Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn's disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F20%3A10411862" target="_blank" >RIV/00216208:11130/20:10411862 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/20:00116174 RIV/00209775:_____/20:N0000012 RIV/00064203:_____/20:10411862

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=wGxn108Dwt" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=wGxn108Dwt</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41419-020-2652-4" target="_blank" >10.1038/s41419-020-2652-4</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn's disease

Popis výsledku v původním jazyce

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2. (C) 2020, The Author(s).

Název v anglickém jazyce

Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn's disease

Popis výsledku anglicky

X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2. (C) 2020, The Author(s).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cell death &amp; disease

ISSN

2041-4889

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

430

Kód UT WoS článku

000552729800006

EID výsledku v databázi Scopus

2-s2.0-85086172601