W211 - High-dimensional Immunophenotyping Reveals Unique Immune Cell Aberrations in Patients with Undiagnosed Inflammatory and Autoimmune Diseases

Takanori Sasaki – Brigham and Women's Hospital; Joshua Keegan; Jennifer Nguyen; Alec Griffith; Alice Horisberger – Brigham and Women's Hospital; Thomas Licata; Elizabeth Fieg – Brigham and Women's Hospital; Ye Cao – Brigham and Women's Hospital; Mehreen Elahee; Kathryne Marks – Brigham and Women's Hospital; Annelise Mah-Som – Brigham and Women's Hospital; Lauren Briere – Massachusetts General Hospital; Laurel Cobban – Brigham and Women's Hospital; Daimon Simmons – Brigham and Women's Hospital; J. Carl Pallais – Brigham and Women's Hospital; Frances High – Massachusetts General Hospital; Melissa Walker – Massachusetts General Hospital; Jeffrey Sparks – Brigham and Women's Hospital; Karen Costenbader – Brigham and Women's Hospital; Undiagnosed Diseases Network (UDN); David Sweetser – Massachusetts General Hospital; Joel Krier – Brigham and Women's Hospital; Joseph Loscalzo – Brigham and Women's Hospital; James Lederer – Brigham and Women's Hospital; Deepak Rao – Brigham and Women's Hospital

Abstract Text: An estimated 25 to 30 million Americans and hundreds of millions of patients worldwide suffer from rare or undiagnosed diseases. While genomic sequencing has proven to be a valuable tool in uncovering disease etiology arising from a monogenic defect, limited diagnostic strategies are available to interrogate immune dysregulation in patients with autoimmune or inflammatory conditions that do fit into traditional disease categories. We employed high-dimensional immunophenotyping through mass cytometry to study patients with severe, undiagnosed immunologic conditions from the Undiagnosed Diseases Network (UDN). Our outlier analyses demonstrated significant enrichment of outlier features in UDN patients, with 5/16 UDN patients (31.3%) exhibiting an unusual expansion of defined or novel cell populations compared with 0/141 (0.0%) control patients. One patient with debilitating global erythroderma, anhidrosis, and alopecia had a markedly expanded population of CD25hiCD127- regulatory T cells (Tregs) comprising 53.9% of all T cells with prominent cutaneous infiltration. T cell receptor clonality studies revealed the Treg population to be polyclonal, and single-cell RNA sequencing (scRNA-seq) analyses showed an activated interferon signature in the Treg and memory CD4+ T cell populations. T cell-directed therapies were trialed, and longitudinal scRNA-seq analyses revealed a reduction in Treg frequency with abatacept and subsequent clinical improvement with Janus kinase inhibitors. Our study demonstrates that high-dimensional immunoprofiling offers a promising approach to defining pathogenic immune dysregulation and guiding therapy in individual patients with unusual immune-mediated diseases.