TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).
ADA2
DADA2
anti-TNF
macrophages
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
07
05
2021
revised:
25
09
2021
accepted:
28
10
2021
pubmed:
16
11
2021
medline:
11
5
2022
entrez:
15
11
2021
Statut:
ppublish
Résumé
Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.
Sections du résumé
BACKGROUND
Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations.
OBJECTIVE
We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients.
METHODS
We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment.
RESULTS
We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2.
CONCLUSIONS
Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.
Identifiants
pubmed: 34780847
pii: S0091-6749(21)01693-6
doi: 10.1016/j.jaci.2021.10.030
pii:
doi:
Substances chimiques
Cytokines
0
Intercellular Signaling Peptides and Proteins
0
Tumor Necrosis Factor Inhibitors
0
Adenosine Deaminase
EC 3.5.4.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1812-1816.e6Informations de copyright
Published by Elsevier Inc.