Of course dhw will point out God allowed this to exist. Iv don't know why, but here we see humans taking up the battle because we have the God-given mental capacity for it.

https://medicalxpress.com/news/2024-11-utis-extraordinarily-common-kidney-infections.html

"Infections in the lower urinary tract rarely migrate to the kidneys, but the precise mechanism that the human body employs to keep the twin organs disease-free has remained a medical mystery—until now.

"A multidisciplinary team at Cambridge University in England solved the conundrum in an elegant series of experiments. Dr. Andrew P. Stewart and colleagues found that highly specialized biological structures called neutrophil extracellular traps—NETs—are pivotal in protecting the kidneys from infection.

"NETs are sticky webs of wispy strands that quite literally serve as traps. They ensnare bacteria that attempt to migrate northward to the kidneys from the lower urinary tract. NETs add to an array of antimicrobial activities mounted by the body to beat back infection.

***

"'These findings highlight the role of NETosis in preventing ascending infections in the urinary tract," Stewart, the study's lead author, wrote. He underscored that NETosis refers to the formation of NETs, which prevent any of the various species of bacteria—E. coli, Enterococcal faecalis, Proteus mirabilis, among others—from migrating upward from the bladder to the kidneys. The study focused on E. coli, the most common bacterial cause of UTIs.

"The process of NETosis is another wonder of human biology. It reveals how the body, and more specifically, the immune system, creates structures to ensnare pathogens. The key entity in NETosis is the neutrophil, an immune cell, which is signaled to undergo a unique form of cell death.

"As it succumbs, the neutrophil releases its DNA, histones, and granule proteins, leaving behind a mesh-like structure, a net. E. coli and other bacteria become entrapped just as insects are snared by a spider's web. The process of NETosis isn't rare because NETs are found in the urine of healthy people, Stewart and colleagues confirmed.

"To get a mental image of a NET, picture a spider's web—not the lacy geometric kind ornamented with dew drops, but the thicker, more heavily woven type found in attics. NETs are created from neutrophils, critically important cells of the immune system. The main difference between a spider's web and a NET is scale. The arachnids' webs are large and visible to the naked eye; a NET is infinitesimal and requires powerful microscopy.

"To be clear, NETs don't stop UTIs from occurring, but they do stop them from spreading and wreaking havoc elsewhere in the urinary tract, the Cambridge team's research demonstrated.

***

"'Lower urinary tract infection is common but only rarely complicated by pyelonephritis," Stewart added. Pyelonephritis refers to an infection in one or both kidneys. The condition, which is marked by pain and potent inflammation, requires immediate medical care, doctors say, because in some instances, pyelonephritis can be life-threatening.

"As part of the study, the Cambridge team analyzed urine samples from 15 healthy people. The scientists found that one biological entity stood out in each of the samples—the presence of NETs. These structures interacted with a protein called uromodulin, which aided in the formation of large webs that entrapped disease-causing bacteria.

"The authors validated these findings in mouse models of UTI caused by E. coli. Stewart and colleagues found that interrupting NET formation allowed bacteria to invade the kidneys.

"We identified neutrophil extracellular traps in healthy human urine that provide an antibacterial defense strategy within the urinary tract," Stewart asserted.

"Additionally, the Cambridge experiments showed that leukocyte esterase dipstick tests—one of the most common for UTI detection—work by highlighting neutrophils. It was long assumed that the test was detecting the overall neutrophil count. But Stewart and collaborators found that it actually was working by pinpointing neutrophils that had released NETs.

"'Not only did this study highlight the role of NETosis … but it also revealed that the mechanistic underpinning of the decades-old and ubiquitous urine dipstick has been somewhat misunderstood," Stewart concluded."

Comment: this form of kidney protection looks like a designed mechanism.

https://www.sciencedaily.com/releases/2024/11/241120121641.htm

"The immune system protects the body from infections and cancer with the help of a diverse array of T cells, a type of white blood cell. T cells must first be trained to recognise threats without attacking the body's own healthy cells. The thymus, a small organ behind the breastbone, is where this crucial T cell training occurs.

"When the thymus malfunctions, it can result in weakened immunity or autoimmune diseases, where the body mistakenly attacks itself, leading to conditions such as type 1 diabetes or rheumatoid arthritis.

"Despite its importance, little is known about the early development of the thymus, as it uniquely functions primarily during infancy and then gradually degenerates over the lifespan2. Studying its early stages could allow us to understand why immunity wanes with age, leaving older adults vulnerable to infection and less responsive to vaccines.

"In this new study, researchers from the Wellcome Sanger Institute and their collaborators tracked thymus and T cell development in samples ranging from eleven weeks post-conception to three years old4 using single cell sequencing and advanced spatial mapping techniques.

"They discovered that the organ's basic structure and function is established as early as twelve weeks post-conception, suggesting that early pregnancy factors may have a more profound impact on lifelong immune function than previously recognised.

"The team uncovered key differences in the development of various T cells types5 -- some that help orchestrate immune responses by directing other immune cells and others that directly attack infected or cancerous cells. This understanding could inform new T cell engineering therapies that selectively boost immunity for cancer treatments or suppress it for autoimmune conditions and transplants.

"The researchers also discovered locations of progenitor cells that give rise to important supporting cells in the thymus which also mimic the body's own environment so that T cells would not react to self. This could help researchers in the future to create an artificial thymus for regenerative immune therapies for older adults or people with compromised immune systems.

***

"OrganAxis lets us integrate different spatial datasets to uncover hidden properties that go unnoticed when viewed individually. Using key structures as reference points, much like a hiker uses landmarks to navigate, we now see how structures are formed early on, enabling us to track T cell training over time."

"Dr Veronika Kedlian, co-first author of the study formerly at the Wellcome Sanger Institute, and now based at the Cambridge Stem Cell Institute, University of Cambridge, said: "Our atlas of healthy thymus development could lead to new strategies for boosting immunity, particularly in older adults or those with thymus deficiencies."

Comment: it is amazing to see immune preparations in the fetus for anticipated future infections. This can't evolve in an evolutionary process conducted solely by chance mutations and is strong evidence for design.

https://www.sciencedaily.com/releases/2024/11/241112123305.htm

"Immune cells are capable of detecting infections just like a sniffer dog, using special sensors known as Toll-like receptors, or TLRs for short. But what signals activate TLRs, and what is the relationship between the scale and nature of this activation and the substance being detected?

***

"TLRs are found in great numbers on the surface of many of our cells, particularly those in the mucous membranes and those ofour immune system. They work like the olfactory receptors in our nose, being activated when they encounter a specific chemical signal. The alarm that they trigger starts a series of reactions inside the cells. When scavenger cells "sniff out" a bacterium, for instance, they initiate a process known as phagocytosis by engulfing and digesting it, while other immune cells release special messengers that call for reinforcements and thus provoke inflammation.

"There are several groups of TLRs, each of which responds to different "smells." "These are molecules that have crystallized into important danger signals over the course of evolution," explains Professor Günther Weindl from the Pharmaceutical Institute at the University of Bonn. Among them are lipopolysaccharides (LPS), which form integral parts of a bacterium's cell wall.

***

"'We were able to demonstrate that these changes in the reflected wavelengths kick in just a few minutes after adding the signal molecule," says Weindl's colleague Dr. Janine Holze. "We also brought cells into contact with E. coli and Salmonella lipopolysaccharides. Although both components of the cell wall stimulate the same TLR, the reflected spectrum changed in a different way after introducing the E. coli LPS than after adding their Salmonella counterparts." This suggests that the same receptor is activated by different molecules in different ways and then triggers specific responses depending on the signal." (my bold)

Comment: these reactions are very specific and suggest strongly that they were designed.

https://www.the-scientist.com/worms-nose-for-danger-helps-ward-off-pathogens-72309

"Just like humans, Caenorhabditis elegans worms encounter gut-attacking bacterial pathogens through their diet. To thrive in their new hosts, bacteria seek out iron. To protect their iron supplies, which are stored in mitochondria, the worms activate a defense tactic. How the worms detect these environmental threats and trigger a mitochondrial response intrigued scientists, including Andrew Dillin, a molecular and cell biologist at the University of California, Berkeley.

***

"Dillin and his team showed that C. elegans worms’ sense of smell coordinates a mitochondrial response, particularly in intestinal cells, to resist bacterial infection.1 The researchers speculate that this process is conserved in mammals for pathogen detection and immune regulation.

"The researchers focused their investigation on a pair of olfactory neurons called amphid wing "C" (AWC), which serve as a scent detection system by activating in the absence of odor and turning off when odors are present. Researchers previously found that ablating these neurons boosted pathogen resistance and improved worm survival.2 However, it was unclear how this might be connected to the mitochondrial stress response.

***

"Not only did these worms show resistance to infection, but they also exhibited an increase in activity of a transcription factor that typically shows up during the mitochondrial unfolded protein response (UPRMT), a process triggered when mitochondria are overwhelmed with an onslaught of misfolded proteins. This led to changes indicative of protective efforts: reduced oxidative phosphorylation, oxygen consumption rates, and mitochondrial DNA (mtDNA) levels.

"Under the microscope, they found that the pathogen triggered mitochondrial responses throughout the bodies of AWC-silenced worms. These worms had a reduced intensity of stain, indicating fewer mitochondria, which correlated with lower activity and mtDNA levels. These findings suggest that smelling a pathogen prepares the worm’s gut against infection.

***

"The researchers tested whether loss of tryptophan hydrolase 1, the gene required for serotonin synthesis, was required for AWC-mediated UPRMT induction. The absence of serotonin signaling inhibited the mitochondrial stress response, but exogenous serotonin supplementation activated UPRMT, showing that mitochondrial changes rely on serotonin signaling.

"Dillin wondered whether the loss of AWC affected mitophagy, another maintenance pathway that removes damaged or excess mitochondria, and if the observed reduction in oxygen consumption and mtDNA was a consequence of mitochondrial clearance. Mutant worms lacking a key mitophagy gene were more sensitive to P. aeruginosa infection. When Dillin and his team delved into the mechanisms underlying this effect, they found that the mitophagy gene is required for the reduction in oxygen consumption and mtDNA observed in AWC-ablated worms.

“'And [this olfactory response] actually does even more than protect mitochondria. It [caused mitophagy], splitting the mitochondria up into smaller units, so there's less opportunities for the pathogen and it can't find all the mitochondria,” said Dillin. Although mitophagy seems to be an anticipatory strategy to resist pathogenic insult, Dillin noted that there is still much to learn about this process."

Comment: this is a clear example of an automatic protein trigger for response to a specific danger. No thought involved.

https://mail.google.com/mail/u/0/#inbox/FMfcgzQXJZsNsSCMXzccGPLGbzdxznnK

"Initially mistaken for neutrophils, a population of atypical macrophages appears in the lungs after severe viral infection, orchestrates tissue repair, and then vanishes.

***

"Monocyte-derived macrophages recruit to the lungs en masse during the short window immediately following viral infection, so Marichal and his colleagues were at a loss as to why they appeared in such large numbers in the lungs of people who had already recovered from the virus.

***

"Now, in a recent Science Immunology study, Marichal and his colleagues confirmed that these unusual cells that emerged following an IAV infection are macrophages, and that they facilitate the repair of alveoli in the lungs following severe viral infections in mice. The findings highlight a novel population of macrophages that could be targeted therapeutically to treat lung damage.

***

"Subsequent single-cell RNA sequencing and transmission electron microscopy experiments further confirmed that the Ly6G+ macrophages were distinct from neutrophils. During severe respiratory illness, such as COVID-19 or IAV, Marichal said, lungs sustain patches of damage to the alveoli, impairing gas exchange. Once the infection has been cleared, the lesions are repaired by progenitor cells, which differentiate into epithelial cells that form new alveoli. Using confocal microscopy to peer into the lungs of mice that had cleared IAV infections, the team found Ly6G+ macrophages located near the damaged tissue in the space between the alveoli, where they clustered with progenitor cells. The team hypothesized that the Ly6G+ macrophages were orchestrating damage repair by giving instructions to the progenitor cells.

"Further experiments confirmed that Ly6G+ macrophages release soluble factors that instruct the progenitor cells to proliferate and differentiate. They found that this function was partly dependent on signaling via the interleukin-4 (IL-4) receptor, which is known to induce a repair phenotype in other macrophages.

"To explore the full capabilities of these interesting cells, the team turned their attention to other types of injury and different organs. They found that Ly6G+ macrophages repair the lungs and liver of mice after drug-induced injuries as well. The team also showed that monocyte-derived macrophages present in samples of lung fluid from humans with suspected pneumonia are transcriptionally similar to Ly6G+ macrophages in mice."

Comment: an amazing group of cells like teams from FEMA in the USA doing emergency management in storm-battered areas. The cells act with purpose and this is more evidence for design.

https://www.the-scientist.com/dna-sensing-enzyme-wins-the-2024-lasker-award-72188

"...for the discovery of the cGAS enzyme that spots DNA threats from foreign pathogens and self-DNA, caused by cellular stress or damage, in the cytosol. Like the first domino in a chain reaction, its activation sparks a cascade of events, triggering immune and inflammatory responses.

***

"DNA is normally contained in the nucleus and mitochondria, so when it shows up where it doesn’t belong—like outside the cell or floating in the cytoplasm—the cell immediately sounds the alarm. Cells have built-in detectors called pattern recognition receptors that sense pathogen- and self-derived threats. Toll-like receptors are one line of defense along the cell surface and endosomes that can detect nucleic acids signaling potential danger. Once the alert goes out, the cell gets busy, cranking out proinflammatory cytokines, chemokines, and type I interferons (IFNs) to rally the troops and take down the pathogen.

***

"In 2005, Chen and his team discovered a novel protein called mitochondrial antiviral signaling (MAVS)—which recognized viral RNA—named in homage to its localization on the mitochondria and the Dallas Mavericks. It was one of the first mitochondrial proteins shown to have a direct role in innate immunity. Suppressing MAVS blocked IFN production, making cells vulnerable to viral replication and death. Overexpression, however, conferred antiviral immunity, shielding cells from damage.

***

"...independently identified an essential adaptor protein on the endoplasmic reticulum that is involved in DNA sensing. This protein, which Barber named stimulator of interferon genes (STING), mobilized cells to activate the transcription factors nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) to pump out type I IFNs like interferon beta (IFN-β). Cells missing the STING protein were highly vulnerable to viral infections. Just as MAVS acted as the adapter protein in the RNA pathway, Barber’s group reported STING as the adapter in the DNA pathway. However, despite STING’s importance, it does not directly sense DNA—there was a missing link.

***

"The team suspected they had discovered a novel second messenger. Upon further investigation, they found that the molecule was GMP and AMP joined together by two phosphodiester bonds: cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), the first cyclic di-nucleotide in mammalian cells. “This pathway is highly conserved during evolution. It originates in bacteria and is very important for immune defense against bacteriophage infection. cGAS’s antiviral function has been conserved for billions of years from bacteria to humans,” remarked Chen.

"Their findings demonstrated that cytoplasmic DNA, not RNA, set off a chain of events. cGAMP functioned as an endogenous second messenger to activate downstream signaling events that trigger antiviral immunity. However, Chen wanted to figure out the enzyme that made cGAMP.

***

"Because cGAS was the only candidate that produced cGAMP activity, this finding solidified its place as the elusive cytosolic DNA sensor to complete the cGAS-cGAMP-STING pathway.

“'It was quite a surprise that this sensor turned out to be an enzyme,” said Chen. “[However], it became very clear after we discovered cGAS [that] it was a very simple and clear mechanism of action.”

"Together, his work established that DNA bound to cGAS directly, changed its conformation, and generated cGAMP to, in turn, prod STING to trigger type I IFN production and elicit an innate immune response.

***

"However, this powerful sensor can be a double-edged sword. While DNA is safely tucked away in the nucleus or mitochondria, some conditions result in self-DNA getting into the cytoplasm and inadvertently activating cGAS. Instead of protecting the body’s cells, this pathway has been linked to many different diseases: autoimmune diseases, like lupus and arthritis; inflammatory diseases, like myocarditis; and neurodegenerative diseases, like Parkinson’s disease and Alzheimer’s disease.13–15 “Our own DNA becomes the culprit of these diseases,” said Chen.

"While aberrant expression of cGAS can wreak havoc on the body, Chen and others uncovered cGAS’s importance in immune defense against DNA viruses, bacteria, and even retroviruses like HIV.16 Plus, this small molecule is a very potent immune adjuvant for boosting antibody production in enhanced T cell activation."

Comment: how can a complex system like this develop? Can an evolutionary system based on chance mutations achieve it? I strongly doubt it. It had to be designed. What is amazing is how many different ways the immune system protects us.

https://www.sciencealert.com/human-defenses-against-viruses-first-evolved-billions-of-y...

"Long before multicellular life evolved, our planet was home to a widespread group of ancestral microbes.

"The living descendants of these ancient microbes were only discovered in 2015 through traces of their DNA, deep in the ocean between Greenland and Norway. Five years later, the lurking lifeforms – a superphylum of archaea called Asgard – were successfully grown in the lab for the first time.

"At first glance, under the microscope, they looked a lot like bacteria. But archaea cells are evolutionarily closer to eukaryotic life forms, like plants and animals, than they are to their simpler microbial cousins.

"Based on their genomes, some scientists think Asgard archaea and our eukaryotic ancestors parted ways around 2 billion years ago, paving the way for all complex life on Earth, including animals, plants, fungi, protists, and most algae.

"Whatever that common ancestor looked like, at some point they had to incorporate a nucleus into their basic structure. Some scientists suspect Asgard ancestors developed one from a virus, which established a protective compartment referred to as a viral factory. Mitochondria, meanwhile, might have come from gobbling up a bacterial ancestor. (my bold)

***

"The team found that compared to bacteria, Asgard archaea have evolved a broad array of defense systems, some of which are also innate in eukaryotes.

"Of all the defense systems in the genomes from Asgard archaea analyzed, roughly 2 percent were linked to an immune protein, called viperin, which combats a wide array of viral infections by seemingly 'silencing' viral reproduction.

"Today, viperin plays a role in the immune systems of all complex life on Earth, which suggests it was present in the last common ancestor of archaea and eukaryotes.

"According to the new findings, eukaryotic viperins and Asgard viperins are "sister proteins and share a common ancestor".

"'It says that not only did eukaryotes get all these rich structural proteins that we've seen before in Asgards," explains integrative biologist Brett Baker from UT, "now it's saying that even some of the defense systems in eukaryotes came from Asgards."

"In addition to viperin, nearly 8 percent of the Asgard archaea defense genes analyzed were associated with argonautes. These are immune proteins that chop up DNA to halt the spread of a virus.

"In all domains of life on our planet, from archaea and bacteria to eukaryotes, argonautes act as "programmable immune systems"."

Comment: dhw asks why viruses were created. This article shows how viruses helped in developing eukaryote cells. ID theorists allow for some natural evolutionary processes at work along with active design work.

https://www.nature.com/articles/s41591-024-03152-x?utm_source=Live+Audience&utm_cam...

"The human brain is usually considered to be beyond the reach of most immune cells. However, analysis of people who have a type of brain tumour called glioblastoma has revealed tumour-targeting T cells in the skull bone marrow adjacent to the tumour. Some of the characteristics of the cells hint that they’re something special. For example, their high expression of sphingosine-1-phosphate receptor 1 (S1PR1) protein, which signals to T cells to go out on the hunt, that the skull bone might serve as a reservoir for immune cells. And T cells isolated from skull bone marrow remain activated after rounds of restimulation — avoiding ‘exhaustion’, which is one of the main obstacles to immunotherapy."

Comment: just an article summary. Finding those cells is a surprise. S1PR1 protein implies design.

https://www.the-scientist.com/vitamin-d-acts-via-the-microbiome-to-boost-cancer-immunit...

"They found that vitamin D acts through a binding protein, Gc globulin, and the gut resident Bacteroides fragilis to stimulate antitumor immunity in mice. These findings demonstrate for the first time a connection between vitamin D metabolism, a specific species of the microbiome, and the immune response to cancer in a living organism.

***

"Vitamin D is best known for its role in bone growth and development, where it facilitates the absorption of calcium, phosphate, and magnesium. More than a century ago, deficiency of this vitamin was identified as the cause of the bone disease rickets. Since then, researchers have found vitamin D to potentially play in a role in a number of other conditions, including cardiovascular diseases, autoimmunity, and cancer. However, vitamin D does not act alone. Recent evidence suggests that the gut microbiome, located at the interface of the intestinal lumen and epithelia where dietary vitamin D is absorbed, works synergistically with this vitamin to modulate the immune system. (my bold)

***

"When Reis e Sousa and his team investigated the secreted form of the actin-severing protein gelsolin (sGSN), which is produced by damaged and cancerous cells, they found that lower levels of sGSN expression, or mutations in actin-associated proteins, correlated with enhanced antitumor immunity and increased patient survival.

“'The serendipity comes from the fact that Gc globulin has a separate actin-binding domain and functions as an actin scavenger with secreted gelsolin,” he noted.

***

"The fecal transplant experiment confirmed that the tumor resistance was transmissible. The team also observed that treating the Gc-deficient mice with antibiotics diminished their tumor resistance following fecal transplant, further implicating the gut microbiome. They found that this resistance was enhanced when they fed the mice a high-vitamin D diet. The fact that they did not observe this effect in mice with deficiencies in other immunity-related genes that underwent the same treatments validated Gc as the protein linking vitamin D metabolism with the gut microbiome.

"Next, Reis e Sousa and his colleagues zeroed in on which microbiome species might confer this resistance. Shotgun metagenomic analysis revealed that one species, B. fragilis, was marginally elevated in the fecal samples from mice on a high vitamin D diet. When the team administered B. fragilis to the mice orally, they noted tumor immunity in mice on a standard vitamin D diet, but not in those on a vitamin D deficient diet. “[B. fragilis] is a candidate as it can phenocopy the effects. But it might work with other microbes, and we need to repeat the experiment in germ-free mice to assess whether other species are involved,” said Reis e Sousa.

***

“'The novelty of this study is not so much that vitamin D regulates the immune response or has a role in cancer. It has not yet been reported mechanistically how vitamin D does this,” said Alessio Fasano, a gastroenterologist and nutritionist at Harvard Medical School, who was not involved in this study. “This article shows how this happens by using both animal models and a human study, and that is why it is so significant.”

"Fasano noted, "It still needs to be captured by clinical trials, but there is applicability of their findings in that vitamin D could be included in cancer treatment and vitamin D levels reported over time…There is new respect for vitamin D.'”

Comment: it has always been acknowledged that Vitamin D helped immunity. But this entangled system involving gut biome is a big surprise, and a major discovery.

https://www.quantamagazine.org/the-brainstem-fine-tunes-inflammation-throughout-the-bod...

"Last month, researchers discovered cells in the brainstem that regulate inflammation throughout the body. In response to an injury, these nerve cells not only sense inflammatory molecules, but also dial their circulating levels up and down to keep infections from harming healthy tissues. The discovery adds control of the immune system to the brainstem’s core functions — a list that also includes monitoring heart rate, breathing and aspects of taste — and suggests new potential targets for treating inflammatory disorders like arthritis and inflammatory bowel disease.

"During an intense workout or high-stakes exam, your brain can sense the spike in your heart rate and help restore a normal rhythm. Likewise, the brain can help stabilize your blood pressure by triggering chemical signals that widen or constrict blood vessels. Such feats often go unnoticed, but they illustrate a fundamental concept of physiology known as homeostasis — the capacity of organisms to keep their internal systems working smoothly and stably amid shifting circumstances.

"Now, in a paper published on May 1 in Nature, researchers describe how homeostatic control extends even to the sprawl of cells and tissues that comprise our immune system.

***

"These neurons operate like a “volume controller” that keeps the animals’ inflammatory responses within a physiological range, said paper author Hao Jin, a neuroimmunologist at the National Institute of Allergy and Infectious Diseases.

"The discovery may come as a surprise to immunologists who assume that the strength of an immune response is governed by the immune system’s own set of regulatory mechanisms, said the immunobiologist Ruslan Medzhitov of Yale University, who was not involved in the study. “We’ve never suspected that there will be something else on top of it, that we need an additional control. But clearly we do,” he said. “That’s what this work revealed: There are parts of the brainstem dedicated to this control.”

***

"Such studies helped usher in a “transformation in the way we think about the brain,” Zuker said. Historically considered the seat of memory and emotion, the brain may devote far less energy to these higher-order functions than to monitoring the body’s organs, physiology and metabolism to maintain homeostasis. “Everyone in the lab began to think about that,” he said. “How far does the brain’s control over body biology go?”

***

"He and his colleagues wanted to figure out which brain circuits were involved. In one experiment, they cut the vagus nerve and saw that, without its input, the brainstem neurons remained inert — demonstrating the vagus nerve’s central role in this brain-body immune circuit. Then they used genetic techniques to dial the brainstem neurons’ activity up or down. When dialed down, the mice experienced an out-of-control inflammatory response, with a corresponding rise in pro-inflammatory molecules and a dip in anti-inflammatory molecules. Dialing up the brainstem cells’ activity did the opposite: Anti-inflammatory molecules shot up, while levels of pro-inflammatory molecules plummeted, putting a damper on inflammation."

Comment: this is typical feedback system used throughout the body to maintain exact controls. It requires an appreciation of the necessity for control. Only design can accomplish this result.

https://medicalxpress.com/news/2024-06-scientists-decades-mystery-nlrc5-sensor.html

"One of the key innate immune strategies to respond to threats is through cell death. New research from St. Jude Children's Research Hospital discovered that NLRC5 plays a previously unknown role as an innate immune sensor, triggering cell death. The findings, published in Cell, show how NLRC5 drives PANoptosis, a prominent type of inflammatory cell death. This understanding has implications for the development of therapeutics that target NLRC5 for the treatment of infections, inflammatory diseases and aging.

***

"Nucleotide-binding oligomerization domain-like receptors (NLRs) are a large family of important molecules involved in inflammatory signaling. They are generally thought to function as innate immune sensors that detect threats. However, the specific roles of several NLRs in sensing are not yet understood. Scientists at St. Jude conducted a large screen, testing a specific NLR, NLRC5, to see what threats activate it. Through their efforts, they discovered that depletion of nicotinamide adenine dinucleotide (NAD), a molecule essential in energy production, triggers NLRC5-mediated cell death through PANoptosis.

***
'
"Among all the combinations we tested, we identified that the combination of heme plus PAMPs or cytokines specifically induces NLRC5-dependent inflammatory cell death, PANoptosis," said co-first author Balamurugan Sundaram, Ph.D., St. Jude Department of Immunology. "Our results showed for the first time that NLRC5 is central to responses to hemolysis, which can occur during infections, inflammatory diseases and cancers."

"Upon identifying the heme-containing PAMP, DAMP and cytokine combinations that trigger NLRC5-dependent inflammatory cell death, the researchers further investigated how NLRC5 is regulated. They found that NAD levels drive NLRC5 protein expression. If NAD is depleted, that sounds an alarm that there is a threat the immune system should recognize. The researchers found that depletion of NAD is sensed by NLRC5, triggering PANoptosis.

"'By supplementing with the NAD precursor, nicotinamide, we reduced NLRC5 protein expression and PANoptosis," said co-first author Nagakannan Pandian, Ph.D., St. Jude Department of Immunology. "Therapeutically, nicotinamide has been widely studied as a nutrient supplement, and our findings suggest it could be helpful in treating inflammatory diseases."

"The researchers also discovered that NLRC5 is in an NLR network with NLRP12, which come together with other cell death molecules and form an NLRC5-PANoptosome complex that triggers inflammatory cell death. The finding builds on previous research by the Kanneganti lab showcasing the role of NLRP12 in PANoptosis."

Comment: cell death is so important it needs these complex steps of control. This was designed, not by chance.

https://www.the-scientist.com/an-immune-mechanism-maintains-memory-71925

"Cooperating neurons form the physical structure of a memory, but how these assemblies form and persist as long-term memories still stumps scientists. After an event, brain activity increases in the hippocampus, which consolidates information and holds short-term memories. However, long-term memories are stored in the cortex, which means that the two regions must be able to communicate.

***

"In neurons, both stress and activation lead to double stranded DNA (dsDNA) breaks predominantly in the mitochondria and genome, respectively.2,3 To determine the source of dsDNA, the team isolated and sequenced extranuclear DNA from neurons after fear conditioning and showed that these fragments belonged to genomic DNA. Additionally, immunofluorescent labeling of a histone variant that denotes dsDNA breaks confirmed that these breaks occurred specifically in neurons.

***

"One hour after conditioning, the researchers showed that channels formed in the nuclear membrane that permitted the dsDNA fragments to exit the nucleus near the endoplasmic membrane where TLR9 also resides; a small number of these channels remained visible through the 96-hour observation period. The team confirmed by using microscopy that TLR9 and dsDNA fragments associated together. Starting at six hours after fear conditioning, the dsDNA localized near the centrosome, where the team also identified a DNA damage repair enzyme.

"To explore the function of dsDNA breaks and TLR9 activation further, the team generated mice with the TLR9 gene knocked out (TLR9 KO) specifically in neurons using adeno-associated viral delivery of Cre-recombinase. TLR9 KO animals exhibited impaired memory and learning after fear training compared to wild type mice.

"While fear conditioning induced expression in genes related to ER proteins, vesicle transport, and interleukin-6 and TLR9, TLR9 KO animals failed to express these genes. Absence of TLR9 in neurons also reduced the localization of DNA repair proteins and the production of extracellular structures previously shown to be important for memory.

"Jacob Raber, a neuroscientist at the Oregon Health and Science University who was not involved with the study, said that the finding linking the immune system to the formation of memory was striking. “It drives home the idea that you need immune activation,” he said. “If you don't have any, it's not good. If you have too much, it's not good. If it's chronic, it's not good.'”

Comment: such specificity of a fragment of DNA strongly suggests design.

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/07_june_2024/420012...

"After antigen stimulation, naïve T cells display reproducible population-level responses, which arise from individual T cells pursuing specific differentiation trajectories. However, cell-intrinsic predeterminants controlling these single-cell decisions remain enigmatic. We found that the subcellular architectures of naïve CD8 T cells, defined by the presence (TØ) or absence (TO) of nuclear envelope invaginations, changed with maturation, activation, and differentiation. Upon T cell receptor (TCR) stimulation, naïve TØ cells displayed increased expression of the early-response gene Nr4a1, dependent upon heightened calcium entry. Subsequently, in vitro differentiation revealed that TØ cells generated effector-like cells more so compared with TO cells, which proliferated less and preferentially adopted a memory-precursor phenotype. These data suggest that cellular architecture may be a predeterminant of naïve CD8 T cell fate.

***

"Together, our results reveal an important role for cellular architecture in regulating T cell function. By combining automated microscopy with deep learning, we provide a morphological framework that can be used to investigate, predict, and control the response of individual T cells upon antigen encounter.

Comment: simply T cells are pre-programmed for specific responses to a variety of antigens. Once responded they maintain a lifetime of protection. A huge article filled with complex data.

https://www.the-scientist.com/cell-surface-rna-helps-neutrophils-get-around-71758?utm_c...

"...when RNA molecules were detected on the surface of several cell types, researchers wondered what purpose they might serve. A recent study has revealed one of their functions: mobilizing immune cells to inflamed tissue.

"Published last month in Cell, a Yale University team led by geneticist Jun Lu and pharmacologist Dianqing Wu described how cell surface RNA helps neutrophils latch onto endothelial cells and infiltrate tissue. Removing the molecules prevents the immune cells from reaching inflammatory sites in mice, highlighting their role in the immune system’s response to potential threats.

***

"Proof of cell-surface RNAs first came to light in 2020, when they were detected on immune cells in human blood.2 The following year, Bertozzi’s group found the molecules littering the surface of cancer cells and stem cells, where they are welded to a sugar chain.3 Like glycoproteins and glycolipids, this new category of molecule, christened glycoRNAs, appeared to bind to immune receptors, pointing to potential immunoregulatory functions.

"When Lu came across these papers, he responded with a healthy dose of skepticism. After all, he reasoned that any exposed RNA should be torn apart by RNases, RNA-degrading enzymes that roam the blood plasma.

***

"His team began by using a chemical marker called biotin to label any sugar chains present on the neutrophil surface, tagging glycoproteins, glycolipids, and—potentially—glycoRNAs. Without rupturing the cell membrane, they purified RNA from labeled cells and then applied RNase at concentrations far higher than typically found in the human body. If the enzyme diminished the biotin signal, some sugars on the cells must be bound to extracellular RNA. To Lu’s surprise, the signal vanished, confirming the presence of glycoRNAs on the cell surface.

"If glycoRNAs share similar functions to glycoproteins and glycolipids, they may help immune cells reach inflammatory sites. To test this, the researchers dyed some neutrophils red and degraded their extracellular glycoRNAs using RNase. They labeled other neutrophils green but left their surface RNAs intact. After injecting the dyed cells into a mouse that had abdominal inflammation, Lu’s team found that the cells lacking glycoRNAs were less likely to reach the stomach.

"To infiltrate tissue, neutrophils must first latch onto exterior cells and then traverse through several cell layers. Lu wondered whether glycoRNAs contributed to both stages of this process, so his team placed neutrophils on one side of a cultured endothelial layer and a chemoattractant on the other. Immune cells lacking glycoRNAs showed less adhesion and reduced migration through the cell layer in vitro. Without the endothelial barrier, the cells migrated normally, suggesting that glycoRNAs do not affect cell mobility.

"To uncover how neutrophil glycoRNAs mediate attachment to endothelial cells, the researchers split the molecule into its sugar and RNA components. Saturating the same cell culture system with glycans blocked the immune cells from migrating through the endothelial layer, while RNA saturation had no effect. The findings suggested that—in a similar manner to other glycoconjugates—the glycan portion latches onto endothelial cells, while the RNA tethers the sugar to the membrane.

***

"After culturing the cells together for three days, the team detected the chemical tags on only green cells, suggesting that the RNA is produced in-house rather than transferred from the external environment.

"Sequencing the glycoRNA molecules turned up hits for ribosomal RNA, transfer RNA, and small nucleolar RNAs, suggesting that they may be repurposed fragments of noncoding nucleic acids. Yet the rules that determine which bits of RNA end up on the membrane, and how they are protected from degradation, are unclear."

Comment: T cells need to be guided to spots requiring inflammation. That RNA's are freely acting as chaperons is an amazing finding. The group of various RNAs are truly the workhorses of the genome. DNA is an inert code until activated by RNA actions.