Scientists at UC San Francisco are getting close to an answer. In a breakthrough that could transform how doctors treat conditions from eczema to allergies, they have discovered a feedback loop centered on a single immune protein called IL-31 that both causes the urge to itch and dials back nearby inflammation.

The findings, published on October 13th in Science Immunology, lay the groundwork for a new generation of drugs that interact more intelligently with the body’s innate ability to self-regulate.

Previous approaches suggested that IL-31 signals itch and promotes skin inflammation. But the UCSF team discovered that nerve cells, or neurons, that respond to IL-31, triggering a scratch, also prevent immune cells from overreacting and causing more widespread irritation.

“We tend to think that immune proteins like IL-31 help immune cells talk to one another, but here, when IL-31 talks to neurons, the neurons talk right back,” said Marlys Fassett, M.D., Ph.D., UCSF professor of dermatology and lead author of the study. “It’s the first time we’ve seen the nervous system directly tamp down an allergic response.”

The discovery could eventually change how asthma, Crohn’s and other inflammatory diseases are treated, due to IL-31’s presence throughout the body.

“IL-31 causes itch in the skin, but it’s also in the lung and in the gut,” said Mark Ansel, Ph.D., UCSF professor of immunology and senior author of the study. “We now have a new lead for fighting the many diseases involving both the immune and nervous systems.”

More than an itch

IL-31 is one of several “itch cytokines” because of its ability to instigate itch in animals and people. Fassett, a dermatologist and a researcher, has wanted to know why since she arrived at UCSF in 2012, a few years after its discovery. She reached out to Ansel, a former colleague and asthma expert who welcomed her into his lab.

First, Fassett removed the IL-31 gene from mice and exposed them to the house dust mite, a common, itchy allergen.

“We wanted to mimic what was actually happening in people who are chronically exposed to environmental allergens,” Fassett said. “As we expected, the dust mite didn’t cause itching in the absence of IL-31, but we were surprised to see that inflammation went up.”

Why was there inflammation but no itching? Fassett and Ansel found that a cadre of immune cells had been called into action in the absence of the itch cytokine. Without IL-31, the body was blindly waging an immunological war.

A balance of forces

Ansel and Fassett then homed in on the nerve cells in the skin that received the IL-31 signal. They saw that the same nerve cells that spurred a scratch also dampened any subsequent immune response. These nerve cells were integral to keeping inflammation in check, but without IL-31, they let the immune system run wild.

The findings squared well with what dermatologists were increasingly seeing with a new drug, nemolizumab, which blocked IL-31 and was developed to treat eczema. While clinical trial patients found that the dry, patchy skin of their eczema receded on the drug, other skin irritation, and even inflammation in the lungs, would sometimes flare up.

“When you give a drug that blocks the IL-31 receptor throughout the whole body, now you’re changing that feedback system, releasing the brakes on allergic reactions everywhere,” Ansel said.

Fassett and Ansel also found that these neurons released their own signal, called CGRP, in response to the itch signal, which could be responsible for dampening the immune response.

“The idea that our nerves contribute to allergy in different tissues is game changing,” Fassett said. “If we can develop drugs that work around these systems, we can really help those patients that get worse flares after treatment for itch.”

Fassett recently founded her own lab at UCSF to tease apart these paradoxes in biology that complicate good outcomes in the clinic. And Ansel is now interested in what this itch cytokine is doing beyond the skin.

“You don’t itch in your lungs, so the question is, what is IL-31 doing there, or in the gut?” Ansel asked. “But it does seem to have an effect on allergic inflammation in the lung. There’s a lot of science ahead for us, with immense potential to improve therapies.”

Recurrent C. difficile infections occur after suppressive antibiotic treatments that knock out almost all of the normal gut flora. Patients suffer watery diarrhea, painful abdominal cramps, a feeling of sickness, fevers and weight loss.

In 2021, researchers at the Icahn School of Medicine at Mount Sinai, New York, gave precise quantification of 150 bacterial strains belonging to 42 bacterial species that showed frequent engraftment after fecal microbial transplants. Importantly, they also tested for engraftment soon after transplant — 36 hours to four weeks — as well as later after transplantation, eight weeks to five years.

Now microbiome experts at the University of Alabama at Birmingham have taken that 2021 study, and a similar study for children who had C. difficile infections, a step further. UAB researchers Hyunmin Koo, Ph.D., and Casey D. Morrow, Ph.D., focused on the commensal microbe Bacteroides vulgatus, one of the most common species found in healthy guts. Using DNA sequences from the two studies and powerful bioinformatics analysis, Koo and Morrow searched for genes, out of a total of 4,911 protein-encoding genes in the B. vulgatus strains, that were unique to the three B. vulgatus donors in the two studies that showed early colonization, as opposed to seven other B. vulgatus strains in the studies that did not show early colonization.

“Analysis of the common genes between the three donors revealed that only 19 were in common out of 4,911 genes encoding known and hypothetical proteins,” Morrow and Koo write in the Scientific Reports study. “The result from our analysis supports the screening of donor B. vulgatus for this gene consortium to enhance colonization following a fecal microbe transplant.”

Morrow and Koo identified two of the 19 genes.

One is a putative chitobiase that the UAB researchers found was located next to genes encoding SusD, SusC, putative anti-sigma factor and RNA polymerase ECF-type sigma factor. Others previously have identified these genes as components of a commensal colonization factor complex in Bacteroides fragilis and B. vulgatus. This complex promotes a specific interaction with the host that facilitates stable, resilient colonization in mice.

“Our results, then, provide support that the commensal colonization factor complex might also function in humans to enhance the colonization of B. vulgatus,” Morrow said.

The other identified gene encodes a unique fimbrillin family protein. Fimbrillins are protein polymers, previously identified in Bacteroides, that can form the hair-like structures that protrude from the surfaces of microbes and serve as anchors for microbial adhesion with host cells.

“Based on their known functions, the identification of both the chitobiase — and subsequently a complete commensal colonization factor complex — and fimbrillin proteins supports the involvement of these proteins in B. vulgatus colonization,” Morrow said.

The other 17 genes are hypothetical proteins with no identified function as yet. Interestingly, genes that mapped near the hypothetical proteins involved activities in DNA mobilization and transposition, meaning the ability to move genes into, around or out of the bacterial genome.

Morrow and Koo acknowledge a weakness in their study.

When they analyzed the 42-paired fecal microbe samples from the Human Microbiome Project data set, they found that none had the complete set of the 19 genes that were found in the three early engraftment B. vulgatus strains. Twenty-six of the samples had both the putative chitobiase and the fimbrillin genes, and another 11 had only the fimbrillin gene. There was a varied presence of the other 17 hypothetical genes in the 42 samples.

“Since none of the Human Microbiome Project pairs had the full 19 genes, we do not know whether any of the pairs would have an early colonizing phenotype in fecal microbe transplants,” Morrow said. “Based on our analysis, we would assume that the commensal colonization factor complex and fimbrillin genes would suffice; but to resolve this issue, additional fecal microbe transplants for recurrent C. difficile in humans using early analysis times post-transplant would need to be done.”

The UAB researchers say a further application of their study could be screening following chemotherapy or transplants, which are known to involve medications that can disrupt normal microbial gut flora. “The capacity to rapidly restore the B. vulgatus community in these patients would be important to reduce the risk of infection by pathogens or antibiotic-resistant microbe pathogens that could impact overall health,” Morrow said.

Support for the Scientific Reports study, “Identification of donor Bacteroides vulgatus genes encoding proteins that correlate with early colonization following fecal transplant of patients with recurrent Clostridium difficile,” came from the Marnix E. Heersink School of Medicine at UAB. Morrow is a professor emeritus in the UAB Department of Cell, Developmental and Integrative Biology, and Koo is a bioinformatician in the UAB Department of Genetics.

“Establishing clear ethical guidelines and governance structures for the deployment of AI around the world is the first step to promoting trust and confidence, mitigating its risks, and ensuring that its benefits are fairly distributed,” says social scientist and co-author James William Santos of the Pontifical Catholic University of Rio Grande do Sul.

“Previous work predominantly centered around North American and European documents, which prompted us to actively seek and include perspectives from regions such as Asia, Latin America, Africa, and beyond,” says lead author Nicholas Kluge Corrêa of the Pontifical Catholic University of Rio Grande do Sul and the University of Bonn.

To determine whether a global consensus exists regarding the ethical development and use of AI, and to help guide such a consensus, the researchers conducted a systematic review of policy and ethical guidelines published between 2014 and 2022. From this, they identified 200 documents related to AI ethics and governance from 37 countries and six continents and written or translated into five different languages (English, Portuguese, French, German, and Spanish). These documents included recommendations, practical guides, policy frameworks, legal landmarks, and codes of conduct.

Then, the team conducted a meta-analysis of these documents to identify the most common ethical principles, examine their global distribution, and assess biases in terms of the type of organizations or people producing these documents.

The researchers found that the most common principles were transparency, security, justice, privacy, and accountability, which appeared in 82.5%, 78%, 75.5%, 68.5%, and 67% of the documents, respectively. The least common principles were labor rights, truthfulness, intellectual property, and children/adolescent rights, which appeared in 19.5%, 8.5%, 7%, and 6% of the documents, and the authors emphasize that these principles deserve more attention. For example, truthfulness — the idea that AI should provide truthful information — is becoming increasingly relevant with the release of generative AI technologies like ChatGPT. And since AI has the potential to displace workers and change the way we work, practical measures are to avoid mass unemployment or monopolies.

Most (96%) of the guidelines were “normative” — describing ethical values that should be considered during AI development and use — while only 2% recommended practical methods of implementing AI ethics, and only 4.5% proposed legally binding forms of AI regulation.

“It’s mostly voluntary commitments that say, ‘these are some principles that we hold important,’ but they lack practical implementations and legal requirements,” says Santos. “If you’re trying to build AI systems or if you’re using AI systems in your enterprise, you have to respect things like privacy and user rights, but how you do that is the gray area that does not appear in these guidelines.”

The researchers also identified several biases in terms of where these guidelines were produced and who produced them. The researchers noted a gender disparity in terms of authorship. Though 66% of samples had no authorship information, the authors of the remaining documents more often had male names (549 = 66% male, 281 = 34% female).

Geographically, most of the guidelines came from countries in Western Europe (31.5%), North America (34.5%), and Asia (11.5%), while less than 4.5% of the documents originated in South America, Africa, and Oceania combined. Some of these imbalances in distribution may be due to language and public access limitations, but the team says that these results suggest that many parts of the Global South are underrepresented in the global discourse on AI ethics. In some cases, this includes countries that are heavily involved in AI research and development, such as China, whose output of AI-related research increased by over 120% between 2016 and 2019.

“Our research demonstrates and reinforces our call for the Global South to wake up and a plea for the Global North to be ready to listen and welcome us,” says co-author Camila Galvão of the Pontifical Catholic University of Rio Grande do Sul. “We must not forget that we live in a plural, unequal, and diverse world. We must remember the voices that, until now, haven’t had the opportunity to claim their preferences, explain their contexts, and perhaps tell us something that we still don’t know.”

As well as incorporating more voices, the researchers say that future efforts should focus on how to practically implement principles of AI ethics. “The next step is to build a bridge between abstract principles of ethics and the practical development of AI systems and applications,” says Santos.

Researchers use the mouse as a model organism to study the structure and function of skeletal muscle, neuromuscular diseases and aging processes in muscle. The scientists are aware of their responsibility in the use of animals and have committed themselves at the University of Basel to rigorously implement the so-called 3R principles — Replacement, Reduction, Refinement — in animal-assisted research and animal husbandry.

The new method developed by Professor Markus Rüegg’s research group at the Biozentrum, University of Basel, is a further step towards reducing the number of laboratory animals. This method also opens new ways to investigate several genes simultaneously or even entire signaling pathways in muscle fibers quickly, cost-effectively and efficiently. The results of the study have now been published in Nature Communications.

The difficulty of studying genes in muscle fibers

Studying gene function in muscle is challenging. On the one hand, muscle fibers are very large and very fragile when isolated. On the other hand, in humans, they are up to half a meter long and contain thousands of nuclei. In order to change and study gene function in muscle fibers, all of the muscle fiber nuclei must be changed, which is difficult to achieve.

For some years now, scientists have been using the CRISPR/Cas9 method to study gene function. This method uses a virus to introduce the so-called Cas9 protein and a specifically designed guide RNA into the organism and thus into the nuclei. The Cas9 protein cuts the genomic DNA at the site recognized by the guide RNA. This combination of Cas9 protein and guide RNA allows altering gene function in the cell.

The CRISPR-Cas9 method can be split up

However, to ensure that the virus only alters the gene expression of muscle fibers and not those of other organs at the same time, the research team combined the CRISPR/Cas9 method with another method: First, the researchers succeeded in breeding mice with the Cas9 protein already present in their muscle fibers — but only there. They then introduced the desired guide RNA into the organism with a so-called adeno-associated virus, which infects muscle.

This combination causes the guide RNA in the muscle fibers to encounter the Cas9 protein, changing the genetic material as desired. “The method enables us to ensure that only the muscle fibers actually change their genetic material,” explains first author Marco Thürkauf.

Fewer laboratory animals and more efficient results

Since the adeno-associated virus can also transport several guide RNAs simultaneously, the team can now use the method to investigate several genes simultaneously or even entire signaling pathways. Furthermore, the method significantly reduces the number of experimental animals required.

“All animals used are suitable for studying genes and do not have to be bred over years. This makes it possible to study muscle fibers as well as neuromuscular diseases without using a large number of mice,” says Marco Thürkauf.

Other research groups have also already signaled their interest. “We already have several interested groups in our research community that would like to use our method,” says Markus Rüegg. “This is a great gain for both muscle research per se as well as for our goal of reducing animal experiments.”