Stories about: immunology

How do cells release IL-1? The answer packs a punch, and could enable better vaccines

In hyperactivated immune cells, gasdermin D punches holes in the cell membrane that let IL-1 out — without killing the cell.

Interleukin-1 (IL-1), first described in 1984, is the original, highly potent member of the large family of cellular signaling molecules called cytokines that regulate immune responses and inflammation. It’s a key part of our immune response to infections, and also plays a role in autoimmune and inflammatory diseases. Several widely used anti-inflammatory drugs, such as anakinra, block IL-1 to treat rheumatoid arthritis, systemic inflammatory diseases, gout and atherosclerosis. IL-1 is also a target of interest in Alzheimer’s disease.

Yet until now, no one knew how IL-1 gets released by our immune cells.

“Most proteins have a secretion signal that causes them to leave the cell,” says Jonathan Kagan, PhD, an immunology researcher in Boston Children’s Hospital’s Division of Gastroenterology. “IL-1 doesn’t have that signal. Many people have championed the idea that IL-1 is passively released from dead cells: you just die and dump everything outside.”

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Breastfeeding protects against food allergy: We have evidence

Mother breastfeeding her baby. Is she helping her child avoid food allergy?

Eating allergenic foods during pregnancy can protect your child from food allergies, especially if you breastfeed, suggests new research. The findings, in a mouse model of allergy, underscore recent advice that pregnant or nursing mothers not avoid allergenic foods like eggs and peanuts.

The study is the first controlled investigation to demonstrate protection against food allergy from breast milk, while also pointing to a biological mechanism for inducing food tolerance. It was published online today in the Journal of Experimental Medicine.

“Whether mothers should eat allergenic foods during pregnancy or avoid them has been controversial,” says Michiko Oyoshi, PhD, of Boston Children’s Division of Allergy and Immunology, who led the study in collaboration with Richard Blumberg, MD, of Brigham and Women’s Hospital, her co-senior author.

“Different studies have found different results, in part because it’s hard in human studies to know when mothers and babies first encountered a specific food,” says Oyoshi. “But in a mouse model, we can control exposure to food.”

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Pre-treated blood stem cells reverse type 1 diabetes in mice

autoimmune attack in type 1 diabetes
In type 1 diabetes, autoreactive T-cells (like the one in yellow) attack insulin-producing beta cells in the pancreas. What if blood stem cells could be taught to neutralize them? (Image: Andrea Panigada)

Type 1 diabetes is caused by an immune attack on the pancreatic beta cells that produce insulin. To curb the attack, some researchers have tried rebooting patients’ immune systems with an autologous bone-marrow transplant, infusing them with their own blood stem cells. But this method has had only partial success.

New research in today’s Science Translational Medicine suggests a reason why.

“We found that in diabetes, blood stem cells are defective, promoting inflammation and possibly leading to the onset of disease,” says Paolo Fiorina, MD, PhD, of Boston Children’s Hospital, senior investigator on the study.

But they also found that the defect can be fixed — by pre-treating the blood stem cells with small molecules or with gene therapy, to get them to make more of a protein called PD-L1.

In experiments, the treated stem cells homed to the pancreas and reversed hyperglycemia in diabetic mice, curing almost all of them of diabetes in the short term. One third maintained normal blood sugar levels for the duration of their lives.

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News Note: Steroids could be counter-productive in severe asthma

severe asthma
Nine years old kid with allergic asthma, inhaling his medication through spacer while looking at with his wide opened eyes perhaps he is getting energy boost

Some 10 to 15 percent of people with asthma have severe disease that medications can’t control. A deep-dive multicenter study finds differences in these patients’ immune systems that may explain why increased dosages of corticosteroids don’t help — and could lead to steroids doing more harm than good. Findings appear online this week in Science Immunology.

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Poison ivy and psoriasis: The treatment we’ve been itching for?

poison ivy psoriasis target CD1a
Poison ivy, psoriasis, eczema and other inflammatory skin conditions could have a shared targeted treatment. (Jessica Kim/Winau Lab)

The skin is a natural barrier against pathogens and harmful chemicals. But it isn’t bulletproof: contact allergens like poison ivy can trigger an immune response causing severe inflammation, itching and tissue damage. Mechanistically, what happens is that Langerhans cells — certain antigen-presenting cells in the immune system — initiate a chain reaction. This rallies helper T cells to the area, causing skin inflammation.

A protein called CD1a (Cluster of Differentiation 1a) has been thought to be part of this reaction. But until recently, its role was poorly understood, at least in part because there was no good test model. Research in Nature Immunology now suggests that targeting CD1a could lead to new therapies for poison ivy and other inflammatory skin conditions like psoriasis and eczema.

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Protecting immune cells from exhaustion

T cell exhaustion
Boosting a naturally occurring protein could prevent T-cells from burning out

Run the first half of a marathon as fast as you can and you’ll likely never finish the race. Run an engine at top speed for too long and you’ll burn it out.

The same principle seems to apply to our T cells, which power the immune system’s battle with chronic infections like HIV and hepatitis B, as well as cancer. Too often, they succumb to “T cell exhaustion” and lose their capacity to attack infected or malignant cells. But could T cells learn to pace themselves and run the full marathon?

That’s the thinking behind a research study published last week by The Journal of Experimental Medicine. “Our research provides a clear explanation for why T cells lose their fighting ability,” says Florian Winau, MD, “and describes the countervailing process that protects their effectiveness.”

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When antibiotics fail: A potential new angle on severe bacterial infection and sepsis

bacterial infection sepsisBacterial infections that don’t respond to antibiotics are of rising concern. And so is sepsis — the immune system’s last-ditch, failed attack on infection that ends up being lethal itself. Sepsis is the largest killer of newborns and children worldwide and, in the U.S. alone, kills a quarter of a million people each year. Like antibiotic-resistant infections, it has no good treatment.

Reporting this week in Nature, scientists in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine (PCMM) describe new potential avenues for controlling both sepsis and the runaway bacterial infections that provoke it.

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Can we supercharge vaccines? Added compound boosts T-cell production

supercharged vaccines oxPAPCBridging our innate and adaptive immune systems, dendritic cells are sentinels that circulate in the body searching out microbes and activating T-cells to destroy the invaders. They do this by presenting bits of the microbes on their surface—explaining why they’re often called antigen-presenting cells.

Reporting in Science this week, researchers describe a way to push dendritic cells into a “hyperactive” state, supercharging their ability to rally T-cells.

The key player, a fatty chemical called oxPAPC, is naturally found in damaged tissues and atherosclerotic plaques. It selectively targets dendritic cells and could, the researchers believe, enhance people’s immunity to a wide range of infections.

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Food allergies: Turning tolerance back on

Mast cell food allergy
Mast cells don’t simply cause acute allergic reactions. They also turn off immune tolerance. But that could change. (Bruce Blaus/Wikimedia Commons)

Hans Oettgen, MD, PhD, is Associate Chief of the Division of Allergy and Immunology at Boston Children’s Hospital.  He leads a research group investigating mechanisms of allergic diseases.

Not long ago I received a wonderful email from “Sam,” an 18-year-old young man with peanut allergy. He was participating in a clinical trial of oral immunotherapy (OIT) being carried out by colleagues here at Boston Children’s Hospital.

In OIT, patients receive initially minute doses of the food to which they are allergic. Then, over many weeks, they ingest increasing amounts, under close medical monitoring at the hospital.

OIT’s goal is to get patients to tolerate previously allergenic foods by inducing their bodies to produce Treg cells, or regulatory T cells. These are the master controllers of our immune responses, and their actions include suppressing allergic responses to foods. Food ingestion, as in OIT, will eventually induce food-specific Treg cells, but it can be a long and cumbersome process. For Sam, ingesting escalating doses of peanuts proved difficult: His email described frequent reactions ranging from stomachaches and itchiness to difficulty breathing.

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Cell therapy for early-onset inflammatory bowel disease?

Macrophage therapy early-onset IBD
Giving patients the right kind of immune cells could curb their IBD, research suggests.

Inflammatory bowel disease (IBD) is miserable for anyone, but when it strikes a child under age 5, it’s much more severe, usually causing bloody diarrhea, wrenching abdominal pain and stunted growth. Early-onset IBD is rare, but on the rise: For reasons unknown, its incidence is increasing by about 5 percent per year in some parts of the world.

A recently identified form of early-onset IBD shows up within months of birth, causing severe inflammation in the large intestine and abscesses around the anus. Recently linked to genetic mutations in the cellular receptor for a signaling protein, interleukin-10 (IL-10), it can also lead to lymphoma later in life.

As with all early-onset IBD, IL-10-receptor deficiency has no good treatment. A bone marrow transplant is actually curative, but carries many risks, especially in infants.

“We’ve been trying to understand why IBD in these children is so severe and presents so early,” says Dror Shouval, MD, a pediatric gastroenterologist at Boston Children’s Hospital and a fellow in the lab of Scott Snapper, MD, PhD. The beginnings of such an understanding—detailed recently in the journal Immunity—could lead to a new treatment approach for this and perhaps other kinds of early-onset IBD.

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