CIITA G-286A promoter polymorphism impairs monocytes HLA-DR expression in septic shock and is rescued by interferon-γ
Jordi Miatello
(1)
,
Anne-Claire Lukaszewicz
(2, 3)
,
Valérie Faivre
(4)
,
Stéphane Hua
(5)
,
Kim Zita Martinet
,
Christine Bourgeois
(6, 7)
,
Lluis Quintana-Murci
(8)
,
Didier Payen
(9)
,
Michele Boniotto
(10)
,
Pierre Tissières
1
AP-HP -
Assistance publique - Hôpitaux de Paris (AP-HP)
2 PI3 - Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression
3 Hôpital Edouard Herriot [CHU - HCL]
4 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
5 Paléospace
6 IDMIT - Infectious Diseases Models for Innovative Therapies
7 Service de neurologie [Le Kremlin Bicêtre]
8 Collège de France - Chaire Génomique humaine et évolution
9 INSERM - Institut National de la Santé et de la Recherche Médicale
10 IMRB - Institut Mondor de Recherche Biomédicale
2 PI3 - Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression
3 Hôpital Edouard Herriot [CHU - HCL]
4 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
5 Paléospace
6 IDMIT - Infectious Diseases Models for Innovative Therapies
7 Service de neurologie [Le Kremlin Bicêtre]
8 Collège de France - Chaire Génomique humaine et évolution
9 INSERM - Institut National de la Santé et de la Recherche Médicale
10 IMRB - Institut Mondor de Recherche Biomédicale
Jordi Miatello
- Fonction : Auteur
- PersonId : 1172498
- IdHAL : jordi-miatello
- ORCID : 0000-0001-5649-8635
- IdRef : 164838589
Valérie Faivre
- Fonction : Auteur
- PersonId : 1223150
- ORCID : 0000-0001-6392-2297
Kim Zita Martinet
- Fonction : Auteur
Christine Bourgeois
- Fonction : Auteur
- PersonId : 794622
- ORCID : 0000-0003-1146-6087
- IdRef : 076448924
Lluis Quintana-Murci
- Fonction : Auteur
- PersonId : 754080
- IdHAL : lluis-quintana-murci
- ORCID : 0000-0003-2429-6320
- IdRef : 127109897
Didier Payen
- Fonction : Auteur
- PersonId : 1303466
- ORCID : 0000-0002-5242-6543
Michele Boniotto
- Fonction : Auteur
- PersonId : 1303467
- ORCID : 0000-0002-9548-2254
Pierre Tissières
- Fonction : Auteur
- PersonId : 1172503
- ORCID : 0000-0001-5423-5532
Résumé
Monocyte HLA-DR is an increasingly recognized markers of sepsis-induced immunodepression, but its regulatory mechanisms remain poorly understood in sepsis. Several evidence for positive selection on the 5’ promoter region of HLA class II transactivator ( CIITA ) gene, the master regulator of MHC class II, have been gathered in the European population, and its role in sepsis has never been demonstrated, whilst suggested in autoimmune disease. We aim to describe the effect of rs3087456 polymorphism, localized on CIITA promoter III (pIII), on mortality of patients with septic shock, and investigate the mechanisms regulating HLA-DR expression. Genotyping of 203 patients with septic shock showed that, in A dominant model, GG genotype was associated with 28-day mortality (OR 2.29; 95%CI: 1.01 to 5.22; P = 0.043). Monocyte HLA-DR remained low in patients with GG genotype whereas it increases as early as at the end of the first week in intensive care in patients with AA or AG genotype. Using site-directed mutagenesis, in vitro reporter gene promoter activity of the pIII was decreased in GG genotype in monocyte cell line. Interferon-γ (IFN-γ) restored pIII activity in GG genotype as well as restore, in ex vivo experiment in healthy volunteers, CIITA pIII expression of GG genotype. Hereby, we demonstrated that rs3087456, a positively selected polymorphism of CIITA proximal promoter, significantly impact monocyte HLA-DR expression in patients with septic shock through CIITA promoter activity, that can be rescued using IFN-γ, offering a new perspective in genetic susceptibility to sepsis and targeted immunomodulatory therapy. Keypoints CIITA G-286A polymorphism reduces promotor activity and significantly impact monocyte HLA-DR expression and mortality in septic shock Downregulatory effects of CIITA G-286A polymorphism on monocyte HLA-DR expression can be reverse by IFN-γ in patients with septic shock
Domaines
Génétique humaineFormat du dépôt | Notice |
---|---|
Type de dépôt | Pré-publication, Document de travail |
Titre |
en
CIITA G-286A promoter polymorphism impairs monocytes HLA-DR expression in septic shock and is rescued by interferon-γ
|
Résumé |
en
Monocyte HLA-DR is an increasingly recognized markers of sepsis-induced immunodepression, but its regulatory mechanisms remain poorly understood in sepsis. Several evidence for positive selection on the 5’ promoter region of HLA class II transactivator ( CIITA ) gene, the master regulator of MHC class II, have been gathered in the European population, and its role in sepsis has never been demonstrated, whilst suggested in autoimmune disease. We aim to describe the effect of rs3087456 polymorphism, localized on CIITA promoter III (pIII), on mortality of patients with septic shock, and investigate the mechanisms regulating HLA-DR expression. Genotyping of 203 patients with septic shock showed that, in A dominant model, GG genotype was associated with 28-day mortality (OR 2.29; 95%CI: 1.01 to 5.22; P = 0.043). Monocyte HLA-DR remained low in patients with GG genotype whereas it increases as early as at the end of the first week in intensive care in patients with AA or AG genotype. Using site-directed mutagenesis, in vitro reporter gene promoter activity of the pIII was decreased in GG genotype in monocyte cell line. Interferon-γ (IFN-γ) restored pIII activity in GG genotype as well as restore, in ex vivo experiment in healthy volunteers, CIITA pIII expression of GG genotype. Hereby, we demonstrated that rs3087456, a positively selected polymorphism of CIITA proximal promoter, significantly impact monocyte HLA-DR expression in patients with septic shock through CIITA promoter activity, that can be rescued using IFN-γ, offering a new perspective in genetic susceptibility to sepsis and targeted immunomodulatory therapy. Keypoints CIITA G-286A polymorphism reduces promotor activity and significantly impact monocyte HLA-DR expression and mortality in septic shock Downregulatory effects of CIITA G-286A polymorphism on monocyte HLA-DR expression can be reverse by IFN-γ in patients with septic shock
|
Auteur(s) |
Jordi Miatello
1
, Anne-Claire Lukaszewicz
2, 3
, Valérie Faivre
4
, Stéphane Hua
5
, Kim Zita Martinet
, Christine Bourgeois
6, 7
, Lluis Quintana-Murci
8
, Didier Payen
9
, Michele Boniotto
10
, Pierre Tissières
1
AP-HP -
Assistance publique - Hôpitaux de Paris (AP-HP)
( 300068 )
- France
2
PI3 -
Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression
( 521795 )
- Hôpital E. Herriot - Hospices Civils de Lyon
5 place d’Arsonval - 69437 Lyon cedex 03 – France
- France
3
Hôpital Edouard Herriot [CHU - HCL]
( 300094 )
- 5 Place d'Arsonval
69003 Lyon
- France
4
NeuroDiderot (UMR_S_1141 / U1141) -
Maladies neurodéveloppementales et neurovasculaires
( 1005068 )
- Hôpital Robert Debré
48 Bd Serurier
75019 Paris
- France
5
Paléospace
( 1123888 )
- 5 Avenue Jean Moulin, 14640, Villers-sur-Mer.
- France
6
IDMIT -
Infectious Diseases Models for Innovative Therapies
( 440095 )
- France
7
Service de neurologie [Le Kremlin Bicêtre]
( 14923 )
- 78 r Gén Leclerc 94270 Le Kremlin Bicêtre
- France
8
Collège de France - Chaire Génomique humaine et évolution
( 1043615 )
- 11 place Marcelin Berthelot F-75231 Paris Cedex 05
- France
9
INSERM -
Institut National de la Santé et de la Recherche Médicale
( 303623 )
- 101, rue de Tolbiac, 75013 Paris
- France
10
IMRB -
Institut Mondor de Recherche Biomédicale
( 266797 )
- 8 rue du Général Sarrail 94010 Créteil
- France
|
Date de publication |
2021-02-23
|
Langue du document |
Anglais
|
Domaine(s) |
|
DOI | 10.1101/2021.02.19.21252097 |
deposit.widget.identifiers.code.medrxiv | 2021.02.19.21252097 |
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