(Press-News.org) PHILADELPHIA - The human gut is loaded with commensal bacteria – "good" microbes that, among other functions, help the body digest food. The gastrointestinal tract contains literally trillions of such cells, and yet the immune system seemingly turns a blind eye. However, in several chronic human diseases such as inflammatory bowel disease (IBD), HIV/AIDS, cancer, cardiovascular disease, and diabetes, the immune system attacks these normally beneficial bacteria, resulting in chronic inflammation and contributing to disease progression.
Now, researchers may finally understand an important mechanism that keeps this friendly truce intact – a finding that may lead to the development of new therapeutic strategies for such chronic diseases.
Gregory F. Sonnenberg, PhD, research associate in the Department of Medicine, Gastroenterology Division, and the Institute for Immunology at the Perelman School of Medicine, University of Pennsylvania, with postdoctoral researcher Matthew Hepworth, PhD, report in Nature that innate lymphoid cells (ILCs) directly limit the response by inflammatory T cells to commensal bacteria in the gut of mice. Loss of this ILC function effectively puts the immune system on an extended war footing against the good, commensal bacteria – a condition observed in multiple chronic inflammatory diseases.
ILCs are a class of rare immune cells that were first described a few years ago. Previous research has implicated these cells in regulating immune responses in the intestine, mostly through their ability to secrete immune-activating cytokines. But until now, researchers have had a hard time studying ILCs because it hasn't been possible to selectively eliminate them in the context of an otherwise intact immune system.
Sonnenberg, Hepworth, and their colleagues deleted a protein called RORt, required for one class of ILCs, in mice. RORt-deficient animals had exacerbated T cell responses against commensal bacteria and systemic inflammation. In contrast, deletion of previously identified ILC effector cytokines such as IL-22 and IL-17 did not elicit an immune response to commensal bacteria, suggesting the ILCs use an unidentified regulatory pathway.
When the team looked at what gene signatures the RORt-dependent ILCs expressed, they found high expression of major histocompatibility complex class II (MHCII) protein, which some cells use to display foreign proteins to the immune system and directly interact with T cells.
This, as with RORγt-deficient mice, selective deletion of MHCII in ILCs resulted in hyperactive T-cell responses directed against commensal bacteria and systemic inflammatory responses, all of which could be alleviated by depletion of commensal bacteria with broad-spectrum antibiotics. What's more, mice with the selective deletion of MHCII in ILCs also developed inflammatory bowel disease, which was driven by aberrant CD4+ T-cell responses to commensal bacteria.
This study is the first to selectively target ILCs in the presence of an intact immune system, and these findings suggest that under normal conditions, ILCs play a critical role in dampening the anti-bacterial T-cell response using MHCII. Indeed, when Sonnenberg's team looked at ILC activity directly, they found that MHCII+ ILCs could present foreign antigen to T cells and limit their expansion and pro-inflammatory properties.
Essentially, ILCs seem to instruct T cells to trust – that is, ignore -- commensal bacteria, thereby allowing the immune system to coexist with these foreign entities. Loss or dysregulation of ILCs, in turn, brought on by genetic or environmental factors such as diet or infection, for example, eliminates that protective action. This can lead to dysregulated immune activity and chronic inflammation.
"Inappropriate immune response to commensal bacteria and subsequent pathologic inflammation is a contributing factor to the pathogenesis and progression of many chronic human diseases, including inflammatory bowel disease, HIV/AIDS, viral hepatitis, cancer, cardiovascular disease, and diabetes," says Sonnenberg.
"This study provides new insight into the pathways that regulate immune responses to commensal bacteria and maintain tissue homeostasis" adds Hepworth.
Importantly, the study also identifies that MHCII+ ILCs are found in the intestinal tissues of healthy human donors. "Although it's still early days for this line of research, these findings provoke the hypothesis that MHCII+ innate lymphoid cells may be an important pathway to therapeutically target in the treatment of some chronic inflammatory diseases," suggests Sonnenberg. The Sonnenberg lab is now trying to establish if that is the case.
INFORMATION:
Other Penn coauthors include Laurel Monticelli, Thomas Fung, Stephanie Grunberg, Rohini Sinha, Adriana Mantegazza, Alison Crawford, Jill Angelosanto, E. John Wherry, Frederic Bushman, and David Artis.
The research was funded by the National Institutes of Health (AI061570, AI087990, AI074878, AI095776, AI102942, AI095466, AI095608, AI097333, T32-AI055428, DK071176, DP5OD012116), the Crohn's and Colitis Foundation of America, and the Burroughs Wellcome Fund.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.
Penn study shows how immune system peacefully co-exists with 'good' bacteria
Understanding how this immunological truce is kept suggests new ways to fight inflammatory diseases
2013-05-23
ELSE PRESS RELEASES FROM THIS DATE:
Slowing the aging process -- only with antibiotics
2013-05-23
VIDEO:
EPFL scientists have revealed the mechanism, hidden deep within cell mitochondria, that is responsible for making organisms age. Nematodes treated with antibiotics designed to disrupt this mechanism lived longer and...
Click here for more information.
Why is it that within a homogeneous population of the same species, some individuals live three times as long as others? This question has stumped scientists for centuries.
Now, EPFL researchers led by Johan Auwerx ...
Fish oil supplements may help fight against Type 2 diabetes
2013-05-23
Chevy Chase, MD—Widely-used fish oil supplements modestly increase amounts of a hormone that is associated with lower risk of diabetes and heart disease, according to a study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM).
Fish oil supplements, also called omega 3 fatty acid capsules, raise levels of adiponectin in the bloodstream. Adiponectin is an important hormone that has beneficial effects on metabolic processes like glucose regulation and the modulation of inflammation. In long-term human studies, higher ...
Mild hypothyroidism raises mortality risk among heart failure patients
2013-05-23
Chevy Chase, MD—Patients with underlying heart failure are more likely to experience adverse outcomes from mild hypothyroidism, according to a recent study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM).
Hypothyroidism occurs when an underactive thyroid does not produce enough hormones. More than 9.5 million people nationwide have hypothyroidism. People who have thyroid function at the low end of the normal range have subclinical hypothyroidism, also called mild hypothyroidism.
"Our data suggest that mild hypothyroidism ...
Swine flu pandemic of 2009 more deadly for younger adults, UCI study finds
2013-05-23
Irvine, Calif. – As the world prepares for what may be the next pandemic strain of influenza virus, in the H7N9 bird flu, a new UC Irvine study reveals that the 2009 H1N1 swine flu pandemic was deadliest for people under the age of 65, while those 65 and over had greater immunity due to previous exposure to similar viruses.
Deaths from flu pandemics tend to skew younger than those from seasonal flu because of "antigenic recycling," or the fact that some parts of flu viruses have already made the rounds. Between 1918 and 1957, all flu viruses in circulation fell into the ...
What the smallest infectious agents reveal about evolution
2013-05-23
Radically different viruses share genes and are likely to share ancestry, according to research published in BioMed Central's open access journal Virology Journal this week. The comprehensive phylogenomic analysis compares giant viruses that infect amoeba with tiny viruses known as virophages and to several groups of transposable elements. The complex network of evolutionary relationships the authors describe suggests that viruses evolved from non-viral mobile genetic elements and vice versa, on more than one occasion.
The recent discovery of virophages inside the giant ...
Researchers complete largest genetic sequencing study of human disease
2013-05-23
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
The exact cause of these diseases – autoimmune thyroid disease, coeliac disease, Crohn's disease, psoriasis, multiple sclerosis and type 1 diabetes– is unknown, but is believed to be a complex combination of genetic and environmental factors. In each disease only aproportion of the heritability is explained by the identifiedgenetic variants. The techniques used to date, have generally identified common ...
The Norway spruce genome sequenced
2013-05-23
Swedish scientists have mapped the gene sequence of Norway spruce (the Christmas tree) – a species with huge economic and ecological importance - and that is the largest genome to have ever been mapped. The genome is complex and seven times larger than that of humans. The results have been published in the prestigious journal Nature.
This major research project has been led by Umeå Plant Science Centre (UPSC) in Umeå and the Science for Life Laboratory (SciLifeLab) in Stockholm.
In addition to its scientific interest this new knowledge has immense importance to the ...
Researchers reveal model of Sun's magnetic field
2013-05-23
Researchers at the Universities of Leeds and Chicago have uncovered an important mechanism behind the generation of astrophysical magnetic fields such as that of the Sun.
Scientists have known since the 18th Century that the Sun regularly oscillates between periods of high and low solar activity in an 11-year cycle, but have been unable to fully explain how this cycle is generated.
In the 'Information Age', it has become increasingly important to be able to understand the Sun's magnetic activity, as it is the changes in its magnetic field that are responsible for ...
Fragile mega-galaxy is missing link in history of cosmos
2013-05-23
Irvine, Calif. – Two hungry young galaxies that collided 11 billion years ago are rapidly forming a massive galaxy about 10 times the size of the Milky Way, according to UC Irvine-led research published Wednesday in the journal Nature.
Capturing the creation of this type of large, short-lived star body is extremely rare – the equivalent of discovering a missing link between winged dinosaurs and early birds, said the scientists, who relied on the once-powerful Herschel space telescope and observatories around the world. The new mega-galaxy, dubbed HXMM01, "is the brightest, ...
Pinpointing how nature's benefits link to human well-being
2013-05-23
What people take from nature – water, food, timber, inspiration, relaxation – are so abundant, it seems self-evident. Until you try to quantitatively understand how and to what extent they contribute to humans.
In today's world, where competition for and degradation of natural resources increases globally, it becomes ever more crucial to quantify the value of ecosystem services – the precise term that defines nature's benefits, and even more important to link how different types of ecosystem services affect various components of human well-being.
Scientists at Michigan ...
LAST 30 PRESS RELEASES:
QUT scientists create material to turn waste heat into clean power
Major new report sets out how to tackle the ‘profound and lasting impact’ of COVID-19 on cardiovascular health
Cosmic crime scene: White dwarf found devouring Pluto-like icy world
Major report tackles Covid’s cardiovascular crisis head-on
A third of licensed GPs in England not working in NHS general practice
ChatGPT “thought on the fly” when put through Ancient Greek maths puzzle
Engineers uncover why tiny particles form clusters in turbulent air
GLP-1RA drugs dramatically reduce death and cardiovascular risk in psoriasis patients
Psoriasis linked to increased risk of vision-threatening eye disease, study finds
Reprogramming obesity: New drug from Italian biotech aims to treat the underlying causes of obesity
Type 2 diabetes may accelerate development of multiple chronic diseases, particularly in the early stages, UK Biobank study suggests
Resistance training may improve nerve health, slow aging process, study shows
Common and inexpensive medicine halves the risk of recurrence in patients with colorectal cancer
SwRI-built instruments to monitor, provide advanced warning of space weather events
Breakthrough advances sodium-based battery design
New targeted radiation therapy shows near-complete response in rare sarcoma patients
Does physical frailty contribute to dementia?
Soccer headers and brain health: Study finds changes within folds of the brain
Decoding plants’ language of light
UNC Greensboro study finds ticks carrying Lyme disease moving into western NC
New implant restores blood pressure balance after spinal cord injury
New York City's medical specialist advantage may be an illusion, new NYU Tandon research shows
Could a local anesthetic that doesn’t impair motor function be within reach?
1 in 8 Italian cetacean strandings show evidence of fishery interactions, with bottlenose and striped dolphins most commonly affected, according to analysis across four decades of data and more than 5
In the wild, chimpanzees likely ingest the equivalent of several alcoholic drinks every day
Warming of 2°C intensifies Arctic carbon sink but weakens Alpine sink, study finds
Bronze and Iron Age cultures in the Middle East were committed to wine production
Indian adolescents are mostly starting their periods at an earlier age than 25 years ago
Temporary medical centers in Gaza known as "Medical Points" (MPs) treat an average of 117 people daily with only about 7 staff per MP
Rates of alcohol-induced deaths among the general population nearly doubled from 1999 to 2024
[Press-News.org] Penn study shows how immune system peacefully co-exists with 'good' bacteriaUnderstanding how this immunological truce is kept suggests new ways to fight inflammatory diseases