A multiple sclerosis-protective coding variant reveals an essential role for HDAC7 in regulatory T cells.

Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. However, identification and functional characterization of causal variants remain challenging. Here, we focused on the immunomodulatory role of a protective variant of histone deacetylase 7 (HDAC7). This variant (rs148755202, HDAC7.p.R166H) was identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analyses, we demonstrate that wild-type HDAC7 regulates genes essential for the function of Foxp3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is generally dysfunctional in patients with MS. Moreover, Treg-specific conditional hemizygous deletion of HDAC7 increased the severity of experimental autoimmune encephalitis (EAE), a mouse model of neuroinflammation. In contrast, Tregs transduced with the protective HDAC7 R166H variant exhibited higher suppressive capacity in an in vitro functional assay, mirroring phenotypes previously observed in patient samples. In vivo modeling of the human HDAC7 R166H variant by generation of a knock-in mouse model bearing an orthologous R150H substitution demonstrated decreased EAE severity linked to transcriptomic alterations of brain-infiltrating Tregs, as assessed by single-cell RNA sequencing. Our data suggest that dysregulation of epigenetic modifiers, a distinct molecular class associated with disease risk, may influence disease onset. Last, our approach provides a template for the translation of genetic susceptibility loci to detailed functional characterization, using in vitro and in vivo modeling.

An Interim Report on the Provision of Prenatal Care for Pregnant Mothers Experiencing Homelessness in Hawai'i.

The State of Hawai'i ranks third in the nation for homelessness. Homelessness disproportionately affects the health care of pregnant mothers and their children. These homeless persons are at risk for malnutrition, physical and psychological trauma, injuries and chronic illnesses, and have difficulty accessing healthcare and social services. With the generous support of a Waiwai Ola grant from AlohaCare, a non-profit health plan in Hawai'i, the Maternal-Fetal Medicine physicians at the University Health Partners of Hawai'i created a pilot program with a midwife and medical assistant to provide prenatal health care and social services for homeless mothers on the island of O'ahu. This innovative project has given the midwife and medical assistant opportunities to perform needs assessments for homeless mothers and pilot new mobile health devices out in the field that can be optimized for delivering prenatal and postpartum health care for the most vulnerable populations of homeless mothers and their newborns.