Abstract
Patients who suffer from autoinflammatory disease (AID) exhibit seemingly uncontrolled release of interleukin (IL)-1β. The presence of this inflammatory cytokine triggers immune activation in absence of pathogens and foreign material. The mechanisms that contribute to ‘sterile inflammation’ episodes in AID patients are not fully understood, although for some AIDs underlying genetic causes have been identified. We show that the serine protease inhibitor B9 (serpinB9) regulates IL-1β release in human monocytes. SerpinB9 function is more commonly known for its role in control of granzyme B. SerpinB9 however also serves to restrain IL-1β maturation through caspase-1 inhibition. We here describe an autoinflammatory disease-associated serpinB9 (c.985G>T, A329S) variant, which we discovered in a patient with unknown AID. Using patient cells and serpinB9 overexpressing monocytic cells, we show the A329S variant of serpinB9 exhibits unobstructed granzyme B inhibition, but compromised caspase-1 inhibition. SerpinB9 gene variants might contribute to AID development.
Highlights
In patients suffering from autoinflammatory disease (AID), the regulation and release of interleukin (IL) 1β is disturbed
In this study we identified a heterozygous A329S variant in the SerpinB9 gene of a patient with AID without genetic diagnosis (periodic high fever (>38°C) with: headache, fatigue and malaise, vomiting, abdominal pain and diarrhea, arthralgia and myalgia in right leg
We considered that defects in serpinB9 function can be associated with decreased numbers of circulating CD8 T-cells, as a consequence to increased sensitivity to apoptosis [6]
Summary
In patients suffering from autoinflammatory disease (AID), the regulation and release of interleukin (IL) 1β is disturbed. We assessed the capability of this serpinB9 protein variant to inhibit both GrB and caspase-1. Whereas the serpinB9 mutant fully retained its ability to block GrB, it failed to fully inhibit caspase-1 activity.
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