Lupus nephritis with corticosteroid responsiveness : molecular changes of CD46-mediated type 1 regulatory T cells

© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc..

BACKGROUND: The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy.

METHODS: We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients.

RESULTS: We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells.

CONCLUSIONS: Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN.

IMPACT: In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17. These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 +  Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment. Enhancing the expression of functional CD4 + CD46 +  Tr1 cells may be a useful therapeutic approach for LN.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:92

Enthalten in:

Pediatric research - 92(2022), 4 vom: 24. Okt., Seite 1099-1107

Sprache:

Englisch

Beteiligte Personen:

Tsai, Yi-Giien [VerfasserIn]
Chien, Jien-Wen [VerfasserIn]
Chiu, Ying-Ming [VerfasserIn]
Su, Tzu-Cheng [VerfasserIn]
Chiu, Ping-Fang [VerfasserIn]
Hsiao, Kai-Hung [VerfasserIn]
Lin, Ching-Yuang [VerfasserIn]

Links:

Volltext

Themen:

130068-27-8
Adrenal Cortex Hormones
CD46 protein, human
EC 2.7.11.1
Interleukin-10
Journal Article
Membrane Cofactor Protein
Methylprednisolone
Protein Isoforms
Proto-Oncogene Proteins c-akt
Receptors, CCR7
Research Support, Non-U.S. Gov't
X4W7ZR7023

Anmerkungen:

Date Completed 25.10.2022

Date Revised 21.12.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1038/s41390-021-01882-z

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM334888360