TY  - JOUR
AU  - Grün, Sarah
AU  - Rensing-Ehl, Anne
AU  - Suske, Tobias
AU  - Wolter-Mess, Julian
AU  - Gehrig, Jonathan
AU  - Mann, Jasmin
AU  - König, Christoph
AU  - Hauri, Mathias
AU  - Heeg, Maximilian
AU  - Leahy, Timothy Ronan
AU  - Genevieve, David
AU  - Gaillard, Jean-Baptiste
AU  - Broly, Martin
AU  - Bourdin, Arnaud
AU  - Castro, Carla
AU  - Seidel, Lea
AU  - Bengsch, Bertram
AU  - Aichele, Peter
AU  - Weißert, Kristoffer
AU  - Fernandez-Orth, Juncal
AU  - Schipperges, Vincent
AU  - Andrieux, Geoffroy
AU  - Boerries, Melanie
AU  - Cabezas-Wallscheid, Nina
AU  - Erlacher, Miriam
AU  - Elling, Roland
AU  - Speckmann, Carsten
AU  - Heller, Lara
AU  - Schulte, Björn
AU  - Lorenz, Myriam
AU  - Schwarz, Klaus
AU  - Moriggl, Richard
AU  - Ehl, Stephan
TI  - Somatic STAT5BN642H mutations shape variable immune landscapes resulting in heterogenous immune diseases.
JO  - The journal of allergy and clinical immunology
VL  - nn
SN  - 0091-6749
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - DKFZ-2025-03062
SP  - nn
PY  - 2025
N1  - epub
AB  - Inborn errors of immunity (IEI) are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking IEI. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5BN642H was linked to severe allergic disease in infancy but its full clinical spectrum and underlying mechanisms remain incompletely defined.To elucidate how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function and clinical phenotypes.We investigated three new patients - including one adult - with STAT5BN642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5BN642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes.Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2-mediated proliferation, effector differentiation, and oligoclonal T cell expansions. In mice, a few mutant HSCs reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients.Our findings illuminate how a single somatic variant in few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.
KW  - Atopy (Other)
KW  - Autoimmunity (Other)
KW  - Clonal hematopoiesis (Other)
KW  - Hematopoietic stem cells (Other)
KW  - Immune dysregulation (Other)
KW  - STAT5B (Other)
KW  - Somatic mosaicism (Other)
KW  - T cell lymphoproliferation (Other)
KW  - mTOR inhibition (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41453450
DO  - DOI:10.1016/j.jaci.2025.12.993
UR  - https://inrepo02.dkfz.de/record/307463
ER  -