New paper out

The latest paper from our lab is out now in Nature Communications!

In “Double-negative B cells and DNASE1L3 colocalise with microbiota in gut-associated lymphoid tissue”, co-authored by myself and Lucia Montorsi along with our collaborators, we used a combination of spatial transcriptomics and multiplexed single-cell technologies to pinpoint the DN2 B cells, known to be enriched in the blood in patients with lupus, as being present in healthy gut. When in the gut, these DN2 B cells interact with dendritic cells co-expressing the lupus autoantigens DNASE1L3 and C1q, adjacent to bacteria.

The normal functions of DN2 B cells, DNASE1L3 and C1q in the gut are likely to relate to bacterial recognition, bacterial killing and disposal of bacterial debris including DNA. Failure of such a system could result in persistence of bacterial DNA that may stimulate an autoimmune response.

Read it here: https://www.nature.com/articles/s41467-024-48267-4

New B cell paper

The latest publication from our lab, “Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood“, is out now in Science Immunology!

Led by Dr Jacqueline Siu and supervised by Prof Jo Spencer and Dr Gavin Pettigrew, we use analysis of gut-associated lymphoid tissue, mesenteric lymph node, and spleen tissues from diseased human transplant donors to show that CD27+IgM+ unswitched B cells differed mostly between tissues. We identified two distinct MZ populations were identified among the cells, which differed in their expression levels of BAFFR, CD24, CCR7, and CD27. RNA-Seq data from the tissues also identified two MZ-like B cell populations with similar characteristics, and also revealed that MZB-1 showed higher mutation levels than MZB-2 cells. RNA-Seq was also used to compare blood B cells from lupus patients and healthy donors, which again clustered MZ-like B cells into two populations that differed in mutation frequency in their V regions. SLE patients lacked MZB-1 cells and this was confirmed by flow cytometry.

Read the paper here.

Two new papers from the lab

The Spencer lab has collaborated on two new papers which have come out recently:

A SIMPLI (Single-cell Identification from MultiPLexed Images) approach for spatially resolved tissue phenotyping at single-cell resolution: A software pipeline, named SIMPLI, for end-to-end analysis of Imaging Mass Cytometry data (software can be found here). Led by Michele Bortolomeazzi, a collaboration with the Ciccarelli lab at Crick.

Disrupted Peyer’s patch microanatomy in COVID-19 including germinal centre atrophy independent of local virus: Covid-19 infection disrupts the Peyer’s patch of the GI tract, regardless of the levels of virus in that location, suggesting the virus impacts the body’s ability to mount an effective intestinal immune response. Led by Silvia Cellone Trevelin, a collaboration with the Neil lab at KCL.

New COVID pre-print

Read the article here: https://www.biorxiv.org/content/10.1101/2021.12.17.473179v1

A new pre-print from our lab in collaboration with the Neil lab at KCL has gone live today. In it, analysis of post-mortem tissues from the gastrointestinal tract of patients who died with COVID-19 showed that virus was present in epithelium and lamina propria macrophages, but not in lymphoid tissues of patients who had PCR-confirmed infection of the GI tract. Germinal centres were disrupted, as were the delineation of B cell and T cell zones, leading to reduced potential for B- and T-cell interaction. These observations suggest the ability to mount an intestinal immune response to COVID-19 is compromised.

Two new pre-prints

I’m pleased to announced that two pieces of work I’ve co-authored are now live on bioRxiv:

In the first, “Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood“, from Jacqueline Siu, we look at human B cell differentiation and dissemination using multiple different technologies, and uncover two distinct subsets of marginal zone B cells. We explore the differences between these subsets in terms of cell surface and transcriptomic profiles, clonal dissemination, hypermutation frequency, and micro-anatomical distribution in healthy spleen, mesenteric lymph node and appendix, and compare them in the blood of healthy patients and those with lupus.

In the second, “A SIMPLI (Single-cell Identification from MultiPLexed Images) approach for spatially resolved tissue phenotyping at single-cell resolution”, from the Ciccarelli Lab, presents a novel technology-agnostic software that unifies all steps of multiplexed imaging data analysis. This new software is shown in action by studying the human colon mucosa for IgA and the human appendix for T follicular helper cells.

B cell paper live in JExMed

Our latest paper has now been published in the Journal of Experimental Medicine: link here. See also this piece from David Nemazee exploring the context of our work.

Abstract:

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.

New editorial piece on TB modelling

Our latest editorial piece from the Infection and Global Health Research Division at the University of St Andrews on the need for mechanistic modelling of within-host tuberculosis dynamics, entitled “How mechanistic in silico modelling can improve our understanding of TB disease and treatment”, is now live in the International Journal of Tuberculosis and Lung disease: link here.

Abstract:

TB is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. Decreasing the length of time for TB treatment is an important step towards the goal of reducing mortality. Mechanistic in silico modelling can provide us with the tools to explore gaps in our knowledge, with the opportunity to model the complicated within-host dynamics of the infection, and simulate new treatment strategies. Significant insight has been gained using this form of modelling when applied to other diseases – much can be learned in infection research from these advances.

New publication

Our latest paper (the final one from my PhD work) is now published. In “Modelling the effects of environmental heterogeneity within the lung on the tuberculosis life-cycle“, we created a model that incorporates the environmental heterogeneity of conditions such as blood perfusion and oxygen tension within the lung to investigate the effects they had on the whole tuberculosis life-cycle, demonstrating how different parameters affect different stages of infection and show how the environmental differentials can drive post-primary disease (where most transmission occurs) to the oxygen-rich apices of the lung.