Hypothyroxinemia (Hpx) is a thyroid hormone deficiency (THD) condition highly frequent during pregnancy, which although asymptomatic for the mother, it can impair the cognitive function of the offspring. Previous studies have shown that maternal hypothyroidism increases the severity of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis (MS). Here, we analyzed the immune response after EAE induction in the adult offspring gestated in Hpx. Mice gestated in Hpx showed an early appearance of EAE symptoms and the increase of all parameters of the disease such as: the pathological score, spinal cord demyelination, and immune cell infiltration in comparison to the adult offspring gestated in euthyroidism. Isolated CD4+CD25+ T cells from spleen of the offspring gestated in Hpx that suffer EAE showed reduced capacity to suppress proliferation of effector T cells (TEff) after being stimulated with anti-CD3 and anti-CD28 antibodies. Moreover, adoptive transfer experiments of CD4+CD25+ T cells from the offspring gestated in Hpx suffering EAE to mice that were induced with EAE showed that the receptor mice suffer more intense EAE pathological score. Even though, no significant differences were detected in the frequency of Treg cells and IL-10 content in the blood, spleen, and brain between mice gestated in Hpx or euthyroidism, T cells CD4+CD25+ from spleen have reduced capacity to differentiate in vitro to Treg and to produce IL-10. Thus, our data support the notion that maternal Hpx can imprint the immune response of the offspring suffering EAE probably due to a reduced capacity to trigger suppression. Such “imprints” on the immune system could contribute to explaining as to why adult offspring gestated in Hpx suffer earlier and more intense EAE.

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

There are more evidences supporting the relevance of a healthy pregnancy over offspring imprinting. This is the case for the maternal endocrine status and the immune system. Hypothyroxinemia (Hpx) is a highly frequent thyroid hormone deficiency condition in pregnant women characterized by low levels of thyroxin (T4) with normal levels of triiodothyronine (T3) and thyroid stimulating hormone (TSH) in the blood. It is known that this condition is asymptomatic for the mother, however it impairs cognition in the offspring. In this work we have shown that the effects of gestational Hpx go beyond the central nervous system by also affecting the immune response. We observed that gestational Hpx increases the immune response in the offspring that suffers experimental autoimmune encephalomyelitis (EAE). EAE is an experimental model used to study multiple sclerosis (MS). We show here that mice C57BL/6 gestated in Hpx induced with EAE suffer earlier and more intense EAE symptoms compared to C57BL/6 mice gestated in euthyroidism. Even though, the population of T regulatory (Treg) cells in the spleen was similar in mice gestated in Hpx and mice gestated in euthyroidism, the Treg cells from mice gestated in Hpx have less capacity to suppress T effector cells and to secret IL-10. Mice gestated in Hpx have high basal levels of TNF-α and IL-17 and present increased brain blood barrier permeability. In this work we analyzed the population of Th-17 and capacity to secret IL-17 from intestine, meninges and spleen in mice gestated in Hpx that suffer EAE. These results are very novel and impact our knowledge of how the immune system of the offspring could be affected by the deficiency of maternal thyroid hormones during gestation.