Interogating MS with new technology, it’s a T & B cell co-operation thang.

I

With new technology is was not a question of if, but a question of when the protein production array of individual cells will be done, You can now look for the antigen-specific receptors of each cell to find out what they target is you can look at the proteins they make to say what cell types are there and this latter aspect was the focus of this study.

They got the protein signatures (transcriptome) from about 43,000 blood cells and 22,000 corresponding CSF single-cells from 5 pwMS and 5 controls.

Genes detected per donor were about 950 in peripheral blood mononuclear cells (PBMCs) and about 1000 in CSF

in their words

They apply single-cell transcriptomics to blood and CSF cells from people with MS and controls

First, they identify a compartment-specific composition and transcriptome, including an enrichment of dendritic cells (a type of antigen presenting cell) in the CSF.

Second, they find that MS mainly affects the cellular composition of the CSF, but the transcriptional phenotype of blood cells is changed. There is an expansion of CD4+ T cells with a cytotoxic phenotype and late-stage B lineage cells in the CSF in MS. In contrast to blood, the cell type composition of CSF was clearly different in MS patients compared to controls 

Three B lineage clusters (CD74CD79A, and IGH gene family) corresponded to naive B cells (B1; CD37 and IGHD), activated B cells (B2; CD27 and IGHM), and plasma blasts (plasma; IGHGCD38, and TNFRSF17/CD269; negative for MS4A1/CD20 and SDC1/CD138, where examined . All B lineage cell clusters (B1, B2, and plasma) significantly expanded in the CSF in MS compared to controls in accordance with flow cytometry and previous studies. Most B lineage cells in the CSF had class-switched and were thus memory B cells or plasma blasts

Third, they observe an expansion of B-cell-helping T follicular helper (TFH) cells and suggest that TFH cells promote CNS autoimmunity and local B cell infiltration. They say this demonstrates “how an unbiased approach aids our understanding of a unique human immune compartment and identifies mechanisms locally driving CNS disease”.

Such unbiased approaches are good, but this study is simply a fancy way of confirming what we already know. Cells in the spinal fluid compartment are different from the blood, we have known this for years, however we are none the wiser about knowing what is really going on. The problem with the unbiased approach is that you say you don’t know where to look so you dont look properly. It sometimes helps if you can focus. So as you read the paper, you are flung here, there and everywhere and so it is not surprising we are led to believe that we don’t know what is going on….let’s have more research.

However, it also means that your clustering is less than ideal because you do not focus on the important cell types adequately, so for example the switched and non-switched B memory cells are not adequately distinguished. However we know that the interesting elements within the pathogenic repertoire is going to be within the memory T and B components, if autoimmunity is important. By spreading the net wide things are missed and no clear message appears. They can go back and do a focussed anlaysis. The study in the end focuses on CD4 T cells. Notably those that help B cells. They do some EAE experiments to say that these T follicular cells are important, but I won’t dwell on them as you know that I think this is rather irrelevant and we know that EAE is CD4 T cell dependent, the B cells are not that important in this type of EAE. However I must say the scoring system did make me laugh

It says “Mice were monitored daily and assigned grades for clinical signs of EAE using the following scoring system: 0, healthy; 1, paralyzed tail tip; 2, paralyzed tail; 3, waddling; 4, hind legs drag on the ground; 5, butt on the ground; 6, one paralyzed hind leg; 7, both paralyzed hind legs; 8, one paralyzed front leg (criterium to stop EAE); 9, both paralyzed front legs; and 10, moribund or death”. It reminds me of American Idol “Pants on the ground, pants on the ground looking like a fool with your pants on the ground” I never knew a mouse had a butt.

What next? the new EAE scoring system on Mouse Twerking

Anyway, has the Th17 cell had its day? Are T cells around to help B cells?

Is there shift in the Tcells immunologists world view?…..No Chance:-(

Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Schafflick D, Xu CA, Hartlehnert M, Cole M, Schulte-Mecklenbeck A, Lautwein T, Wolbert J, Heming M, Meuth SG, Kuhlmann T, Gross CC, Wiendl H, Yosef N, Meyer Zu Horste G. Nat Commun. 2020 Jan 14;11(1):247. doi: 10.1038/s41467-019-14118-w.

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leucocytes remains superficial. Here, using single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) – an autoimmune disease of the CNS – increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.

It’s open access here

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