Autoinflammation in patients with leukocytic CBL loss-of-heterozygosity is caused by constitutive ERK-mediated monocyte activation

Patients heterozygous for germline CBL loss-of-function (LOF) variants can developvasculitis if some of their leukocytes become homozygous for these variants due to asomatic loss-of-heterozygosity (LOH) due to uniparental isodisomy (UPD). We findthat the inflammatory gene expression signature is upregulated in whole blood fromthese patients, mimicking monogenic inborn errors underlying autoinflammation.Remarkably, these patients have constitutively activated monocytes that secrete 10 to100 times more inflammatory cytokines than healthy individuals and CBL LOFheterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells(HSPC) outgrow the other cells, accounting for the persistence of peripheral monocyteshomozygous for the CBL LOF variant. Activation of the ERK pathway is required forthe excessive production of cytokines by both resting and stimulated CBL LOFmonocytes, as shown in monocytic cell lines. In summary, somatic LOH at the CBLlocus in the monocytes of CBL-mutated patients underlies chronic monocyte activation,driving clinical autoinflammation, particularly vasculitis.