Inflammatory bowel disease is miserable for anyone, but when it strikes a child under age five, it’s also quite severe, usually causing bloody diarrhea, wrenching abdominal pain, and stunted growth. Early-onset IBD is rare but, for unknown reasons, is on the rise, with its incidence increasing by about 5 percent annually 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 the 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 effective treatment. A bone marrow transplant is a cure but carries many risks, especially for infants.
“We’ve been trying to understand why IBD in these children is so severe and presents so early,” says Dror Shouval, an HMS clinical fellow in pediatrics at Boston Children’s Hospital. The beginnings of such an understanding, reported by Shouval, as lead author, and colleagues in the May 15 issue of Immunity, could lead to a new treatment approach for this and perhaps other kinds of early-onset IBD.
Working through its receptor, IL-10 quiets inflammatory immune responses during periods when there’s no threat of infection. Working with mouse models, the researchers showed that when innate immune cells near the intestine didn’t receive IL-10 signals, the mice lost weight and developed rapid, severe intestinal inflammation. They also found that without the ability to sense IL-10, the mice could churn out proinflammatory macrophages but produced comparatively few having anti-inflammatory properties. The macrophages they did produce functioned poorly. As a result, the murine immune systems also produced fewer, and less well-functioning, T-regulatory cells, another type of calming immune cell.
Simply put, their intestinal immune responses were out of whack.
The researchers then tapped a worldwide patient cohort study of early-onset IBD, identified seven children from as many countries who manifested IBD and IL-10-receptor mutations, and studied their disease in the laboratory. The results mirrored those found in the mouse model.
The mouse studies had another, more hopeful, finding. By transferring anti-inflammatory macrophages into the IL-10-receptor-deficient mice, the researchers were able to ameliorate their IBD.
Image: Dr. Mark J. Winter/Science Source