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Reduced vaccine-induced germinal center outputs in inflammatory bowel disease patients treated with anti-TNF biologics

ABSTRACT: Tumor necrosis factor (TNF) blocking agents are widely used to treat patients with immune-mediated inflammatory diseases. The complete absence of TNF in mice impairs germinal center responses. Less is known about the impact of anti-TNF therapy on specific immune responses in humans. The widespread vaccination against SARS-CoV-2 offered an unprecedented opportunity to investigate the effects of biological therapies on the response to a specific immunization. Previous work demonstrated that inflammatory bowel disease (IBD) patients treated with anti-TNF agents exhibit decreased Spike (S)-specific antibody responses compared to IBD patients treated with anti-IL-12/23 or healthy controls, even after four doses of mRNA vaccine. Here, we performed immune profiling of S-specific memory B cells (MBCs) isolated from anti-TNF treated- or anti-IL-12/23- treated IBD patients and healthy controls via 5' single cell RNA-sequencing, CITE-sequencing, and BCR-sequencing, to examine the transcriptome of and breadth of memory B cell responses to SARS-CoV-2 mRNA vaccination. This study provided in vivo evidence that anti-TNF, but not anti-IL-12/23, therapy impairs the quantity of and quality of antigen-specific germinal center outputs in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290006 | GEO | 2025/07/16

REPOSITORIES: GEO

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Project description:Objectives: Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct anti-inflammatory effect and anti-atherogenic effects of PNLA on activated purified CD14 monocytes from peripheral blood of patients with rheumatoid arthritis (RA) in vitro. Methods: Flow cytometry was used to assess the proportions of CD14 monocytes expressing TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptome (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing. Results: PNLA reduced percentage of monocytes expressing cytokines: TNF-a by 23% (p=0.048), IL-6 by 25% (p=0.011), IL-1B by 23% (p=0.050), IL-8 by 20% (p=0.066). Pathway analysis identified upstream activation of peroxisomes proliferator-activated receptors (PPARs), sirtuin3, and let7miRNA, KLF15 which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-a, and IL-6 signal transduction, were inhibited. Canonical Pathway analysis showed that PNLA inhibited oxidative phosphorylation (p=9.14E-09) and mitochondrial dysfunction (p=4.18E-08), while the sirtuin (SIRTs) signalling pathway was activated (p=8.89E-06) which interfere with the pathophysiologic process of atherosclerosis. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and Acetyl-CoA Acyltranferase2 (ACAA2); genes implicated in regulation of lipid and cell metabolism, inflammation, and mitochondrial dysfunction. Conclusion: PNLA has potential anti-atherogenic and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation regulates key miRNAs that are involved in metabolic, mitochondrial, and inflammatory pathways.

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Reduced vaccine-induced germinal center outputs in inflammatory bowel disease patients treated with anti-TNF biologics

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