Dataset Information

An antibody to CD40 ligand prevents meningeal B cell aggregates and mitigates progressive disease in a spontaneous mouse model of chronic multiple sclerosis

ABSTRACT: Compartmentalized inflammation within the CNS is considered to drive progressive immunopathology in multiple sclerosis (MS) independently of relapses. Meningeal tertiary lymphoid structures (TLS) represent an immune niche associated with histological signs of immunopathology, including demyelination in the adjacent CNS parenchyma. Here, we show that the opticospinal encephalomyelitis (OSE) mouse model, in which meningeal TLS develop spontaneously based on the interaction of myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic T cells with MOG B cell receptor (BCR) transgenic B cells, recapitulates the dynamics and the histological features of meningeal TLS observed in human MS. Based on scRNAseq data sets of meningeal TLS from OSE mice, the CD40L-CD40 pathway is highly active in the T cell-B cell interaction in this niche. Accordingly, a monoclonal antibody to CD40L, applied systemically, abrogates the T-B interaction in the systemic compartment and even more so in the meningeal compartment. This leads to near-complete clearance of meningeal TLS, concomitant with clinical improvement of the progressive disease phase of OSE mice. In contrast, systemic B cell depletion with a monoclonal antibody to CD20 does not improve signs of progressive disease in the OSE model. Treatment with anti-CD40L is more effective in disrupting T-B interaction, the more the T-B interaction relies on the CD40L-CD40 pathway, and thus leads to a "semiselective" targeting of meningeal TLS. In addition, we observed a general remodeling of any antigen-presenting cells in the CNS that respond to CD40 engagement. Since these effects are sustained even after withdrawal of anti-CD40L treatment, no resumption of progression or rebound effects occur. In conclusion, anti-CD40L treatment may be an appropriate intervention to mitigate progressive immunopathology associated with meningeal TLS and the CD40-dependent antigen-presenting compartment in progressive MS.

ORGANISM(S): Mus musculus

PROVIDER: GSE338368 | GEO | 2026/09/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other
	GSE338368_processed_barcodes.tsv.gz	Tabular
	GSE338368_processed_features.tsv.gz	Tabular
	GSE338368_processed_matrix.mtx.gz	Other

Items per page:

1 - 4 of 4

Similar Datasets

Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human Î²-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 Î², which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (GroÎ±), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither Î²-cell death and did not enhanced TNF-Î± mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and Î²-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in Î²-cells, induces secretion of diabetogenic cytokines IFNÎ³ and TNF-Î±. Furthermore, incubation of islets containing ductal cells with CD40L decreased Î²-cells viability as assessed by measurement of their mitochondrial membrane potential Experiment Overall Design: We isolated islet cells from three patients. Part of islet cells from each patient has been treated with CD40L. We compared gene expression in treated cells vs untreated for each patient using dye-swap.

Project description:Expression of CD40 in non-hematopoietic cells has been linked to inflammation. We presented evidence that CD40, a T-cell costimulatory molecule, is expressed in human β-cells and the engagement of CD40 in insulinoma cells activated the NFKB and ERK1/2 pathways. CD40 activation in human islets cells induced secretion of IL-8, MCP-1 and MIP-1 β, which is abrogated by inhibitors of NFkB and ERK1/2 inhibitors. In this study, we have studied gene expression mediated by CD40-CD40L interaction in islet cells. This approach identified 90 genes and transcripts exhibiting at least a 1.7 fold increase in their expression intensity after treatment with soluble CD40L. A significant number of genes were related to inflammation and oxidative stress. We have a strong overexpression of CXCL1 (Groα), CXCL2 (Mif2) and CXCL3; chemokines belonging to CXC family structurally related to Il-8. 11 genes were selected from this group and further quantified by Real Time PCR, including CXCL1. Activation of islet cells with CD40L induced the secretion of CXCL1 in a NFKB dependent manner. Engagement of CD40 in islet cells did not induce apoptosis, neither β-cell death and did not enhanced TNF-α mediated cell death as observed in insulinoma cells. CD40 activation in insulinoma cells, results in ERK1/2 dependent phsophorylation of synapsin I, a protein associated with the exocytosis machinery in neurons and β-cells. However, treatment of islets with soluble CD40L did not affect glucose induced insulin secretion. It has been reported that ductal cells always present in human islet preparations express CD40 constitutively (ref). We found that CD40-CD40L interaction in ductal cells, unlike in β-cells, induces secretion of diabetogenic cytokines IFNγ and TNF-α. Furthermore, incubation of islets containing ductal cells with CD40L decreased β-cells viability as assessed by measurement of their mitochondrial membrane potential Keywords: Pancreas, Islets of Langerhans, chemokines, cytokines, inflammation, apoptosis, Nuclear Factor-κB(NFκB)

Dataset Information

An antibody to CD40 ligand prevents meningeal B cell aggregates and mitigates progressive disease in a spontaneous mouse model of chronic multiple sclerosis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets