Immunology

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



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Background

Inborn errors of immunity 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 inborn errors of immunity, revealing the roles of
immunologically important genes in human pathologies. However, despite this progress,
treatment is still extremely challenging.

Objective

We sought to 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.

Methods

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.

Results

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 TNF-α, 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 1/2 inhibitor ruxolitinib in inflammatory lung disease.

Conclusions

We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory
disorder of inborn errors of immunity.



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