DAVID: Where are cell communities in the paragraph? Bacteria are individuals in colonies , and are programmed to dictate necessary mutations, as if with purpose..

dhw: A colony is a community, and the above specifies that the process is “translated across the tree of life” when all “cells/organisms are maladapted to their environments”. I don’t know why you refuse to recognize that organisms consist of cell communities. It is your belief that they are programmed, whereas many scientists believe they work things out for themselves.

DAVID: Just because bacteria live together, doesn't mean they cooperate. However there are special forms of amoeba that show great cooperation. It is a step up in evolution.

So different individual cells form a community (e.g. a biofilm), and we know that they communicate, and we know that they can play different roles within that community which can then perform feats which the individual bacterium cannot perform on its own, but according to you that doesn’t mean they cooperate.

DAVID: We're back to the same argument about the possible presence of purpose and design.

dhw: Of course there is purpose and design: in my hypothesis, the purpose is to adapt to or exploit new conditions in order to improve chances of survival, and the design is done by the cells/cell communities themselves with their possibly God-given intelligence. The question of your God’s purpose in setting it all up continues to be debated under “Big brain evolution”.

DAVID: I can accept God-given instructions, as usual.

You can believe in them if you wish, but that does not alter the fact that my hypothesis provides purpose and design.

DAVID: The issue is how did bacteria develop the ability to self-mutate?

dhw: The issue in this post is whether bacteria do their own designing using their (possibly God-given) intelligence, or your God provided the first cells with programmes to be passed on for every single mutation throughout the history of life. I really don’t know how often I have to repeat that my hypothesis of cellular intelligence leaves open the question of origin, but I usually append “possibly God-given”. Please stop changing the subject and setting up straw men!

DAVID: Not a straw man. You can postulate cell intelligence, but can't tell me where it came from. Intelligence requires Thinking and a mind.

Nobody can tell us where life came from, and no believer can tell us where his God came from. That is why we theorize. The fact that you believe God exists, and that he provided the first cells with programmes for every single undabbled life form, econiche etc. does not in any way invalidate the postulation of cellular intelligence. I agree that intelligence requires a form of thinking, but that does not mean the cell has to have a brain like ours.

Appears it is a matter of time interval:

https://www.sciencedaily.com/releases/2019/05/190503100812.htm

"A team led by the Freiburg biologists Prof. Dr. Wolfgang Schamel and Prof. Dr. Wilfried Weber conducted an experiment in which they controlled the duration of the interaction of a specific protein with T cells, a type of white blood cells, thereby showing how the immune system differentiates between self and non-self molecules.

"The function of the immune system is to distinguish between the body's own cells and pathogens. To protect the body from disease, it must recognize and attack these pathogens without damaging its own cells. T cells are an important cell type of the immune system that have a central role in this process. Via their T cell receptor, they bind not only to non-self, pathogen molecules but also to their own, non-pathogenic molecules.

"Exactly how T cells differentiate between self and non-self molecules is a central question in immunology. Since 1995, it has been assumed that the T cell measures how long the molecule interacts with the receptor. If a molecule binds for a long time, it is classified as a pathogen; if it binds briefly, it is self. Because it has not yet been possible to experimentally control the duration of the binding, this hypothesis could until now neither be confirmed nor refuted.

***

"The Freiburg experiments supports the theory that T cells distinguish self and non-self, pathogenic molecules on the basis of the interaction time."

Comment: Immunity to protect living organisms must exist in all or life would not survive. It must be assumed and appears supported by genome research that dangerous viruses appeared as life started. The immune systems must have been designed from the beginning, an d are so complex chance development is not possible.

Immunity varies in the gut, depending on the level:

https://medicalxpress.com/news/2019-05-reveals-gut-segments-function.html

"As food enters the intestine, it embarks on windy, lengthy journey. For most of the route, its surroundings don't appear to change much. But new research from Rockefeller's Daniel Mucida shows that the food-processing canal consists of compartments that pace the immune system's reactions to the food passing through—with less aggressive defenses in the first segments where nutrients are absorbed, and more forceful responses at the end, where pathogens are eliminated.

"The findings, published in Nature, provide new insights about how the intestine maximizes nutrient uptake while protecting the body from potentially dangerous invading microbes, two seemingly conflicting functions. The research has potential to improve drugs for gastrointestinal disorders, as well as inform the development of oral vaccines.

"'At first glance the intestine appears uniform throughout," says Mucida. "But we've found a sophisticated functional system lurking beneath the surface, organized in segments to allow different immune system functions in different locations."

"Mucida and colleagues uncovered a functional segmentation in mice by examining intestinal structures called gut draining lymph nodes, which orchestrate immune responses. The researchers found that nodes in different part of the intestine had different cell composition, and when they challenged the mice with a pathogen such as Salmonella, they saw different immune responses between segments.

"Having immune responses separated by location likely increases the chance that the immune system reacts appropriately to what's passing through, Mucida says. Once most nutrients have been absorbed, the system can focus more aggressively on eliminating pathogens without interfering with food uptake."

Comment: as long guts were developed, it is obvious the immune system had to be designed this way for protection from pathogens. if organisms waited for chance development, they have not survived to evolve further.

All our lives we must develop new defenses against newly contacted illnesses. This article tells us how it is done:

https://phys.org/news/2019-09-loops-dna-packaging-diverse-antibodies.html

" Diversity is good, especially when it comes to antibodies. It's long been known that a gene assembly process called V(D)J recombination allows our immune system to mix and match bits of genetic code, generating new antibodies to conquer newly encountered threats. But how these gene segments come together to be spliced has been a mystery.

"A pair of enzymes called RAG1 and RAG2, the researchers show, couple with mechanisms involved in making the chromatin loops to initiate the first step of V(D)J recombination—joining the D and J segments. The RAG 1/2 complex first binds to a site on an antibody gene known as the "recombination center." As the DNA scrolls past during the process of loop formation ("extrusion"), the RAG complex scans for the D and J segments the cell wants to combine. Other factors then impede the extrusion process, pausing the scrolling DNA at the recombination center so that RAG can access the desired segments.

"'The loop extrusion process is harnessed by antibody gene loci to properly present substrate gene segments to the RAG complex for V(D)J recombination," says Alt.

"While many of the hard-wired chromatin loops are formed and anchored by a factor known as CTCF, the Alt lab shows that other factors are involved in dynamic situations, like antibody formation, that require new loops on the fly. The study also establishes the role of a protein called cohesin in driving the loop extrusion/RAG scanning process.

"'While these findings have been made in the context of V(D)J recombination in antibody formation, they have implications for processes that could be involved in gene regulation more generally," says Alt."

Comment: Again a very necessary mechanism which is irreducibly complex and had to present from the beginning to offer disease protection or life would not have survived. More evidence for design

Once an infections is defeated there must be a memory for the next time that same infection is attempted:

https://medicalxpress.com/news/2019-10-migratory-dendritic-cells-tgf-prior.html

"A team of researchers affiliated with several institutions in the U.S. and one in the U.K. has found that migratory dendritic cells (DCs) activate TGF-β prior to conditioning naïve CD8+ T cells, allowing for transformation to TRM cells that take up residence in the skin. In their paper published in the journal Science, the group describes their study of such cells and how they are preconditioned before moving to the epidermis.

***

"Prior research has found that there is a kind of memory T cell that remains in tissue rather than circulating in the body. Such tissue-resident T cells (TRM) are created when the body successfully defeats an invasive element, such as a virus—they are how the body remembers to fight the same virus the next time it is encountered. One such kind of TRM are CD8+ epithelial TRM (eTRM) cells that exist in the skin. Prior research has also shown that after T cells are made in the bone marrow, they travel to lymph nodes, where they are trained to become the kinds of T cells that are needed by the body to support a normal immune response. These specialized T cells rely on a transforming growth factor–β (TGF-β) to mature properly. But the process by which this occurs is still under investigation. In this new effort, the researchers looked at the role αV integrin–expressing DCs, play in the transformation process.

"The work involved removing αV integrins from CD11c+ DCs in mouse models to measure the maturation process of naïve CD8+ T cells. This led to a dramatic reduction in CD8+ T cells in the skin, but not in the lymph nodes. Thhis indicates that migratory DCs play a role in activating TGF-β as a means of preconditioning naïve CD8+ T cells. Additionally, this indicates that pre-immune T cells might be less uniform than has been thought."

Comment: this maintenance of memory has several steps, and as such cannot be the result of chance mutations, but requires specific design beforehand. Development from experience would allow initial infections to end life before this mechanism could be set in place.

A newborn is protected by the Mother's colostrum, if it nurses. Thereafter the newborn immune system must learn to know all the challenges by experiencing them, or by being vaccinated:

https://medicalxpress.com/news/2020-03-principles-vertebrate-immunity.html

"All vertebrates, including humans, developed a very sophisticated self-protection device, the adaptive immune system. Specialized immune cells called T cells and B cells detect and destroy invading pathogens. One of its key features and its secret weapon is immunological memory. The cells remember infections leading to an even more efficient reaction to the same pathogen when re-exposed.

***

"The scientists know that all vertebrates share the two lineages of T and B cells that are equipped with receptors capable of recognizing foreign structures, often referred to as antigens. Because the immune system has to distinguish between very different types of antigens, the structures of the receptors also vary; they are made up of similar but not identical building blocks that are produced in a random fashion during the development of T and B cells.

***

"The CDA2 gene is of great interest to immunologists, because it is related to a gene, called AID, of jawed vertebrates that helps to refine the specificity of their antibodies. "It seems, that nature has chosen molecules from a shared tool-kit to support the formation of useful antibodies in both types of vertebrates."

Comment: this study is primarily one that looks at evolution and eh development of memory system that allows for the development of precise antibodies to attack intruders. The control of this process requires both functional information and specific instructions.

A new study showing how they develop:

https://www.sciencedaily.com/releases/2020/04/200414122750.htm

"The discovery that immune T cells have a spectrum of responsiveness could shed light on how our immune system responds to infections and cancer, and what goes wrong in immune diseases. Researchers found that T cells responded very differently to immune signals the more 'training' they had been exposed to.

***

"T cells are key white blood cells that fight infection and disease, and act like police directing the immune system response. Babies are born with inexperienced -- naïve -- T cells, which change as they come into contact with bacteria or viruses, to create specific memory T cells that can 'remember' fighting against these infections. These memory T cells can then react more quickly the next time they meet the same threat, telling the immune system to remove the infection rapidly. This is how vaccination protects against disease, by delivering a safe form of an invading virus or bacterium, to train our immune system by building up specific memory T cells.

***

"The researchers discovered that instead of having a simple switch, from naïve to memory cell, there appeared to be a whole continuum of T cell development. They revealed that the more often a T cell had been activated by one signal, the further along the line of memory T cell development -- its 'training' -- it was, and the faster it could respond to that specific signal.

***

" 'Previously people thought that memory T cells had two stages of development, but we discovered there is a whole spectrum of memory experience. From naïve T cells that have never been activated, to highly trained memory T cells which can react quickly, and many intermediate T cells in between. This spectrum not only affects how fast a cell can respond, but even what signals it can respond to."

"The study showed the T cells also had a continuum of responsiveness to other chemical signals, revealing they were less specialised than previously thought. They found that even highly trained memory T cells could be triggered by other, new immune signals.

"The researchers discovered that some signals created very different responses in memory cells, depending on their experience level. When a specific chemical signal (transforming growth factor -TGF) was added to naïve T cells, they responded by producing regulatory T cells to calm down the immune system. However, the same chemical had the opposite effect on experienced memory cells, triggering them to release more chemicals that cause inflammation."

Comment: Fighting infections is a lifelong battle. T cells are beautifully designed for the
battle, but not perfectly. They can overreact and cause autoimmune diseases.

Skimming through a review of our troops:

https://evolutionnews.org/2020/04/physicians-diary-our-remarkable-healing-processes-and...

"Normally, billions of white cells, including complex B and T lymphocytes, neutrophils, macrophages, dendritic cells, and plasma cells, stand guard throughout the body. They are like sentinels with a whole host of weapons in hand. When confronted by a foreign intruder, they quickly determine if this new protein, DNA or RNA particle, bacteria, fungus, virus, or a changed cell (cancer) is a friend or foe. If they deem it worrisome, they immediately punch holes in it with tiny grenades called “complement” and tear it apart, figuratively limb-by-limb. Select pieces are sent back to the rear-lines (lymph nodes) for analysis.

"The analysis leads to manufacturing antibodies, often Y-shaped chemicals to capture all or part of the intruder in the wedge of the Y. Antibodies will often attach to invaders at specific locations along their outer shell. Think of a submicroscopic porcupine rolled into a ball. If the virus foreigner were covered with triangular spikes, the antibodies might have “catcher’s mitts” with triangular-shaped pouches. Electrical charges and specific chemical bonds also play a role.

***

"Newly manufactured, shorter-lived antibodies are the first on the scene. Days to weeks later, smaller, often lifelong, antibodies begin arriving. They may also become part of your permanent immunity.

***

"If there is an overwhelming army of invaders, the sentinels will send for emergency reinforcements. White cells, like the cavalry, rapidly arrive by the millions. They travel through lymph channels, race from other organs, and squeeze in and out of blood vessels. Pus is often the result of these battles. This material is composed of millions of dead invaders and white cells, various bodily fluids, and all sorts of spent biological weapons, tools, and chemicals. Recall teenage pimples or any abscess; the fight is concluded when the body moves these pus pockets to the skin surface for drainage.

***

"Millions of different foreign proteins enter our body every day through breaks in the skin, our gums and gut while eating, our nose and lungs while inhaling, and even through portals in the eyes from another person’s sneeze or cough. Most intruders are benign. Many others are non-life threatening irritants, as with allergies, which prompt a slightly different response. The deadly invasions, of course, must be confronted immediately.

***

"Vaccines prompt the body to make antibodies by mimicking aspects of the virus, but the trick is creating the right antibodies. Sometimes, the created antibodies get in the way. Hyperimmune globulin (IGG, consisting of antibodies collected from donors) was used during the polio epidemic in the 1950s; it was given to patients with the worst cases, with paralysis, and many improved."

Comment: A fantastic system, designed for great protection. Yes, designed, not by chance. The author is wrong about how IGG was used. I was one of several senior medical students in the summer before school started up again, who worked for the N.Y. State Health Department and gave hundreds of well kids the IGG by injections in the butt. Hard to do. My hand was sore each day from pushing ice cold thick liquid into the kids. They did n't enjoy it either, but it broke the epidemic in the areas we visited over weekends, being bused from our regular jobs in Syracuse, N.Y.

Another complex molecular system:

https://medicalxpress.com/news/2020-05-component-innate-immune.html

"How cells recognize pathogens and alert the immune system swiftly is a fundamental process of high importance for the survival of any species, including humans. A key role is ascribed to so-called adapters—little molecular platforms inside cells where signals from pathogen detectors are integrated for safety and accuracy and conveyed to lasting signals leading to the activation of the major "red alarm" genes, like interferons.

***

'The new protein, named TASL, is indispensable for the signaling of so-called Toll-like receptors (TLR) in the endosomes leading to activation of the gene-activator IRF5 in certain immune cells. Sensitive 'tuning' of the machinery is highly important as too much output causes inflammation also in the absence of the pathogen, as occurs in auto-immune diseases. This particular version of the machinery seems particularly associated with disorders such as systemic lupus erythematosus (SLE).

***

"In their study, first author Leonhard Heinz and the team, including Boehringer Ingelheim researchers in Ridgefield, undertook a precise investigative work, not taking for granted previous findings on SLC15A4 and the connection to this group of specially located TLRs. They painstakingly determined by biochemistry and mass spectrometry the molecular interactions that involved SLC15A4. This led to the identification of an uncharacterized protein CXorf21, belonging to the functionally orphan genes that are merely numbered and assigned to the chromosome of origin. The gene, like SLC15A4, had been previously loosely associated with SLE.

"The team demonstrated that the interaction between TASL and SLC15A4 was crucial for the localization and function of the TASL protein and could pinpoint the precise involved portions of both proteins. A eureka moment for the understanding of the protein came with the observation that TASL harbors a specific motif essential for the recruitment and activation of IRF5. "After STING, MAVS and TRIF, the new protein TASL is the fourth key innate immunity adaptor functioning as a platform for the encounter of a kinase and a gene activator of the IRF family," says Manuele Rebsamen, CeMM senior postdoctoral fellow and project leader of the study."

Comment: Once again we see a complex set of specified molecular reactions by precise molecules. Since organisms must be able to fight dangerous infections when they first appear in evolution, this mechanism must have been there from the beginning, and therefor designed, since chance is so unlikely to find this series of molecules and its purpose.

Immunity cells respond in two ways depending upon the infection and where it is located, in or outside of cells:

https://www.sciencedaily.com/releases/2020/06/200612120148.htm

"Viruses and other disease-causing microbes influence the type of immune response their hosts will develop against them. In some cases, the predominant response involves antibodies, proteins made by the immune system that specifically recognize parts of the invading microbe and mediate its destruction. In other cases, immune cells are trained to recognize the microbe and lead the attack against it.

***

"Research has shown that two factors related to microbes significantly affect the type of immune response that will predominate. On one hand are the microbial components (parts of proteins or genetic material, called pathogen-associated molecular patterns or PAMPs), and on the other is the location of the microbes, whether they tend to be inside or outside cells. Cells have means to recognize PAMPs ? some cellular proteins recognize PAMPs inside cells, while others detect PAMPs outside cells.

"Research on viruses has shown that when viral genetic material is detected inside cells, a cell-mediated immune response develops, while the detection of viral proteins outside the cell triggers antibody-mediated responses.

"The implementation of these immune responses involves cellular proteins called Pattern Recognition Receptors, or PRRs. Antigen-presenting cells, such as dendritic cells, are involved in the first steps of developing a specific immune response. During these first steps, antigen-presenting cells sample both the intracellular and extracellular environments by binding PAMPs to their PRRs. Recognition of a PAMP by a PRR turns on the danger alarm and alerts the rest of the immune system to the presence of a foreign microbial invader.

"In addition to these well-studied signals that mediate classic immune responses, Baylor researchers have proposed and demonstrated a different mechanism that directs the immune response toward a cellular type. This new mechanism also involves surveillance of both the intracellular and extracellular environments but by a different class of proteins called the Major Histocompatibility Complex, or MHC. MHC Class I binds protein fragments found inside of cells whereas MHC Class II binds protein fragments present on the outside of cells.

"'This mechanism appears to take place mostly when a fulminant viral infection occurs," said Decker, associate professor of pathology and immunology and corresponding author of this work.

***

"'We found ample evidence that supports the novel mechanism and described a large molecular sensor complex we propose plays a central role in comparing the amino acids sequences of intracellular and extracellular protein fragments," said Halpert,

Comment: These kinds of interlocking defense systems require careful design, with especial care not to allow attacks on one own's tissues, especially when the virus is located intracellularly. This is not something 'cell committees' can develop, since the mechanisms must be present when the organism first appears in evolution. Survival depends upon it.

The bladder must open to the outside which allows infections in making urine infections common, especially in women. One molecule protects:

https://www.sciencemagazinedigital.org/sciencemagazine/21_august_2020/MobilePagedArticl...

"Human urinary tracts are highly susceptible to bacterial infections. Pathogenic bacteria initiate infections by attaching to sugar chains (glycans) exposed on the surface of the urinary tract epithelium. It has long been suspected that uromodulin (UMOD)—the most abundant protein in human urine—prevents bacteria from binding to urinary tract glycans, thus defending the organism from such infections. However, the mechanism underlying this protection has remained elusive. Now, Weiss et al. reveal, at the molecular level, how UMOD filaments interact with uropathogenic Escherichia coli cells in human urine. These results provide a structural basis for understanding the protective function of UMOD.

***

"Weiss et al. deciphered a comprehensive map of the glycosylation pattern of UMOD, the structure of UMOD filaments, and the nature of bacteria–filament interaction. Infective E. coli cells attach to the urinary tract epithelium through needlelike structures called pili. At their tip, E. coli type I pili consist of the protein FimH (type 1 fimbrin D-mannose specific adhesin). The authors show that the armlike structures extending from UMOD filaments interact with FimH. The interaction between UMOD and FimH is biochemically strong and likely leads to stable binding. Indeed, Weiss et al. show that through this binding, UMOD mediates the stable formation of clumps of bacteria.

"The suggested mechanism of UMOD-based defense is notably simple and robust: The abundant UMOD filaments outcompete receptors on the urinary tract walls in binding to bacterial pili. Each flexible filament has multiple binding sites, and each bacterium can have several pili. Therefore, this multitude of interactions causes bacterial aggregation, effectively preventing individual bacterial cells from attaching to and infecting the urinary tract. In case of the E. coli strain studied by Weiss et al., the interaction between UMOD and bacterial cells occurs through specific binding of FimH to a glycan at asparagine 275 of the UMOD protein.

"However, UMOD contains several other complex glycosylation sites whose functions have not yet been dissected. A compelling possibility is that these serve as binding sites for proteins of other uropathogenic bacteria. In line with this idea, when Weiss et al. imaged urine from patients infected with different bacteria, namely Klebsiella, Pseudomonas, and Streptococcus, the authors found similarly aggregated bacterial cells embedded in UMOD filaments. Given its implication in various aspects of kidney function, UMOD might have other molecular roles that rely on its distinct glycosylation pattern or its adoption of a filamentous structure, besides protection from bacterial infections.

Comment: this highly complex arrangement of active molecules has to be designed. Not by chance! Try to imagine this developing by a hunt-and-peck process of rial and error.

Another mechanism described:

https://www.sciencedaily.com/releases/2020/08/200828091953.htm

"Cells that are infected by a virus or carry a carcinogenic mutation, for example, produce proteins foreign to the body. Antigenic peptides resulting from the degradation of these exogenous proteins inside the cell are loaded by the peptide-loading complex onto so-called major histocompatibility complex molecules (MHC for short) and presented on the cell surface. There, they are specifically identified by T-killer cells, which ultimately leads to the elimination of the infected cells. This is how our immune system defends us against pathogens.

"The peptide-loading complex ensures that the MHC molecules are correctly loaded with antigens. "The peptide-loading complex is a biological nanomachine that has to work with atomic precision in order to efficiently protect us against pathogens that cause disease," says Professor Lars Schäfer,

***

"...with our computer-based methods were we able to extract the maximum information content contained in the experimental data," explains Schröder. The atomic model enabled the researchers to perform detailed molecular dynamics computer simulations of the peptide-loading complex and thus to study not only the structure but also the dynamics of the biological nanomachine.

"Since the simulated system is extremely large with its 1.6 million atoms, the computing time at the Leibnitz Supercomputing Centre in Munich aided this task considerably. "Using the high-performance computer, we were able to push into the microsecond time scale in our simulations. This revealed the role of sugar groups bound to the protein for the mechanism of peptide loading, which had previously only been incompletely understood,'"

Comment: A massive system of t his size requires design to work effectively.

They have very similar molecules:

https://phys.org/news/2020-11-animal-immune-similarities.html

"Now, in a study published in the journal Cell Host & Microbe, Zhang and colleagues have discovered that plants have evolved a family of proteins that bear a striking resemblance to proteins called mixed lineage kinase domain-like proteins (MLKLs), which trigger cell death in vertebrates as part of the immune response. In uncovering and characterizing an important new family of plant immune proteins, the authors' study, which involved collaboration with fellow MPIPZ researchers Paul Schulze-Lefert, Jane Parker and Jijie Chai, provides intriguing new insights into how plants protect themselves from microbial invaders.

"Regulated cell death often accompanies immunity against infection in plants, animals and fungi. One pervasive theory suggests that highly localized cell death responses serve to strictly limit the spread of infection. Although starting from independent origins, this shared response seems to also involve highly similar machinery: many proteins involved in cell death in different kingdoms of life contain a so-called HeLo domain, a bundle structure made up of four helices, which causes resistance and cell death by disturbing the integrity of cellular membranes or forming ion channels.

"Based on the similarities between animal and plant immune systems and on the key role played by HeLo domains in cell death, Maekawa hypothesized that plants might also contain other proteins with HeLo domains. Making use of bioinformatic and structural analysis, he and his team discovered a new family of HeLo domain-containing proteins that are widely shared among different plant species, indicating that they are important for plant physiology.

"Maekawa termed the proteins plant MLKLs, and for further studies he focused on MLKLs expressed in the model plant Arabidopsis thaliana. He and his team isolated MLKL proteins from A. thaliana and determined that plant MLKLs possess the same overall protein architecture as their vertebrate counterparts and also assemble into tetramer, likely auto-inhibited, structures when they're not active. Importantly, plant MLKLs also play a role in immunity, as plants in which genes encoding these proteins were mutated and thus non-functional were susceptible to pathogen infection.

Comment: Another form of convergence. My view remains hese dsefigned moleculES must be present when tH organisms appear.

The best way for pathogens to get the brain is through the blood from teh gut, so it is gut immune cells that protect the brain:

https://www.sciencenews.org/article/brain-infection-gut-immune-system

"A new study in mice finds that immune cells are first trained in the gut to recognize and launch attacks on pathogens, and then migrate to the brain’s surface to protect it, researchers report online November 4 in Nature. These cells were also found in surgically removed parts of human brains.

***

"The most common route for a pathogen to end up in the bloodstream is from the gut. “So, it makes perfect sense for these [immune cells] to be educated, trained and selected to recognize things that are present in the gut,” says Menna Clatworthy, an immunologist at the University of Cambridge.

"Clatworthy’s team found antibody-producing plasma cells in the leathery meninges, which lie between the brain and skull, in both mice and humans. These immune cells produced a class of antibodies called immunoglobulin A, or IgA.

"These cells and antibodies are mainly found in the inner lining of the gut and lungs, so the scientists wondered if the cells on the brain had any link to the gut. It turned out that there was: Germ-free mice, which had no microbes in their guts, didn’t have any plasma cells in their meninges either. However, when bacteria from the poop of other mice and humans were transplanted into the mice’s intestines, their gut microbiomes were restored, and the plasma cells then appeared in the meninges.

“'This was a powerful demonstration of how important the gut could be at determining what is found in the meninges,” Clatworthy says.

***

“'To my knowledge, this is the first time anyone has shown the presence of plasma cells in the meninges. The study has rewritten the paradigm of what we know about these plasma cells and how they play a critical role in keeping our brain healthy,” says Matthew Hepworth, an immunologist at the University of Manchester in England who was not involved with the study. More research is needed to classify how many of the plasma cells in the meninges come from the gut, he says."

Comment: Based on the source of pathogens in the gut, this design of brain immunity makes perfect sense. The source of Eben Alexander's E. coli meningitis is explained by this concept.

They attack and help healing:

https://phys.org/news/2021-01-closer-immune-cells.html

"Macrophages—immune cells that both fight infections and fix the damage they cause—are often placed into two categories: those that increase inflammation (known as "M1") to attack, and those that decrease inflammation to begin the healing process ("M2").

"Researchers in the lab of Kathryn Miller-Jensen, associate professor of biomedical engineering and molecular, cellular & developmental biology, used single-cell RNA sequencing to get a closer read on how individual macrophages react to different stimuli. They found that, while these cells tend to be multitaskers, some are more inclined toward responding to certain cues than others.

***

"'No one had looked at that, and we decided to try it with single-cell sequencing," Miller-Jensen said. By doing so, the Miller-Jensen lab was able to get a much more detailed picture of macrophages' responses when stimulated with both inflammatory and resolving stimuli. They found a great deal of variability, including a subset of cells that seem to respond to only one cue or the other for certain key functions like secretion.

"'The stimuli are the environmental cues, but we're thinking that there might be some variability in the regulatory network inside the cells that allow some of them to respond more strongly to one cue versus another at any given time," Miller-Jensen said.

"It's an important step toward a better understanding of the different types of macrophages.

"'It could help us identify how macrophages exist in these different states in a tumor, or non-healing wounds, and other disease environments," she said. "If we had a more sophisticated understanding of what subsets exist, we might better figure out how to target them or regulate them."

"The researchers note that the diverse responses to opposing cues may allow macrophages to more readily adapt to changing environments, as well as to quickly transition from attack mode to focusing on tissue repair.

"'They might need to respond to a lot of cues at the same time, so a few of the macrophages might be primed to respond and be the attackers," she said. "So when they see both of those cues at the same time, it's important to have at least some of those cells to secrete what needs to be secreted—but maybe not all of those cells, because some may need to do something else.'"

Comment: Very clever design to have these cells multitask.

Immune cells build up populations in all organs over a lifetime:

https://www.nytimes.com/2021/04/20/health/sleep-dementia-risk.html?campaign_id=60&e...

"University of Minnesota Medical School researchers have offered new ways to think about the immune system thanks to a recent study published in Nature. Their research, which indicates organ tissues become increasingly immune throughout life, may begin to alter fundamental ideas regarding the rules of vaccination and the immune system's function within the body.

"'Historically, studies of the immune system have emphasized its renewable nature through bone marrow, lymphoid organs and blood. Our work shows how much this model fails to account for the many immune cells distributed throughout other organs of the body, where most infections and tumors arise," Wijeyesinghe said. "What we found ends up painting a much broader picture of how the immune system accomplishes surveillance of the entire body for pathogens, tissue damage and tumors."

"The study's major findings, include:

"Antiviral T cells that reside in most organs of the body persist over time and in the face of extensive infectious exposures;

"Unlike other organ systems, the immune system becomes increasingly immune throughout life, which is a natural response to accumulated microbial exposures over time;

"Up to 25% of the cells in organs were immune cells, indicating that the immune system significantly contributes to the cellular makeup of the body;

"And, along with antiviral T cells, most other immune cells are durably tissue-resident in organs as well."

Comment: A complete system, well designed, recognizing bad bugs (in our view) are all around. I wish we knew the reason God provided them

New research on T call response to infection:

https://medicalxpress.com/news/2021-11-cells-infection-disease.html

"T cells communicate with other cells in the body in search of infections or diseases. This crosstalk relies on specialized receptors known as T cell receptors that recognize foreign molecular fragments from an infection or cancer that are presented for detection by particular molecules called major histocompatibility complex (MHC) or MHC-like.

"In this study, Monash Biomedicine Discovery Institute scientists have expanded the understanding of how a poorly defined class of gamma delta T cells recognizes an MHC-like molecule known as MR1. MR1 is a protein sensor that takes cellular products generated during infections or disease and presents them for T cells to detect, thereby alerting the immune system.

***

"By using a high-intensity X-ray beam at the Australian Synchrotron, the scientists were able to obtain a detailed 3D atomic model of how the gamma delta T cell receptor recognizes MR1. What sets these cells apart from others seems to be the unusual ways in which they interact with MR1. This work further recasts our understanding of how T cell receptors can interact with specialized MHC-like molecules and represents a notable development for our understanding of T cell biology.

"Mr Rice stated: "By using high-resolution protein imaging and biochemical assays, we were able to identify key mechanisms that govern gamma delta T cell receptor recognition of MR1, a key sensor of bacterial infection."

"Co-lead author Dr. Gully said: "These cells have evaded characterisation for a long time, leading to many assumptions on how they become activated. Here we have shown that these gamma delta T cells can recognize MHC-like molecules in their own unique ways and in ways we could not have predicted."

Comment: here is a marvelous example of how T cells act automatically to fight infections and cancer. The whole immune system is programmed to fit infections and invasions (note the red skin around a splinter) The cells are not innately intelligent, but completely automatic. Cells act automatically, and following intelligent information (instructions) appear to BE intelligent, inferring they use an innate intelligence they do not have.

Many T cells are tissue residents, not free floating in the circulation and have other functions than as killers:

https://www.science.org/doi/10.1126/science.abf0095

"Conventional T cells recognize peptides that are presented by polymorphic major histocompatibility complexes (MHCs). By contrast, many tissue-resident T cells, such as mucosal-associated invariant T cells, invariant natural killer T cells, and γδ T cells, respond to modified peptides and small molecules presented by conserved MHC-like molecules. Unconventional T cells are important for host defense and tissue repair and seed tissues during critical early-life windows of development.

"In addition to providing antimicrobial immunity, the immune system governs numerous aspects of host physiology, in part through the coordinated action of tissue-resident lymphocytes. Although conventional T cells recognize peptides presented by polymorphic major histocompatibility complexes (MHCs), a large proportion of T cells within tissues are specific for modified peptides and small molecules. These unconventional T cells are restricted by monomorphic MHC molecules, many of which exhibit a high level of conservation across species, suggesting an essential role for these cells throughout evolution. Some unconventional T cells express semi-invariant T cell receptors (TCRs) that limit their antigenic range analogously to innate immune receptors. Termed innate-like T cells, these populations developmentally acquire effector characteristics prior to thymic egress, including rapid cytokine release and expression of chemokine receptors and integrins. Without the necessity of antigen-mediated activation within secondary lymphoid organs, innate-like T cells accumulate within tissues earlier than conventional effector T cells. Consequently, recent work has shown that these unconventional T cells are particularly responsive to early-life signals and promote the maintenance of tissue homeostasis as a coordinated network.

"As a consequence of their emergence in early life, unconventional T cells contribute to the initial dialog between the host and the microbiota, on which some subsets depend for their development. Exposure to commensal microbes during the first weeks of life imprints the abundance of mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells in tissues, due to both TCR-mediated activation and modulation of tissue-specific chemokines. Epithelial cell expression of host molecules in early life is also necessary for the accumulation of a defined subset of γδ T cells. Absence of these early-life signals cannot be compensated for later in life and has long-lasting consequences for host physiology, rendering adult animals more susceptible to inflammation.....Although unconventional T cells exhibit overlapping roles, their disparate stratification within epithelial tissues suggests that each population may serve a unique purpose in maintaining tissue homeostasis. Animal models deficient in subsets of unconventional T cells exhibit compensatory increases of other unconventional T cells, indicating that these populations constitute a network of redundant cellular mechanisms that contribute to tissue resilience. However, inflammation can abrogate the expression of epithelial molecules that maintain a subset γδ T cells, resulting in a compensatory increase in more inflammatory γδ T cells that predispose the tissue to chronic inflammation."

Comment: the key to the importance of these cells is that they develop at birth and quickly learn to recognize and neutralize foreign proteins. Obviously, continuing to live without dangerous infections is a requirement for life and this system is designed for just that protection. The cells arrive at birth with this built-in ability. Unfortunately, improper inflammatory responses can happen as noted here and in our previous discussions. Much of this research is directed at finding correcting therapy.

More complexity is found:

https://medicalxpress.com/news/2022-02-stowaway-cells-lungs-blueprint-flu.html

"Does a distinct population of B cells emerge after influenza infection, and if so, are these cells uniquely identified by specific biological signatures? The answers to both questions are resoundingly, "yes." Yet the institute's research didn't end there.

"As part of the same group of studies, Australian immunologists also found that these B cells are not only flu-specific, they sequester themselves in the lungs in a residential positioning that allows a strategic advantage. Should flu—or possibly any other respiratory infection—strike in the future, these stowaway B cells can leap into action more efficiently.

"'Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues," explained Dr. Hyon-Xhi Tan, writing in Science Immunology.

***

"The flu-specific B cells, the researchers found, are analogous to the already well-described tissue-resident T cells. The research suggests that B resident memory cells may be special players in B cell immunity. They stay in the lung mucosa to offer a swift response against not only influenza but possibly viral respiratory infections of all kinds.

***

"B cells, or B lymphocytes, as they are more precisely known, are part of the highly specific portion of the immune system, which includes T cells. Together, these two broad categories of lymphocytes are at the heart of the adaptive immune response. The adaptive response is interchangeably known as acquired immunity, or the humoral response, which differs from innate immunity. That broad unrestrained response is mediated by a cascade of cells and proteins. Natural killer cells are part of the innate response, as are cytokines and the explosive, uncontrolled reaction called the cytokine storm.

"The innate response, which is present at birth and is the first throughout life to converge on sites of infection or tissue injury, differs from the adaptive. Emerging around the time babies enter the toddler stage, the adaptive immune response is far more targeted and specific.

"B cells, for example, can form memories of previous infections and also produce antibodies. Memory B cells recognize antigens from earlier infectious assaults on the body. They differentiate into antibody-producing plasma B cells when the antigen is again encountered and a rapid antibody response is required. The first time a B cell encounters an antigen, it can take up to 15 days to produce sufficient neutralizing antibodies to quell the pathogen. The second time the same pathogen is encountered, memory B cells, which morph into antibody-producing plasma cells, respond in as few as five days and flood infiltrating pathogens with 100 times more antibodies than during the first encounter.

***

"The stowaway B cells that researchers discovered are located in bronchus-associated lymphoid tissue in the lungs of mice and express the lung residency marker proteins CXCR3, CCR6, and CD69. The team additionally studied human cell lines to further their analyses of these critical cells, and again found resident B cells as stowaways in the lungs.

"'These data suggest that B resident memory cells may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections," Tan wrote in Science Immunology.

"The investigators found that B resident memory cells have distinct transcriptional signatures in both mice and humans that differ from regular memory B cells in the blood or spleen.

"Resident B cells in the lungs show partial resemblance to memory B cells in lung-draining lymph nodes. Lung-resident memory B cells establish themselves in the lungs after pulmonary influenza and display distinct transcriptional and phenotypic profiles, the research concluded."

Comment: the newborn starts with interferon and other early innate defenses provided by Mother's colostrum. but B cells and T cells, each in their own way, build a full library of
antibodies tov display when necessary. The cells are programmed to do this. We are still discovering the complexity of God's design

It picks up foreign protein signals:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/27_january_2023/407...

"Within multicellular organisms, innate immune pattern recognition receptors (PRRs) control host defenses to infection. These receptors are activated by microbes, which facilitate their own demise by producing PRR ligands called pathogen-associated molecular patterns (PAMPs). Notably, the mechanisms of PRR-mediated microbial detection are inconsistent with the sensing of successful pathogens. I propose that PRRs do not detect pathogenic agents per se. Rather, PRRs detect PAMPs that are released from microbes as a result of biochemical infidelities, or mistakes, that occur during infection. These mistakes render individuals within an otherwise infectious population noninfectious but immunostimulatory. Microbes could evolve strategies that increase the fidelity of their infectious strategies to evade PRRs. However, imperfect activities enable biochemical innovations that ensure the survival of the species. By detecting PAMPs that are released as a result of low-fidelity biochemical activities, PRRs may, in effect, be targeting the very process that microbes need for long-term survival—evolvability.

***

"The specific nucleic acids detected by TLRs suggest preferential detection of dead microbes. Free guanosines and uridines represent cofactors that, along with single-stranded RNA (ssRNA), activate TLR7 and TLR8, respectively (1). Similarly, trinucleotides containing cytosines synergize with CpG-containing ssDNA to activate TLR9. The requirement of short nucleotide sequences (or free nucleosides) to activate several TLRs supports the idea that lysed microbial cells or degraded virions are detected after their genomes have been hydrolyzed.

[Many specific reactions are presented as examples of the battle.]

***

"Like all areas of biology, exceptions to suggested biological rules exist. For example, PRRs that detect bacterial LPS molecules and lipoproteins may represent examples of pathogen detection systems. These molecules are displayed on the surface of bacteria and are detected by specific TLRs in their intact forms. Similarly, the PRRs dectin-1 and dectin-2 recognize b-glucans and a-mannans, respectively, whose positioning on the fungal cell wall facilitates detection. However, there are possible explanations for these exceptions. The mammalian LPS detection systems are not as ancient as other PRR networks, such as the endosomal TLRs, RLRs, cGAS, and STING. These ancient PRR systems detect the most definitive example of PAMPs that are released as a result of infection infidelity—nucleic acids. Outside of mammals, few examples of immunostimulatory LPS activities (or LPS receptors) exist. Indeed, the genes encoding the mammalian LPS receptors CD14, TLR4, and MD2 are absent from the genomes of fish and invertebrates (which constitute >90% of metazoan life). Thus, exceptions to the error-centric theme of pattern recognition may be a recent evolutionary innovation.

***

"Even if low-fidelity biochemical reactions were rarely detected by PRRs during infection, the rarity would need to approach zero for host defenses to be avoided. The very nature of the mammalian inflammatory and plant hypersensitive responses induced by PRRs enables tissue (and likely systemic) defenses to be executed against the entire microbial community. Studies of infection at the single-cell level could reveal the generality of these concepts and how they affect defense. Additional work is also needed to understand how inflammatory activities that drive tissue repair after infection resolution may be affected by residual PAMPs derived from dead microbes.

"An implication of the infection infidelity concept is that it provides the opportunity to develop anti-infective drugs that are also immunotherapies. It is possible that drugs that disrupt viral life cycles would, in immunocompetent cells, result in the release of PAMPs to the host immune system. Similarly, antibiotics that target bacterial cell walls may cause the release of cell wall components or cyclic dinucleotides that stimulate PRRs. Integrating PRR assays in anti-infective clinical pipelines may therefore offer opportunities for drug development."

Comment: I presented this article to show the complexity of the innate immune system in detecting foreign protein that is, fighting infections.

Cloaking and a specialized protein:

https://www.the-scientist.com/the-literature/how-chlamydia-guards-itself-against-the-im...

"Coers has spent years figuring out how Chlamydia trachomatis, the causative bacterium in humans, evades destruction. In a recent study, Coers and his team discovered a key protein that allows C. trachomatis to slip past the body’s defenses.

"To enter a host cell, Chlamydia cloaks itself in a piece of the host cell’s membrane, forming a vacuole, or inclusion, where it grows and divides uninterrupted by immune cells. T cells can detect Chlamydia in the brief time it lives outside the cell and, in response, release gamma interferon (IFN-γ), an inflammatory cytokine that triggers destruction of the pathogen. But something about the inclusion allows Chlamydia to hide from the immune response and persist for months or years.

***

"The team performed a genetic screen of various mutated C. trachomatis strains grown inside human epithelial cells in the presence and absence of IFN-γ. The C. trachomatis strains most susceptible to IFN-γ-mediated destruction had mutations in a gene that encodes a protein the researchers named GarD (formerly CTL0390), indicating that GarD is important for C. trachomatis’s survival. Imaging experiments on IFN-γ-resistant C. trachomatis strains revealed that GarD blocks ubiquitin binding by inserting itself into the inclusion membrane. Disabling GarD allowed ubiquitin binding and left the bacteria vulnerable. Meanwhile, mice defend themselves from rodent-infecting C. muridarum by blocking ubiquitin via a different mechanism entirely.

“'When the GarD protein is there, the inclusion . . . disguises itself, like an invisibility cloak from Harry Potter,” Coers explains. “Now we understand why interferon-γ is not able to clear infections and why these infections last for such a long time.”

“'I think it’s an important and reliable result,” says Bob Brunham, an infectious disease scientist and professor emeritus at the University of British Columbia who was not involved in the study. “It shows just how evasive Chlamydia is.”

"The researchers also discovered that IFN-γ activates a protein called mysterin (also called RNF213) that’s responsible for attaching ubiquitin to the inclusion, though Coers notes that how exactly GarD prevents mysterin from doing so remains, aptly, a mystery."

Comment: either Chlamydia invented the protective molecule or it appeared by luck. Would God have been involved? I don't know. All unknowns

Another review:

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

"When a foreign substance enters the body, it puts the immune system on high alert. Helper T cells sound the alarm, prompting their deadlier relatives—the so-called killer T cells—to go on the offensive. To make sure these warriors don’t go too far, regulatory T cells (Tregs) tamp down inflammation and try to prevent the immune system from attacking the body’s own tissues.

"Once an infection has cleared, some immune cells stick around the lymph node and become memory T cells, which can quickly mobilize if they’re exposed to the same pathogen again in the future. Both helper and killer T cells can turn into memory T cells, but until recently, scientists didn't know much about the behavior of Tregs, and whether they, too, hang out in lymph nodes for long periods of time. It turns out they do, according to research published in Science Immunology. And this newly described population of memory-like Tregs could open new potential avenues for fine-tuning a person’s immune activity and reducing inflammation in chronic immune conditions.

***

"...while most Tregs leave the structures post-infection, up to 20% can remain in the same lymph node for weeks to months. These ‘resident’ Tregs behaved differently from their circulating counterparts and resembled memory T cells found in other tissues."

The actual paper abstract:

https://www.science.org/doi/10.1126/sciimmunol.adj5789?utm_source=sfmc&utm_medium=e...

"Regulatory T cells (Treg) are present in lymphoid and non-lymphoid tissues where they restrict immune activation, prevent autoimmunity and regulate inflammation. Treg in non-lymphoid tissues are typically resident, while those in lymph nodes (LNs) are considered to recirculate. However, Treg in LNs are not a homogenous population and circulation kinetics of different Treg subsets are poorly characterized. Furthermore, whether Treg can acquire memory T cell properties and persist for extended periods after their activation in LNs is unclear. Here, we used in situ labeling with a stabilized photoconvertible protein to uncover turnover rates of Treg in LNs in vivo. We found that while the majority of Treg in LNs recirculate, 10–20% are memory-like resident cells that remain in their respective LNs for weeks to months. Single cell RNA sequencing revealed that LN-resident cells are a functionally and ontogenetically heterogeneous population and share the same core residency gene signature with conventional CD4+ and CD8+ T cells. Resident cells in LNs did not actively proliferate and did not require continuous TCR signaling for their residency. Yet, resident and circulating Treg had distinct TCR repertoires, and each LN contained exclusive clonal subpopulations of resident Treg. Our results demonstrate that, similar to conventional T cells, Treg can form resident memory-like populations in LNs after adaptive immune responses. Specific and local suppression of immune responses by resident Treg in draining LNs might provide new therapeutic opportunities for the treatment of local chronic inflammatory conditions."

Comment: this sophisticated array of differentiated T cells with purposeful integration reeks of design. Not by the chance mutation of Darwin theory.