Autoimmune diseases, in which the body’s defense system turns against itself, may arise much sooner than previously thought. A recent discovery seems to indicate that in rare cases the disease begins even before birth. Brazilian researchers have identified two cases of families—one in São Paulo State and another in Paraná State—in which shortly after birth the children presented signs of an unusual and serious autoimmune disease: immunodysregulation polyendocrinopathy enteropathy syndrome linked to the X chromosome (IPEX). In this syndrome, the infant’s own immune cells attack multiple organs, which after weeks or months of continuous aggression cease to function properly and generate clinical signs that can be recognized by pediatricians. Since the São Paulo and Paraná babies presented signs of IPEX in the first hours of life, the researchers concluded that the immune attack could only have started much earlier, still in pregnancy.
The finding was published in the December 2014 issue of Clinical Immunology and surprised experts. “We never thought that autoimmune diseases could occur during intrauterine life,” says Dr. Magda Carneiro-Sampaio, a pediatrician and professor at the University of São Paulo School of Medicine (FMUSP) and the coordinator of the research study.
Immunologic diseases initiated in the fetus during pregnancy are not uncommon. The most well known is fetal erythroblastosis, which is caused by an incompatibility between the mother’s blood group and that of the baby. In this disease, however, the problem is caused by antibodies produced by the mother’s immune cells are transferred to the child through the placenta and umbilical cord. By contrast, in the cases described by Dr. Carneiro-Sampaio’s group in Clinical Immunology, it is the cells of the fetus’s own immune system that harm the organism. “To our knowledge, these are the first proven cases of autoimmune disease initiated in pregnancy,” says Dr. Carneiro-Sampaio.
The cases described in Clinical Immunology result from changes in a gene that compromise the maturation of a specific group of immune cells: regulatory T lymphocytes. Responsible for coordinating the action of other immune cells, these lymphocytes undergo a maturation phase in the thymus, an organ located in the upper chest, in which they learn to identify the body’s own cells and safeguard them from attack by cells of invading organisms. But problems in this maturation stage cause these lymphocytes to unleash an attack against the body itself.
Since 2008, Dr. Carneiro-Sampaio’s group has been investigating autoimmune diseases that affect infants and children early in life. Even though some immunologists have explored the idea that autoimmune problems could begin in the fetal stage, the group’s researchers just did not expect them to reach fetuses. “There are cases in the medical literature of babies with severe immune deficiencies at birth,” says Dr. Carneiro-Sampaio. “This type of disease does not just suddenly appear from one day to the next.”
The first case presented in Clinical Immunology became known to Dr. Carneiro-Sampaio many years ago, a case reported by Dr. Edson Suzuki, a pediatrician at the Marilia Medical School. But confirmation would only come with the study of two male fetuses from the same family, who died as a result of a complication in their development, and with the case of another family, identified by Dr. Mariana Xavier da Silva, an endocrinologist and researcher at Londrina State University, who did her residency at USP’s Children’s Institute.
In that city in Paraná State, Dr. Xavier da Silva had treated a male infant who was born prematurely and had diabetes that was difficult to control in the first hours of life. Laboratory tests revealed that his body was producing antibodies against the insulin-producing cells of the pancreas. Signs of inflammation on the skin, in the intestines and other organs were used to identify the problem as IPEX.
In 93% of cases, this syndrome manifests itself in the first year of life, although some cases are identified shortly after birth. Its origin stems from specific changes in the forkhead box P3 (FOXP3) gene, which controls the maturation of regulatory T lymphocytes.
Located on the X chromosome, there is a double copy of this gene in women and a single one in men. For this reason, the mothers in the two families had not developed the syndrome, although they presented one of the altered copies, which was inherited by the children with IPEX. In investigating the history of the disease in these families, the researchers also saw that mothers and grandmothers (in one of the families also the great-grandmother) had lost other male babies during pregnancy.
The researchers searched the medical literature for other reports of miscarriages and premature births associated with IPEX, a sign that the syndrome would have appeared during pregnancy. Between 2000 and 2014, they found another 130 cases. “In 45% of the cases, the autoimmune signs appeared in the first month of life, and 11 of them on the first day,” says Dr. Carneiro-Sampaio. “But none of the researchers suggested that the disease began during intrauterine life,” she says.
The finding that the problem can begin in pregnancy led the group to propose a new mechanism to explain the development of IPEX. Medical schools teach that such autoimmune diseases arise when the regulatory T lymphocytes lose their ability to distinguish cells of the body from those of invading microorganisms. According to this model, known as breach of tolerance, the problem arises only after the immune system goes through a maturation phase, previously considered impossible in fetal life. “In these cases there would be no breach of tolerance, since tolerance had never been established,” says Dr. Carneiro-Sampaio.
According to António Coutinho, an immunologist at the Portugal based Gulbenkian Institute of Science who collaborates with the group, this is a substantial shift in the thinking that has long prevailed among experts. He believes this work should serve to make pediatricians and neonatologists aware of the possibility that newborns could present autoimmune diseases. The sooner they are identified, the better the treatment outcomes and greater chances of a cure—most autoimmune diseases are treated with immunosuppressive drugs and IPEX is treated with stem cell transplants. “These are procedures that can save a child’s life,” says Coutinho.
Obstetricians can use the new information to direct patients to genetic counseling when there are cases of repeat miscarriages or losses of male newborns in the family. “If there is a risk that the pregnancy will result in a severe syndrome that only affects boys, such as IPEX, the alternative is to do in vitro fertilization and select a female embryo,” says Maria de Lourdes Brizot, a specialist in fetal medicine at FMUSP. A Federal Medical Council resolution authorizes this procedure in order to prevent diseases linked to the sex of the child. “In such a case,” says de Lourdes Brizot, “the choice is not discriminatory, but to save the baby’s health and life.”
Autoimmunity in children: investigation of the molecular and cellular bases of early onset autoimmunity (No. 2008/58238-4); Grant mechanism: Thematic Project; Principal investigator: Magda Maria Sales Carneiro-Sampaio (FM-USP); Investment: R$1,807,886.18 (FAPESP – for the entire project).
XAVIER DA SILVA, M.M. et al. Fetal-onset FM-USP: report of two families and review of literature. Clinical Immunology. V. 156, No. 2, p. 131-140. February 2015.