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The spleen-specific proteome

The spleen is located inside the abdominal cavity on the upper left side. It weighs about 150 grams, can be subdivided into two functional compartments, the red pulp and the white pulp, and represents the largest lymphatic organ in the body. The red pulp filters large volumes of blood, and in the process detects antigens and selects damaged and old red blood cells and platelets for destruction. The transcriptome analysis shows that 66% of all human proteins (n=20344) are expressed in the spleen and 200 of these genes show an elevated expression in spleen compared to other tissue types. An analysis of the genes with elevated expression in spleen, with regards to subcellular localization, reveals that corresponding proteins are predominantly located in the cytoplasmic membrane.

  • 8 spleen enriched genes
  • 200 genes defined as elevated in the spleen
  • Most proteins elevated in lymph node are involved in immune system processes and regulation of immune response
  • 47 genes defined as group enriched in spleen and 2-7 additional tissues
  • Most group-enriched genes are shared with appendix

Figure 1. The distribution of all genes across the five categories based on transcript abundance in spleen as well as in all other tissues.

200 genes show some level of elevated expression in the spleen compared to other tissues. The three categories of genes with elevated expression in spleen compared to other organs are shown in Table 1.

Table 1. The genes with elevated expression in spleen


Number of genes


Tissue enriched 8 At least five-fold higher mRNA levels in a particular tissue as compared to all other tissues
Group enriched 47 At least five-fold higher mRNA levels in a group of 2-7 tissues
Tissue enhanced 145 At least five-fold higher mRNA levels in a particular tissue as compared to average levels in all tissues
Total 200 Total number of elevated genes in spleen

Table 2. The 8 genes with the highest level of enriched expression in spleen. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. "mRNA (tissue)" shows the transcript level as FPKM values, TS-score (Tissue Specificity score) corresponds to the score calculated as the fold change to the second highest tissue.



Predicted localization

mRNA (tissue)


OR5AK2 olfactory receptor, family 5, subfamily AK, member 2 Membrane 4.9 49
C15ORF31 Secreted 1.1 11
CD5L CD5 molecule-like Secreted 432.2 11
SPIC Spi-C transcription factor (Spi-1/PU.1 related) Intracellular 18.8 9
FAM9C family with sequence similarity 9, member C Membrane 32.1 8
NOS3 nitric oxide synthase 3 (endothelial cell) Intracellular 71.5 8
CCM2L cerebral cavernous malformation 2-like Intracellular 73.6 8
HBCBP HBcAg-binding protein; Uncharacterized protein Intracellular 7.4 5

Some of the proteins predicted to be membrane-spanning are intracellular, e.g., in the Golgi or mitochondrial membranes, and some of the proteins predicted to be secreted can potentially be retained in a compartment belonging to the secretory pathway, such as the ER, or remain attached to the outer face of the cell membrane by a GPI anchor.

The spleen transcriptome

An analysis of the expression levels of each gene makes it possible to calculate the relative mRNA pool for each of the categories. The analysis shows that 88% of the mRNA molecules in the spleen correspond to housekeeping genes and only 2% of the mRNA pool corresponds to genes categorized to be either spleen enriched, group enriched, or enhanced. Thus, most of the transcriptional activity in the spleen relates to proteins with presumed housekeeping functions as they are found in all tissues and cells analyzed.

Protein expression of genes elevated in spleen

The list of elevated genes (n=200) are well in-line with the function of the spleen, as it includes an overrepresentation of proteins associated with immune system processes and regulation of immune response, as exemplified by killer cell receptors (KIR3DL1, KIR2DL4, KIR2DL3, KLRF1, KLRD1), natural killer cell receptor CD244, B-cell co-receptor CD79B, and T-cell co-receptor CD8A.

Proteins specifically expressed in T-cells

CD8A is the alpha chain of the cell surface glycoprotein CD8, a co-receptor to the T-cell receptor found on most cytotoxic T-lymphocytes. RNA-data implies an enhanced expression in spleen, which is in concordance with IHC staining of the protein (HPA037756 and CAB000012). Positive lymphocytes are also seen in the other three hematological organs and in some other tissues. Furthermore, sinusoids in spleen were strongly stained, which may contribute to the elevated expression in this tissue.

Protein specifically expressed in natural killer (NK) cells

FCGR3A, Fc gamma receptor III A, also known as CD16A, is expressed on natural killer cells as an integral membrane glycoprotein. It binds aggregated as well as monomeric IgG, and is involved in the removal of antigen-antibody complexes from the circulation as well as other antibody-dependent responses.

Proteins specifically expressed in endothelial cells

The G protein-coupled receptor GPR182 is fairly uncharacterized, but has been shown to be highly expressed in endothelial cells of mouse embryos (Takase, Matsumoto et al., 2012) and in in vitro-cultured tumor-derived endothelial cells (Xiao et al, 2014). The transcription of GPR182 shows moderate enrichment in spleen, and IHC (HPA027037) shows expression of the protein in blood vessels, with the strongest staining seen in spleen and lymph node.

Genes shared between spleen and other tissues

There are 47 group enriched genes expressed in the spleen. Group enriched genes are defined as genes showing a 5-fold higher average level of mRNA expression in a group of 2-7 tissues, including spleen, compared to all other tissues.

In order to illustrate the relation of spleen tissue to other tissue types, a network plot was generated, displaying the number of commonly expressed genes between different tissue types.

Figure 2. An interactive network plot of the spleen enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of spleen enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 5 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

The network plot shows that most genes are shared with appendix, although most genes shared with appendix are also shared with other tissues harboring a major component of lymphoid cells, i.e. tonsil and lymph node.

Spleen function

The spleen is divided into two main compartments, the red pulp and the white pulp, and is surrounded by a dense fibrous covering called the splenic capsule. The main functions (in the adult) can be described as follows:

  1. Antigen detection. The white pulp is the infection-fighting lymphoid tissue, consisting of periarteriolar lymphoid sheaths (PALS) and lymphatic nodules. The sheaths surround central arteries within the spleen and contain T-lymphocytes that attack foreign bodies as the blood is filtered into the spleen.
  2. Removal of dead erythrocytes. The red pulp is made up of cords of connective tissue and wide blood vessels called splenic sinusoids. Blood is filtered as it passes through gaps in the sinusoid lining, which prevents old, damaged or abnormal red blood cells from entering back into circulation.
  3. Antibody production. The lymphoid follicles contain large masses of B-lymphocytes. B-cell follicles are similar in structure to large lymph nodes and can expand and develop germinal centers following antigen activation. The marginal sinuses are linked to the red pulp sinuses.

Spleen histology

The spleen consists of red pulp and white pulp within a meshwork of reticular fibers enclosed by a dense connective tissue capsule. The white pulp consists of lymphatic tissue and monitors the incoming blood for harmful substances. Aggregations of mainly T-lymphocytes envelop the central arteries in a periarterial lymphatic sheath (PALS). At places the white pulp expands into greater spherical aggregations to form splenic nodules containing a light germinal center, consisting of proliferating B-cells. Surrounding the B-cells is a darker stained mantel zone and peripheral to this a lighter stained marginal zone that marks the border to the red pulp. The splenic nodules have an appearance similar to lymph follicles, with the exception of a central located artery.

The red pulp filters blood to detect damaged and old red blood cells and platelets. Cells that are selected for breakdown are phagocytized by splenic macrophages. The abundance of red blood cells, erythrocytes, in red pulp is accountable for the red, eosin staining observed when stained with HE. The red pulp consists of splenic cords and splenic sinuses. A meshwork of reticular cells and fibers, together with dendritic cells, macrophages, a relatively smaller amount of lymphatic cells and a great number of red blood cells constitute the splenic cords. Branches of the central arteries penetrate into the red pulp where they further branch into smaller macrophage sheathed capillaries. Within the splenic cords, the red blood cells are exposed to the macrophages and can be selected for breakdown.

The histology of human spleen including detailed images and information about the different cell types can be viewed in the Protein Atlas Histology Dictionary.


Here, the protein-coding genes expressed in the spleen are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize protein expression patterns of proteins that correspond to genes with elevated expression in the spleen.

Transcript profiling and RNA-data analyses based on normal human tissues have been described previously (Fagerberg et al., 2013). Analyses of mRNA expression including over 99% of all human protein-coding genes was performed using deep RNA sequencing of 122 individual samples corresponding to 32 different human normal tissue types. RNA sequencing results of 4 fresh frozen tissues representing normal spleen was compared to 118 other tissue samples corresponding to 31 tissue types, in order to determine genes with elevated expression in spleen. A tissue-specific score, defined as the ratio between mRNA levels in spleen compared to the mRNA levels in all other tissues, was used to divide the genes into different categories of expression. These categories include: genes with elevated expression in spleen, genes expressed in all tissues, genes with a mixed expression pattern, genes not expressed in spleen, and genes not expressed in any tissue. Genes with elevated expression in spleen were further sub-categorized as i) genes with enriched expression in spleen, ii) genes with group enriched expression including spleen and iii) genes with enhanced expression in spleen.

Human tissue samples used for protein and mRNA expression analyses were collected and handled in accordance with Swedish laws and regulation and obtained from the Department of Pathology, Uppsala University Hospital, Uppsala, Sweden as part of the sample collection governed by the Uppsala Biobank. All human tissue samples used in the present study were anonymized in accordance with approval and advisory report from the Uppsala Ethical Review Board.

Uhlen et al (2015). Tissue-based map of the human proteome. Science.
DOI: 10.1126/science.1260419

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Genome-wide identification of endothelial cell-enriched genes in the mouse embryo

Histology dictionary - spleen

The spleen-specific proteome
The spleen transcriptome
Protein expression of genes elevated in spleen
Proteins specifically expressed in T-cells
Protein specifically expressed in natural killer (NK) cells
Proteins specifically expressed in endothelial cells
Genes shared between spleen and other tissues
Spleen function
Spleen histology
Relevant links and publications

Bone marrow and lymphatic tissues
Bone marrow
Lymph node