Mikko R. Seppänen, Finland

HUS Helsinki University Hospital Rare Disease Center, Children and Adolescents and Adult Immunodeficiency Unit, Inflammation Center

Presenter Of 6 Presentations

Industry Symposium No Topic Needed

WELCOME AND INTRODUCTION

Lecture Time
16:02 - 16:10
Room
Gold
Date
18.09.2019, Wednesday
Session Time
16:00 - 17:30
Presentation Topic
No Topic Needed
Industry Symposium No Topic Needed

STOP THE DELAY – SIMPLIFYING DIAGNOSIS IN PID

Lecture Time
16:10 - 16:30
Room
Gold
Date
18.09.2019, Wednesday
Session Time
16:00 - 17:30
Presentation Topic
No Topic Needed
Industry Symposium No Topic Needed

Q&A

Lecture Time
17:10 - 17:25
Room
Gold
Date
18.09.2019, Wednesday
Session Time
16:00 - 17:30
Presentation Topic
No Topic Needed
Industry Symposium No Topic Needed

SUMMARY AND CLOSE

Lecture Time
17:25 - 17:30
Room
Gold
Date
18.09.2019, Wednesday
Session Time
16:00 - 17:30
Presentation Topic
No Topic Needed
Working Party No Topic Needed

INTRODUCTION

Lecture Time
07:45 - 07:55
Room
Gold
Date
20.09.2019, Friday
Session Time
07:45 - 08:45
Presentation Topic
No Topic Needed
Oral Communications Autoinflammation

GAIN-OF-FUNCTION CEBPE MUTATION CAUSES NON-CANONICAL AUTOINFLAMMATORY INFLAMMASOMOPATHY

Lecture Time
12:20 - 12:30
Room
Gold
Date
20.09.2019, Friday
Session Time
11:00 - 12:40
Presentation Topic
Autoinflammation

Abstract

Background and Aims

C/EBPε is a transcription factor involved in late myeloid lineage differentiation and cellular function previously known to cause neutrophil-specific granule deficiency. To molecularly characterize the effects of C/EBPε transcription factor gene’s p.Arg219His mutation in an autoinflammatory and immunodeficiency syndrome.

Methods

Genetic analysis, proteomics, genome-wide transcriptional profiling by RNAsequencing, ChIP-sequencing and assessment of the inflammasome function of primary macrophages were performed.

Results

Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated non-canonical inflammasome activation due to decreased association with transcriptional repressors leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLRP3 and constitutively expressed caspase-5 in macrophages.

Conclusions

We describe a novel autoinflammatory disease with defective neutrophil function caused by homozygous p.Arg219His mutation in transcription factor CEBPE. Mutated CEBPE acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and non-canonical inflammasomopathy/immunodeficiency. The same mutation causes both LOF and GOF, i.e. there is variation-of-function (VOF). This widely dysregulated transcription is likely not unique for C/EBPε. Similar multiomics approaches should be utilized when studying other transcription factor-associated diseases.

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Moderator Of 4 Sessions

Industry Symposium
Room
Gold
Date
18.09.2019, Wednesday
Session Time
16:00 - 17:30
E-Poster Discussion
Room
Station 2
Date
19.09.2019, Thursday
Session Time
13:15 - 14:20
Parallel Session
Room
Bozar
Date
20.09.2019, Friday
Session Time
16:30 - 18:10