Stroebel, T. | Search bioRxiv

bioRxiv2024

Ex vivo Model of Functioning Human Lymph Node Reveals Pivotal Role for Innate Lymphoid Cells and Stromal Populations in Response to Vaccine Adjuvant

Immunological processes that underpin the administration of therapeutics and vaccines are poorly defined due to a lack of models which faithfully recapitulate human immune responses. Inbred mice lack the diversity inherent to people, while the microanatomical organisation of human tissue is lost in isolated cell suspensions. We describe precision-cut human lymph node (LN) slices as architecturally-preserved, functioning lymphoid tissue model system, and explore early inflammatory responses to a potent vaccine liposomal adjuvant containing a TLR4-agonist and QS21 saponin. Combining scRNA-seq, multiplexed immunofluorescence and secretome analysis, we dissect direct and indirect signalling pathways in both leukocytes and stromal cells to reveal communication networks linking innate and adaptive immunity. Application of molecular inhibitors reveals that secretion of IL-1{beta}, but not IL-18, is TLR4-dependent in human LN. Retaining donor-to-donor immune variation, this ex vivo LN model system enables the study of pathways previously difficult to observe in humans, paving the way towards precision medicine.

immunology↗

bioRxiv2017

TECPR2 a positive regulator of autophagy is implicated in healthy brain ageing

Understanding the healthy brain aging process is key to uncovering the mechanisms leading to pathological age-related neurodegeneration, including progression to Alzheimers disease (AD). Here, we report the first deep whole genome sequencing study aiming to identify variants that are associated specifically to healthy brain aging defined on both clinical and neuropathological level, thus tacking the issue of pathological heterogeneity that often underlies a clinical AD diagnosis. We studied samples from the VITA brain bank and followed an extreme phenotypic ends study design comparing neuropathologically \"healthy\" aging individuals above 80 years of age with pure AD patients of the same age. Focusing on the extreme ends of the phenotypic distribution, and potentially functional variants, we discover a single variant (rs10149146) carried by 53.6% of the \"healthy\" brain elderly individuals in our study (15/28 individuals) and none of the 12 AD cases. This variant lies on the autophagy and cell cycle associated TECPR2 gene. Autophagy dysfunction has been previously implicated in multiple progressive neurodegenerative diseases. An additional non-synonymous variant on the CINP gene (encoding a cell-cycle checkpoint protein) is also found in 46% of healthy controls and absent from all the AD cases. TECPR2 and CINP appear to be \"partner\" genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. Our study is the first to support the hypothesis that a TECPR2 non-synonymous variant carries a significant neuroprotective effect pointing to key molecules for the involvement of autophagy and cell cycle control in protection from neurodegeneration.

genomics↗