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000307463 1001_ $$aGrün, Sarah$$b0
000307463 245__ $$aSomatic STAT5BN642H mutations shape variable immune landscapes resulting in heterogenous immune diseases.
000307463 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2025
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000307463 520__ $$aInborn errors of immunity (IEI) are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking IEI. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5BN642H was linked to severe allergic disease in infancy but its full clinical spectrum and underlying mechanisms remain incompletely defined.To elucidate how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function and clinical phenotypes.We investigated three new patients - including one adult - with STAT5BN642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5BN642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes.Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2-mediated proliferation, effector differentiation, and oligoclonal T cell expansions. In mice, a few mutant HSCs reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients.Our findings illuminate how a single somatic variant in few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.
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000307463 650_7 $$2Other$$aAtopy
000307463 650_7 $$2Other$$aAutoimmunity
000307463 650_7 $$2Other$$aClonal hematopoiesis
000307463 650_7 $$2Other$$aHematopoietic stem cells
000307463 650_7 $$2Other$$aImmune dysregulation
000307463 650_7 $$2Other$$aSTAT5B
000307463 650_7 $$2Other$$aSomatic mosaicism
000307463 650_7 $$2Other$$aT cell lymphoproliferation
000307463 650_7 $$2Other$$amTOR inhibition
000307463 7001_ $$aRensing-Ehl, Anne$$b1
000307463 7001_ $$aSuske, Tobias$$b2
000307463 7001_ $$aWolter-Mess, Julian$$b3
000307463 7001_ $$aGehrig, Jonathan$$b4
000307463 7001_ $$aMann, Jasmin$$b5
000307463 7001_ $$aKönig, Christoph$$b6
000307463 7001_ $$aHauri, Mathias$$b7
000307463 7001_ $$aHeeg, Maximilian$$b8
000307463 7001_ $$aLeahy, Timothy Ronan$$b9
000307463 7001_ $$aGenevieve, David$$b10
000307463 7001_ $$aGaillard, Jean-Baptiste$$b11
000307463 7001_ $$aBroly, Martin$$b12
000307463 7001_ $$aBourdin, Arnaud$$b13
000307463 7001_ $$aCastro, Carla$$b14
000307463 7001_ $$aSeidel, Lea$$b15
000307463 7001_ $$aBengsch, Bertram$$b16
000307463 7001_ $$aAichele, Peter$$b17
000307463 7001_ $$aWeißert, Kristoffer$$b18
000307463 7001_ $$aFernandez-Orth, Juncal$$b19
000307463 7001_ $$aSchipperges, Vincent$$b20
000307463 7001_ $$aAndrieux, Geoffroy$$b21
000307463 7001_ $$0P:(DE-HGF)0$$aBoerries, Melanie$$b22
000307463 7001_ $$aCabezas-Wallscheid, Nina$$b23
000307463 7001_ $$aErlacher, Miriam$$b24
000307463 7001_ $$aElling, Roland$$b25
000307463 7001_ $$aSpeckmann, Carsten$$b26
000307463 7001_ $$aHeller, Lara$$b27
000307463 7001_ $$aSchulte, Björn$$b28
000307463 7001_ $$aLorenz, Myriam$$b29
000307463 7001_ $$aSchwarz, Klaus$$b30
000307463 7001_ $$aMoriggl, Richard$$b31
000307463 7001_ $$aEhl, Stephan$$b32
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