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Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function

  1. Author:
    Aluri, Jahnavi
    Bach, Alicia
    Kaviany, Saara
    Paracatu, Luana Chiquetto
    Kitcharoensakkul, Maleewan
    Walkiewicz, Magdalena A.
    Putnam, Christopher D.
    Shinawi, Marwan
    Saucier, Nermina
    Rizzi, Elise M.
    Harmon, Michael T.
    Keppel, Molly P.
    Ritter, Michelle
    Similuk, Morgan
    Kulm,Elaine
    Joyce, Michael
    de Jesus, Adriana A.
    Goldbach-Mansky, Raphaela
    Lee, Yi-Shan
    Cella, Marina
    Kendall, Peggy L.
    Dinauer, Mary C.
    Bednarski, Jeffrey J.
    Bemrich-Stolz, Christina
    Canna, Scott W.
    Abraham, Shirley M.
    Demczko, Matthew M.
    Powell, Jonathan
    Jones, Stacie M.
    Scurlock, Amy M.
    De Ravin, Suk See
    Bleesing, Jack J.
    Connelly, James A.
    Rao, V. Koneti
    Schuettpelz, Laura G.
    Cooper, Megan A.

  2. Author Address

    Washington Univ, Div Rheumatol Immunol, Sch Med, St Louis, MO 63110 USA.Washington Univ, Div Hematol Oncol, Dept Pediat, Sch Med, St Louis, MO 63110 USA.Vanderbilt Univ, Pediat Hematol Oncol, Med Ctr, Nashville, TN USA.Washington Univ, Div Allergy & Pulm Med, Dept Pediat, Sch Med, St Louis, MO 63110 USA.NIAID, Centralized Sequencing Initiat, Div Intramural Res, NIH, Bethesda, MD USA.Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA.Ludwig Inst Canc Res, San Diego Branch, La Jolla, CA USA.Washington Univ, Div Genet & Genom Med, Dept Pediat, Sch Med, St Louis, MO 63110 USA.Washington Univ, Div Allergy & Immunol, Dept Med, Sch Med, St Louis, MO 63110 USA.NCI, Clin Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA.Nemours Childrens Specialty Care, Jacksonville, FL USA.NIAID, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA.Washington Univ, Div Anat & Mol Pathol, Sch Med, St Louis, MO 63110 USA.Washington Univ, Div Immunol, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA.Univ Alabama Birmingham, Div Hematol & Oncol, Dept Pediat, Sch Med, Birmingham, AL USA.UPMC Childrens Hosp Pittsburgh, Div Pediat Rheumatol, Pittsburgh, PA USA.UPMC Childrens Hosp Pittsburgh, RK Mellon Inst, Dept Pediat, Pittsburgh, PA USA.Univ Pittsburgh, Pittsburgh, PA USA.Univ New Mexico, Div Hematol & Oncol, Dept Pediat, Albuquerque, NM USA.Nemours Alfred I DuPont Hosp Children, Div Diagnost Referral, Wilmington, DE USA.Nemours Alfred I DuPont Hosp Children, Div Pediat Hematol Oncol, Dept Pediat, Wilmington, DE USA.Univ Arkansas Med Sci, Div Allergy & Immunol, Dept Pediat, Little Rock, AR USA.Arkansas Childrens Hosp, Little Rock, AR USA.NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, NIH, Bethesda, MD USA.Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immunodeficiency, Cincinnati, OH USA.
    1. Year: 2021
    2. Date: May 6
  2. Journal: Blood
  3. AMER SOC HEMATOLOGY,
    1. 137
    2. 18
    3. Pages: 2450-2462
  5. Type of Article: Article
  6. ISSN: 0006-4971
  1. 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 mosaicismis a prominent molecular mechanism of this new disease.

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External Sources

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  2. DOI: 10.1182/blood.2020009620
  3. PMID: 33512449
  4. PMCID: PMC8109013
  5. View record in Web of Science®
  6. WOS: 000648518900008

Library Notes

  1. Fiscal Year: FY2020-2021
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