Dataset Information

A preliminary study of KAT2A on cGAS-related immunity in inflammation amplification of systemic lupus erythematosus

ABSTRACT: Previous studies demonstrated that cGAS pathway is related to the inflammation amplification in a variety of autoimmune diseases. Lysine acetyltransferase family (KATs) can regulate the nuclear transcription or cytoplasmic activation of cGAS through different mechanisms. However, its role and related immunity patterns in systemic lupus erythematosus (SLE) have not been explored. In this study, RNA-seq and scRNA-seq profiling were performed for peripheral blood mononuclear cells (PBMCs) from patients with SLE. R packages were used for bioinformatic analysis. Cell culture, RT-PCR, western blotting, immunofluorescence, immunohistochemistry, and ELISA were used to explore gene expression in vitro or clinical specimens. Plasmid transfection and mass spectrometry were used to detect protein modifications. Eight acetyltransferase and deacetylase family members with significantly differential expression in SLE were found. Among them, KAT2A was abnormally upregulated and positively correlated with disease activity index. Further, KAT2A-cGAS pathway was aberrantly expressed in specific immune cell subsets in SLE. In vitro studies showed KAT2A modulated cGAS through increasing expression and post-translational modification. Our research provides novel insights for accurately positioning specific immune-cell subgroups in which KAT2A-cGAS reaction mainly works and KAT2A regulation patterns.

SUBMITTER: Tang Y

PROVIDER: S-EPMC8557211 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known outcomes or the potential for targeting these factors in SLE.

Project description:BackgroundFactor H (FH) is a major soluble inhibitor of the complement system and part of a family comprising five related proteins (FHRs 1-5). Deficiency of FHR1 was described to be linked to an elevated risk of systemic lupus erythematosus (SLE). As FHR1 can partially antagonize the functionality of FH, an altered FHR1/FH ratio could not only enhance SLE vulnerability but also affect the disease expression. This study focuses on the analysis of FH and FHR1 at a protein level, and the occurrence of anti-FH autoantibodies (anti-FH) in a large cohort of SLE patients to explore their association with disease activity and/or expression.MethodsWe assessed FH and FHR1 levels in plasma from 378 SLE patients compared to 84 healthy controls (normal human plasma, NHP), and sera from another cohort of 84 healthy individuals (normal human serum, NHS), using RayBio® CFH and CFHR1 ELISA kits. Patients were recruited by the Swiss SLE Cohort Study (SSCS). Unmeasurable FHR1 levels were all confirmed by Western blot, and in a subgroup of patients by PCR. Anti-FH were measured in SLE patients with non-detectable FHR1 levels and matched control patients using Abnova's CFH IgG ELISA kit.ResultsOverall, FH and FHR1 levels were significantly higher in healthy controls, but there was no significant difference in FHR1/FH ratios between SLE patients and NHPs. However, SLE patients showed a significantly higher prevalence of undetectable FHR1 compared to all healthy controls (35/378 SLE patients versus 6/168 healthy controls; p= 0.0214, OR=2.751, 95% CI = 1.115 - 8.164), with a consistent trend across all ethnic subgroups. Levels of FH and FHR1, FHR1/FH ratios and absence of FHR1 were not consistently associated with disease activity and/or specific disease manifestations, but absence of FHR1 (primarily equivalent to CFHR1 deficiency) was linked to the presence of anti-FH in SLE patients (p=0.039).ConclusionsDeficiency of FHR1 is associated with a markedly elevated risk of developing SLE. A small proportion of FHR1-deficient SLE patients was found to have autoantibodies against FH but did not show clinical signs of microangiopathy.

Dataset Information

A preliminary study of KAT2A on cGAS-related immunity in inflammation amplification of systemic lupus erythematosus

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets