Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK.

Abstract

Inborn errors of immunity (IEI) are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of IEI, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. We report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515*, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. Whole-exome sequencing, Sanger sequencing, mass spectrometry and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8 and TNFα and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib in inflammatory lung disease. We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of IEI.