Cellular targets

C

A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Uhlen M, Karlsson MJ, Zhong W, Tebani A, Pou C, Mikes J, Lakshmikanth T, Forsström B, Edfors F, Odeberg J, Mardinoglu A, Zhang C, von Feilitzen K, Mulder J, Sjöstedt E, Hober A, Oksvold P, Zwahlen M, Ponten F, Lindskog C, Sivertsson Å, Fagerberg L, Brodin P. Science. 2019; 366(6472). pii: eaax9198. doi: 10.1126/science.aax9198

Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.

You can now genome sequence individual cells to see what proteins they produce and for the science buffs this can be a new science tool for hunting for targets.

(A) A schematic view of the hematopoietic differentiation. This study analyzes the cell types shown in the bottom row. NK, natural killer. (B) Network plot showing the number of cell type– (red) and group-enriched (yellow) genes in the 18 cell types. The network is limited to nodes with a minimum of seven genes. DC, dendritic cell; T-reg, regulatory T cell; gdT cell, gamma delta T cell; MAIT, mucosal associated invariant.

This open source so I had a quick look at guess what?

You got it.

Memory B-cells

Memory B-cells are formed within germinal centers following primary infection, and are important in generating an accelerated and more robust antibody-mediated immune response in the case of re-infection. They are localized in areas of facilitated antigen encounter and compared to naive B-cells they have higher affinity to the immunizing antigen, a lifespan of decades instead of weeks, and faster and more efficient proliferation and differentiation.

In the Blood Atlas we have 45 memory B-cell enriched genes and  4 of these genes has the highest expression in blood or lymphoid tissues when comparing all tissues and organs analysed. In addition,284 genes are cell type group enriched and an additional 189 genes are enhanced in this cell type. Altogether,518 genes are elevated and among these  121 also show highest expression in blood or lymphoid tissues when comparing all tissues and organs analysed.

The memory B-cells were isolated from PBMCs. Debris and cell aggregates were eliminated based on scatter profiles. Subsequently, monocytes were eliminated by selecting CD14neg/SSClow sub-population of lymphocytes (FSClow/SSClow). B-cells population was selected as CD19+/CD3neg population. At the final step, population of CD19+/CD27+ memory B-cells was sorted and 5,000 – 19,000 cells were sorted per sample for transcriptomic analysis by mRNA-sequencing. The transcriptome analysis shows that 53% (n=10,370) of all human proteins (n=19,670) are expressed in the memory B-cells and 284 of these genes show an elevated expression in memory B-cells compared to the other 17 cell types (see figure above).

If we look at the 45 gene products enriched in memory B cells, none of them are remotely specific as they are all expressed outside the immune system and antibodies to these target do not appear to have useful binding suggesting that they are unlikely to be a useful target for therapy.

Therefore we will have to be clever about how we specifically target memory B cells. Good job we work with clever people.

Alternatively we need to remove a broader population of cells. Would CD138 syndecam (found in this search) do the job?…it is unlikely as CD138 is low or absent from memory cells and is mainly a plasma cell (antibody producing cell).

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