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B cells require "nurturing" by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus.

ABSTRACT: The murine chronic GVH (cGVH) model of SLE is induced by allo-recognition of foreign major histocompatibility complex (MHC) class II determinants. Previous studies have shown that syngeneic CD4(+) T cells are needed during B cell development in order to induce cGVH response in CD4KO mice. Our present studies show that B cells require "nurturing" by CD4 T cells through much of their ontogeny in order to respond to allo-signaling and become autoreactive. The nurturing process does not require antigen-specific cognate interactions between CD4 T cells and B cells. It is mediated by IL-4, but not IL-10, IL-6 and IFN-gamma. The CD4 T cell nurturing may be supplanted by large doses of IL-4 and/or by agonistic anti-CD40 mAb. Understanding the mechanism of this "nurturing" process may yield clues to the role of CD4 T cells in lupus and in host defense in general.

SUBMITTER: Choudhury A

PROVIDER: S-EPMC2891082 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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B cells require "nurturing" by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus.

Choudhury Arpita A Cohen Philip L PL Eisenberg Robert A RA

Clinical immunology (Orlando, Fla.) 20100408 1

The murine chronic GVH (cGVH) model of SLE is induced by allo-recognition of foreign major histocompatibility complex (MHC) class II determinants. Previous studies have shown that syngeneic CD4(+) T cells are needed during B cell development in order to induce cGVH response in CD4KO mice. Our present studies show that B cells require "nurturing" by CD4 T cells through much of their ontogeny in order to respond to allo-signaling and become autoreactive. The nurturing process does not require anti ...[more]

PMID: 20381429

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Project description:The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (ac4C) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA ac4C modification are involved in systemic lupus erythematosus (SLE) remains unclear. Herein, we detected eleven modifications in CD4+ T cells of SLE patients using mass spectrometry (LC-MS/MS). Furthermore, using samples from four CD4+ T cell pools, we identified lower modification of ac4C mRNA in SLE patients as compared to that in healthy controls (HCs). Meanwhile, significantly lower mRNA acetyltransferase NAT10 expression was detected in lupus CD4+ T cells by RT-qPCR. We then illustrated the transcriptome-wide ac4C profile in CD4+ T cells of SLE patients by ac4C-RIP-Seq and found ac4C distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 ac4C hyper-acetylated and hypoacetylated peaks found in SLE samples, respectively, were found to be significantly involved in SLE-related function enrichments, including multiple metabolic and transcription-related processes, ROS-induced cellular signaling, apoptosis signaling, and NF-κB signaling. Moreover, we demonstrated the ac4C-modified regulatory network of gene biological functions in lupus CD4+ T cells. Notably, we determined that the 26 upregulated genes with hyperacetylation played essential roles in autoimmune diseases and disease-related processes. Additionally, the unique ac4C-related transcripts, including USP18, GPX1, and RGL1, regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated ac4C mRNAs associated with critical immune and inflammatory responses, that have translational potential in lupus CD4+ T cells. Hence, our findings reveal transcriptional significance and potential therapeutic targets of mRNA ac4C modifications in SLE pathogenesis.

Dataset Information

B cells require "nurturing" by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus.

Publications

B cells require "nurturing" by CD4 T cells during development in order to respond in chronic graft-versus-host model of systemic lupus erythematosus.

Similar Datasets

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