Multiple sclerosis (MS) is an autoimmune disease characterized by a robust inflammatory response against myelin sheath antigens, which causes astrocyte and microglial activation and demyelination of the central nervous system (CNS). Multiple genetic predispositions and environmental factors are known to influence the immune response in autoimmune diseases, such as MS, and in the experimental autoimmune encephalomyelitis (EAE) model. Although the predisposition to suffer from MS seems to be a multifactorial process, a highly sensitive period is pregnancy due to factors that alter the development and differentiation of the CNS and the immune system, which increases the offspring’s susceptibility to develop MS. In this regard, there is evidence that thyroid hormone deficiency during gestation, such as hypothyroidism or hypothyroxinemia, may increase susceptibility to autoimmune diseases such as MS. In this review, we discuss the relevance of the gestational period for the development of MS in adulthood.

Gestational hypothyroxinemia (HTX) is associated with cognitive impairments and autism traits in offspring. However, the underlying mechanisms remain unclear. Prenatal inflammation impairs cortical development and induces diverse neurodevelopmental outcomes. Since thyroid dysfunction elicits inflammation, we sought to investigate whether HTX triggers prenatal pro-inflammatory responses. Using a mouse model of gestational HTX, we found elevated levels of IL-6 and IL-17 A in maternal serum, placental tissues, and embryonic brains at embryonic day (E)14 compared to euthyroid (EUT) dams. We also found increased proportions of dendritic cells, NK cells, M1-like macrophages, and monocytes in the placental tissues of HTX dams. Furthermore, gestational HTX exposure led to reduced Tbr2⁺ progenitors, increased Tbr1⁺ neurons, and an expanded Iba1⁺ microglial population in HTX-exposed embryos compared to EUT-exposed embryos. At postnatal day (P)55, the offspring gestated under HTX exhibited reduced hippocampal dendritic spine density and maturity compared to the progeny gestated under EUT. Notably, restoring T₄ levels during HTX induction (HTX + T₄ dams) prevented these alterations during pregnancy and in the offspring of HTX + T₄ dams. These findings show that gestational HTX causes inflammation during pregnancy and has neurodevelopmental effects on the progeny, opening new pathways related to how maternal HTX impairs neurodevelopment in the offspring.

Down syndrome (DS), caused by trisomy 21, is characterized by complex immune dysregulation that increases susceptibility to infections and alters vaccine responsiveness. Gene dosage effects involving interferon receptor loci on chromosome 21 contribute to chronic type I interferon hyperactivation, sustained JAK-STAT signaling, and persistent expression of interferon-stimulated genes. This baseline inflammatory state is accompanied by quantitative and functional defects in both innate and adaptive immunity, including impaired neutrophil chemotaxis, pro-inflammatory monocyte polarization, reduced naïve T- and B-cell compartments, restricted antigen receptor diversity, diminished class-switched memory B cells, and features of accelerated immunosenescence. Clinically, these immune alterations are associated with an increased risk of severe respiratory viral infections, such as respiratory syncytial virus, influenza, and SARS-CoV-2, as well as reduced magnitude and durability of vaccine-induced immunity. Cohort studies in both pediatric and adult populations have reported higher rates of hospitalization and mortality, along with lower peak antibody titers and more rapid waning of immunity following vaccination. This review integrates molecular, cellular, and clinical evidence to define the interferon-driven immune phenotype in DS and its implications for susceptibility to infection and vaccination response. A mechanistic understanding of this immune landscape provides a framework for developing tailored preventive strategies and optimizing vaccination approaches in this vulnerable population.

Prevalence of autism spectrum disorder (ASD) has increased over the past three decades. In this regard, there is growing evidence suggesting that environmental factors during pregnancy may contribute as risk factors for ASD, potentially playing a role in this rising trend. Gestational hypothyroxinemia (HTX) is an asymptomatic and frequent thyroid condition characterized by low levels of thyroxine (T4) in blood, with normal range of T3 and TSH. When this condition occurs in early pregnancy it impairs fetal neurodevelopment and diminishes cognitive capacities in the offspring. Additionally, retrospective human studies have shown that gestational HTX is associated with autistic outcomes in the offspring, however, there is an absence of knowledge about the cellular and molecular autism-like traits in the offspring gestated under gestational HTX (HTX-offspring). In this work, autistic-like phenotypes were evaluated in HTX-offspring, using a mouse model of gestational HTX. Consistent with autism-like behaviors of mice models, HTX-offspring exhibited anxiety-related behavior and impaired social interaction skills. Similar to humans, these features were more pronounced in male HTXoffspring. At the molecular level, the expression of NLGN3 and HOMER1 was increased in the prefrontal cortex and hippocampus of male HTX-offspring, compared to the offspring gestated under euthyroidism. Moreover, HTX-offspring showed increased proinflammatory cytokines in serum and an increased ratio of Th17 lymphocytes relative to T regulatory lymphocytes (Th17/Treg), as well as high neuroinflammatory-like traits in the prefrontal cortex and hippocampus, which were also more pronounced in male HTX-offspring. Notably, by administering T4 to pregnant mice during the induction of HTX, the offspring was protected from developing the observed autism-like traits. These findings support that gestational HTX constitutes a significant risk factor for the development of autism-like phenotypes in the offspring and strongly emphasizes the importance of monitoring thyroid function in early pregnancy.