Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function
Jahnavi Aluri, Alicia Bach, Saara Kaviany, Luana Chiquetto Paracatu, Maleewan Kitcharoensakkul, Magdalena Walkiewicz, Christopher D. Putnam, Marwan Shinawi, Nermina Saucier, Elise Rizzi, Michael T. Harmon, Molly P. Keppel, Michelle Ritter, Morgan Similuk, Elaine Kulm, Michael Joyce, Adriana A. de Jesus, Raphaela Goldbach‐Mansky, Yi-Shan Lee, Marina Cella, Peggy L. Kendall, Mary C. Dinauer, Jeffrey J. Bednarski, Christina J. Bemrich‐Stolz, Scott Canna, Shirley Abraham, Matthew M. Demczko, Jonathan Powell, Stacie M. Jones, Amy M. Scurlock, Suk See De Ravin, Jack Bleesing, James A. Connelly, V. Koneti Rao, Laura G. Schuettpelz, Megan A. Cooper
Abstract
Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.