Immune System Now Implicated in Rare Disorder, Study Shows
UC San Francisco researchers have shed light on how the immune system of a fetus can run amok, triggering inflammation in the developing intestines that protrude outside of the body through a hole beside the belly button.
Their findings, published online May 13, 2016, in the Journal of Immunology point to a treatment strategy for the condition known as in gastroschisis, and to the cellular mechanisms within the fetal immune system that may lead to aberrant development.
Gastroschisis is a potentially life-threatening condition occurring in approximately one in 2,000 babies born in the United States, according to the Centers for Disease Control and Prevention (CDC).
Before birth, the fetal immune system develops to a more advanced degree than scientists previously appreciated, according to principal investigator and senior author Tippi MacKenzie, MD, a pediatric surgeon and associate professor in the Department of Surgery at UCSF Benioff Children’s Hospital San Francisco.
“In the past, we had assumed that contact with the amniotic fluid is what causes bowel damage in gastroschisis, but we have now shown that the bowel damage is due to inherent changes in the fetal immune system, which mounts an immune response,” she said. “As a result, our ideas about how we might treat gastroschisis have changed.”
Immune Cells, Signaling Molecules Key to Inflammation
“The current treatment for gastroschisis involves placing the intestines back in the belly and closing the hole,” said MacKenzie, who is co-director of the UCSF Center for Maternal-Fetal Precision Medicine, which develops new therapies for patients with birth defects. “But the intestines remain inflamed, and the neonates are in the intensive care unit for weeks, sometimes months, just waiting for the intestines to recover. We need to understand what causes this inflammation so we can directly treat it.”
In their analysis of umbilical cord blood and intestines of neonatal patients with gastroschisis, and in studies of mice with a form of the anomaly, the researchers identified immune cells and signaling molecules that trigger chronic inflammation, not only within the part of the intestines exposed to amniotic fluid, but also throughout the intestines.
“The bowel is not only sick on the outside, where it has been directly exposed to the amniotic fluid,” said first author Michela Frascoli, PhD, a postdoctoral fellow in the of the Departments of Surgery at UCSF Benioff Children’s Hospital San Francisco and of UCSF Eli and Edythe Broad Center of Regeneration Medicine. “We found these cells in the blood in the fetus. This tells us that the inflammation goes throughout the intestines, and unless you treat the fetus systemically, the treatment cannot be expected to cure the inflammation in the bowel.”
Surgeons have previously attempted, unsuccessfully, to quiet inflammation by extracting amniotic fluid during pregnancy and replacing it with a saline solution, MacKenzie said.
In the mice, the researchers were able to dampen the immune response with treatment targeted to the immune cells that help trigger it, raising hope for development of a therapy for the chronic inflammation, which is detectible during routine prenatal ultrasound.
In the study, the UCSF researchers collected maternal and fetal cord blood at the time of delivery from 27 gastroschisis patients and 23 healthy newborns. Fetal blood in gastroschisis contained elevated levels of inflammatory immune cells and several signaling molecules that help govern immune responses. The researchers also examined surgical samples of intestine and determined that the bowel tissue was flooded with inflammatory immune cells, specifically T cells and eosinophils.
Condition More Common in Offspring of Teen Mothers
The researchers confirmed the findings using mouse model of the disease. They bred male and female mice that were carriers of a specific gene mutation that resulted in one-quarter of mouse embryos developing gastroschisis in utero. The scientists found that treatment of mouse embryos or mothers with an antibody against a molecule called IL5 reduced the population of inflammatory eosinophils.
In January the CDC reported that gastroschisis has increased in prevalence by 30 percent. Children of mothers under age 20 and those who are economically disadvantaged are more likely to be affected, but prevalence has increased in every age group and race.
The reason for this increase is puzzling. Another mystery involves the high rate of preterm birth in these patients, which could be related to the fetal inflammation and can worsen the condition, MacKenzie said. Her team is continuing to investigate strategies to quiet inflammation in animal models, with the hope of developing a successful in-utero treatment.
The study was supported by funding from the American College of Surgeons, the National Institute of Allergy and Infection Diseases and the March of Dimes.
Co-authors of the study are Cerine Jeanty, MD, Patriss Moradi, Aras Mattis, MD, PhD, Shannon Fleck, MPH, and Qizhi Tang, PhD, of UCSF; and Sheila Keating, PhD, of the Blood Systems Research Institute, San Francisco.
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.