MENU- THE HUMAN PROTEOME
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The blood & immune cell-specific proteomeBlood and immune cells develop from hematopoietic stem cells (HSCs), which are multipotent cells with the ability to self-renew that can differentiate into all types of blood cells included in the lymphoid and the myeloid lineage. These cells reside in the medullary region of the bone marrow. Mature blood cells and immune cells circulate in the blood, and certain immune cells also reside within different tissues, e.g. liver and placenta. Transcriptome analysis shows that 75% (n=14812) of all human proteins (n=19670) are detected in blood & immune cells and 2440 of these genes show an elevated expression in any blood & immune cells compared to other cell type groups. The blood & immune cell transcriptomeThe scRNA-seq-based blood & immune cell transcriptome can be analyzed with regard to specificity, illustrating the number of genes with elevated expression in each specific blood & immune cell type compared to other cell types (Table 1). Genes with an elevated expression are divided into three subcategories:
Protein expression of genes elevated in blood & immune cellsIn-depth analysis of the elevated genes in blood & immune cells using scRNA-seq and antibody-based protein profiling allowed us to visualize the expression patterns of these proteins in different types of blood & immune cells: B-lymphocytes, T-lymphocytes, granulocytes, monocytes, macrophages, Hofbauer cells, Kupffer cells, erythroid cells and other immune cells.
B-cells - lymphoid systemAs shown in Table 1, 255 genes are elevated in B-cells compared to other cell types. B-lymphocytes or B-cells are a type of white blood cell of the lymphocyte subtype, that mature in the bone marrow. They express B-cell receptors on their surface that allow them to bind specific antigens, and function in the humoral immunity component of the adaptive immune system by secreting antibodies. Membrane Spanning 4-Domains A1 (MS4A1) is a group enriched in blood, intestine and lymphoid tissue and expressed on the surface of B cells during maturation and absent in early pro-B cells and the fully differentiated plasma cells. B-lymphocyte antigen CD19 (CD19) functions as a coreceptor for the B-cell antigen receptor complex (BCR) on B-lymphocytes.
T-cells - lymphoid systemAs shown in Table 1, 380 genes are elevated in T-cells compared to other cell types. T-lymphocytes or T-cells are a type of lymphocyte that is a part of the adaptive immune system together with B-lymphocytes. An example of a protein with elevated expression is T-cell surface glycoprotein CD8 beta chain (CD8B) which is the beta chain of the cell surface glycoprotein CD8 and is an important molecule mediating cell-cell interactions in the lymphoid tissues. Acting as a coreceptor to the T-cell receptor on the T-cell, it recognizes MHC class I molecules displayed by an antigen-presenting cell. Thymocyte Selection Associated (THEMIS) encodes a protein involved in the late phases of T-cell development. It is necessary for lineage commitment and functions through T-cell antigen receptor signaling.
GranulocytesAs shown in Table 1, 576 genes are elevated in granulocytes compared to other cell types. Granulocytes, also known as polymorphonuclear leukocyte (PML) are the major type of white blood cells and part of the innate immune system against bacterial infection. They are characterized by their high content of granules in the cytoplasm and have a nucleus that is lobe-shaped or segmented into two or more connected lobes. The granulocyte population includes eosinophils, basophils, and neutrophils which is also the most abundant type. Matrix metallopeptidase 9 (MMP9) is a protein detected in neutrophils and may play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration. CCAAT/enhancer binding protein epsilon (CEBPE) is a transcription factor that is involved in terminal differentiation and functional maturation of committed granulocyte progenitor.
MonocytesAs shown in Table 1, 596 genes are elevated in monocytes compared to other cell types. Monocytes compose 2-10% of all white blood cells in the human body. The proliferation takes place in the bone marrow and then circulates the bloodstream until they migrate to tissues and body cavities where they are differentiated into macrophages and dendritic cells. They also possess antimicrobial functions. Integrin alpha M (ITGAM) is expressed predominantly on human monocytes but also macrophages, granulocytes, and natural killer cells.
MacrophagesAs shown in Table 1, 407 genes are elevated in macrophages compared to other cell types. Macrophages belong to a group of white blood cells called phagocytes, which is a type of cells specialized in phagocytosis, a process that protects the body by ingesting cellular debris, dead cells or pathogens. Mature macrophages are found throughout the body in most tissues, they do not travel far and are rarely seen in the bloodstream, instead they are guarding locally and waiting to be activated. Macrophage polarization is a process where they adopt different functions depending on the signals received from the environment and the two major states are the M1(pro-inflammatory) and the M2(anti-inflammatory). Macrophage mannose receptor 1 (MRC1) is a type I membrane receptor that can bind on the surface of viruses, bacteria, and fungi, to mediate phagocytosis. Macrophage scavenger receptor 1 (MSR1) encodes a receptor on the macrophage cell surface that has a homeostatic function by clearing modified lipids and proteins.
Hofbauer cells - placentaAs shown in Table 1, 660 genes are elevated in Hofbauer cells compared to other cell types. Hofbauer cells are fetal macrophages that can be found in the villous stroma at all stages of gestation. The term is used for any fetal derived macrophages in the placental villous core, amnion and chorionic lavae. They have several proposed functions including preventing vertical transmission, i.e transmission from the mother to the fetus, being pro-angiogenic and playing a role in placental morphogenesis. V-set immunoglobulin-domain-containing 4 (VSIG4) is a protein that is expressed in Hofbauer cells. It is a phagocytic receptor, a strong negative regulator of T-cell proliferation and IL2 production. Potent inhibitor of the alternative complement pathway convertases. Another protein expressed in Hofbauer cells is (CD68), a transmembrane glycoprotein that is highly expressed by human monocytes and tissue macrophages.
Kupffer cells - liverAs shown in Table 1, 615 genes are elevated in Kupffer cells compared to other cell types. Kupffer cells are part of the innate immune defense in the liver, they are specialized macrophages lining the liver sinusoidal endothelial walls and filter the blood from microbial debris and particles which enter through the hepatic portal vein. Kupffer cells make up to 80-90% of all macrophages in the body and their function and structures differ depending on if they reside in the centrilobular or periportal region. Macrophage receptor with collagenous structure (MARCO) is a protein expressed on macrophages including Kupffer cells that may bind both gram-positive and gram-negative bacterias.
Erythroid cells - bloodAs shown in Table 1, 349 genes are elevated in erythroid cells compared to other cell types. Erythroid cells, also called erythrocytes or red blood cells, acquire oxygen from the inhaled air in the lungs and transport the oxygen to all tissues of the body via the circulatory system. Hemoglobin subunit beta HBB and subunit delta HBD are components of the hemoglobin molecule which is expressed exclusively in erythroid cells and bind oxygen.
Other immune cellsDendritic cells are antigen-presenting cells present in tissues that are in contact with the external environment, e.g. skin, but also in an immature state in the blood, and upon activation they migrate to the lymph nodes to interact with T-cells and B-cells. They act as messengers between the innate and the adaptive immune systems. CD207 molecule (CD207) is a receptor expressed on the surface of Langerhans cells, the dendritic cells of the skin. Thanks to this receptor, Langerhans cells bind and absorb antigens on the surface of infectious agents and present the antigens to T-cells.
Natural killer cells (NK-cells) are a type of cytotoxic lymphocyte that circulate in the blood. As a critical part of the innate immune system, they patrol the body and, upon contact with virus-infected cells, tumor formation and stressed cells, respond rapidly by releasing cytotoxic granules that destroy the target cell(s). NK-cells recognize abnormal cells through different types of receptor protein complexes, including the protein killer cell lectin like receptor K1 (KLRK1), which functions as an activating and costimulatory receptor upon binding to various cellular stress-inducible ligands displayed at the surface of autologous tumor cells and virus-infected cells.
Mast cells are found in the connective tissue throughout the body, in particular in the skin, respiratory system, gastrointestinal and urinary tracts. They are part of the innate and adaptive immune system and are also involved in the maintenance of a healthy vascular system. Mast cells have also been connected to diseases such as allergy and asthma. Two well-known proteins found in mast cells are tryptase delta 1 (TPSD1), a protease that is secreted when mast cells are activated, and hematopoietic prostaglandin D synthase (HPGDS), a protein involved in the production of prostanoids in the immune system.
Platelets are produced by megakaryocytes in the bone marrow and are released to the circulating blood. Their main role is to initiate blood clot formation in response to blood vessel injury. In addition, they have possible roles in the regulation of immunity and inflammation. A protein expressed on the surface of platelets is glycoprotein IX platelet ({hpa:tissueLink}GP9{/hpa), which allows attachment to damaged blood vessels.
Blood & immune cell functionThe blood has many important functions including oxygen/carbon dioxide transport, removal of waste, coagulation, and body temperature regulation etc. Blood that accounts for about 7% of the human body weight circulates the body through blood vessels and is synthesized in the hematopoiesis process. The HSCs can give rise to all blood cells including; B-lymphocytes, T-lymphocytes, natural killer cells, granulocytes, monocytes, erythrocytes, and platelets. Studies have suggested two models for hematopoiesis: deterministic or stochastic. In the deterministic model, it is suggested that different factors in the hematopoietic microenvironment decide what the HSCs should differentiate into. In the stochastic model, the HSCs differentiate into the specific blood cells by randomness. In addition to antibody production in response to contact with antigens, B-cells are also classical antigen-presenting cells and secrete cytokines. Naive B lymphocytes reside in lymph nodes and have not yet been exposed to an antigen. Upon antigen activation they will differentiate to either plasma cells or memory B-cells. Memory B lymphocytes 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 a higher affinity to the immunizing antigen, a lifespan of decades instead of weeks, and faster and more efficient proliferation and differentiation. T-cells originate from hematopoietic cells in the bone marrow, which develop into immature thymocytes in the thymus. The thymocytes differentiate into several types of mature T-cells; T-helper cells, cytotoxic T-cells, memory T-cells, regulatory T-cells and natural killer T-cells. During maturation, T-cells undergo β-selection and positive selection in the thymic cortex and negative selection in the thymic medulla. The histology of organs that contain blood & immune cells, including interactive images, is described in the Protein Atlas Histology Dictionary. BackgroundHere, the protein-coding genes expressed in blood & immune cells are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in different blood & immune cell types. The transcript profiling was based on publicly available genome-wide expression data from scRNA-seq experiments covering 13 different normal tissues, as well as analysis of human peripheral blood mononuclear cells (PBMCs). All datasets (unfiltered read counts of cells) were clustered separately using louvain clustering and the clusters obtained were gathered at the end, resulting in a total of 192 different cell type clusters. The clusters were then manually annotated based on a survey of known tissue and cell type-specific markers. The scRNA-seq data from each cluster of cells was aggregated to average normalized protein-coding transcripts per million (pTPM) and the normalized expression value (nTPM) across all protein-coding genes. A specificity and distribution classification was performed to determine the number of genes elevated in these single cell types, and the number of genes detected in one, several or all cell types, respectively. It should be noted that since the analysis was limited to datasets from 13 organs only, not all human cell types are represented. Furthermore, some cell types are present only in low amounts, or identified only in mixed cell clusters, which may affect the results and bias the cell type specificity.
Relevant links and publications Uhlén M et al., Tissue-based map of the human proteome. Science (2015) |
The Project
The Human Protein Atlas
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