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Bentkowska, K.

Publications and source records attributed to Bentkowska, K..

2 recordsLinked to original sources
bioRxiv2023

Pericardial & Mediastinal Fat-Associated Lymphoid Clusters are rapidly activated in an alkane induced model of Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease predominated by auto-antibodies that recognise cellular components. Pleural involvement is the most common SLE-related lung disease. Natural antibodies are rapidly secreted by innate-like B cells following perturbation of homeostasis and are important in the early stages of immune activation. The serous cavities are home to large numbers of innate-like B cells present both within serous fluid and resident within fat-associated lymphoid clusters (FALCs). FALCs are important hubs for B-cell activation and local antibody secretion within the body cavities. Patients with SLE can develop anti-phospholipid antibodies and in rare situations develop alveolar haemorrhage. Utilising delivery of the hydrocarbon oil pristane in C57BL/6 mice as a model of SLE we identify a rapid expansion of pleural cavity B cells as early as day 3 after intra-peritoneal pristane delivery. Following pristane delivery, pericardial B1 B cells are proliferative, express the plasma-cell surface marker CD138 and secrete both innate and class switched antibodies highlighting that this cavity niche may play an unrecognised role in the initiation of lupus pleuritis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/549766v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@18ea5bforg.highwire.dtl.DTLVardef@23d9deorg.highwire.dtl.DTLVardef@1b48b3aorg.highwire.dtl.DTLVardef@20a133_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗
bioRxiv2023

Asparagine availability controls germinal centre B cell homeostasis

Germinal centre (GC) B cells proliferate at some of the highest rates of any mammalian cell, yet the metabolic processes which enable this are poorly understood. We performed integrated metabolomic and transcriptomic profiling of GC B cells, and found that metabolism of the non-essential amino acid asparagine (Asn) was highly upregulated. Asn was conditionally essential to B cells, and its synthetic enzyme, asparagine synthetase (ASNS) was upregulated following their activation, particularly more markedly in the absence of Asn, through the integrated stress response sensor general control non-derepressible 2 (GCN2). When Asns is deleted B cell survival and proliferation in low Asn conditions were strongly impaired, and removal of environmental Asn by asparaginase or dietary restriction markedly compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Using stable isotope tracing and single cell RNA sequencing, we found that metabolic adaptation to the absence of Asn requires ASNS, and that oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides was particularly sensitive to Asn deprivation. Altogether, we reveal that Asn metabolism acts as a key regulator of B cell function and GC homeostasis. The one sentence summaryAsparagine metabolism is a critical regulator of B cell function, maintaining the germinal centre reaction.

immunology↗