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Introduction
Mechanistic Overview of Autoinflammatory Diseases
ADA2 Deficiency
VEXAS Syndrome, A Prototypic Hematoinflammatory Disease
SHARPIN HETEROZYGOUS MUTATION IS RESPONSIBLE FOR AUTOIMMUNITY, INFLAMMATORY MANIFESTATIONS AND PRIMARY IMMUNE DEFICIENCY
Abstract
Background and Aims
LUBAC is a heterotrimeric complex composed of SHARPIN, HOIL-1 and HOIP. LUBAC is involved in NFkB pathway activation and cell survival. Patients with complete HOIL-1 or HOIP deficiency suffer from inflammatory manifestations and immune deficiency. We identified by whole exome sequencing a heterozygous SHARPIN mutation in a patient with autoimmunity, inflammatory manifestations and primary antibody deficiency. We aimed to study the link between this mutation and the disease of the patient.
Methods
To study the mutation’s impact on the production, stability and function of the protein we transiently transfected HEK293T cells and complemented SHARPIN-/- Jurkat cells by lentiviral infection. We also evaluated LUBAC-dependent functions in patient’s PBMCs and SV40-transformed fibroblasts.
Results
The mutation led to a premature STOP codon and the diminished production of a non-functional truncated protein.
Patient’s cells presented a decreased TNFα and IL-1β-induced canonical NFkB activation and an excess of TNFα -induced cell death.
Patient’s monocytes secreted higher amount of IL6 after IL-1β stimulation than healthy controls.
Anti-cytokine biotherapies (anti-TNFα and IL1receptor antagonist) led to a partial improvement of the patient’s inflammatory manifestations.
Conclusions
We describe the first dominant hypomorphic SHARPIN mutation in a patient with autoimmunity, inflammatory manifestations and primary immune deficiency.
Clinical manifestations and experimental data are similar, although milder, to those described in HOIL-1 or HOIP deficient patients. Study of such rare inborn errors of immunity contribute to a better understanding of inflammatory and autoimmune diseases and lead to identification of new therapeutic targets.
ABERRANT INFLAMMATORY RESPONSES TO TYPE I INTERFERON IN STAT2 OR IRF9 DEFICIENCY
Abstract
Background and Aims
Inflammatory phenomena such as hyperinflammation or hemophagocytic lymphohistiocytosis are a frequent yet paradoxical accompaniment to viral susceptibility in patients with impairment of type I IFN (IFN-I) signalling caused by deficiency of STAT2 or IRF9.
We hypothesized that altered and/or prolonged IFN-I signalling contributes to inflammatory complications in these patients.
Methods
We explored the signalling kinetics and residual transcriptional responses of IFN-stimulated primary cells from individuals with complete loss of either STAT1, STAT2 or IRF9 as well as gene-edited iPSC-derived macrophages.
Results
Deficiency of any ISGF3 component suppressed but did not abrogate IFN-I receptor signalling, which was abnormally prolonged in keeping with insufficient induction of negative regulators such as USP18. In cells lacking either STAT2 or IRF9, this late transcriptional response to IFNα2b mimicked the effect of IFNγ.
Conclusions
Our data suggest a model wherein the failure to limit an ineffective antiviral response leads to immune dysregulation. Aberrant IFNAR signalling in STAT2- and IRF9-deficient cells switches the transcriptional output to a prolonged, IFNγ-like response and likely contributes to clinically overt inflammation in these individuals.