Macrophages are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, foreign substances, cancer cells, anything else that does not have the type of proteins specific to healthy body cells on its surface in a process called phagocytosis. These large phagocytes are found in all tissues, where they patrol for potential pathogens by amoeboid movement, they take various forms throughout the body. Besides phagocytosis, they play a critical role in nonspecific defense and help initiate specific defense mechanisms by recruiting other immune cells such as lymphocytes. For example, they are important as antigen presenters to T cells. In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections. Beyond increasing inflammation and stimulating the immune system, macrophages play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines. Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages.
This difference is reflected in their metabolism. However, this dichotomy has been questioned as further complexity has been discovered. Human macrophages are about 21 micrometres in diameter and are produced by the differentiation of monocytes in tissues, they can be identified using flow cytometry or immunohistochemical staining by their specific expression of proteins such as CD14, CD40, CD11b, CD64, F4/80 /EMR1, lysozyme M, MAC-1/MAC-3 and CD68. Macrophages were first discovered by Élie Metchnikoff, a Russian zoologist, in 1884. A majority of macrophages are stationed at strategic points where microbial invasion or accumulation of foreign particles is to occur; these cells together as a group are known as the mononuclear phagocyte system and were known as the reticuloendothelial system. Each type of macrophage, determined by its location, has a specific name: Investigations concerning Kupffer cells are hampered because in humans, Kupffer cells are only accessible for immunohistochemical analysis from biopsies or autopsies.
From rats and mice, they are difficult to isolate, after purification, only 5 million cells can be obtained from one mouse. Macrophages can express paracrine functions within organs that are specific to the function of that organ. In the testis for example, macrophages have been shown to be able to interact with Leydig cells by secreting 25-hydroxycholesterol, an oxysterol that can be converted to testosterone by neighbouring Leydig cells. Testicular macrophages may participate in creating an immune privileged environment in the testis, in mediating infertility during inflammation of the testis. Cardiac resident macrophages participate in electrical conduction via gap junction communication with cardiac myocytes. Macrophages can be classified on basis of the fundamental activation. According to this grouping there are classically activated macrophages, wound-healing macrophages and regulatory macrophages. Macrophages that reside in adult healthy tissues either derive from circulating monocytes or are established before birth and maintained during adult life independently of monocytes.
By contrast, most of the macrophages that accumulate at diseased sites derive from circulating monocytes. When a monocyte enters damaged tissue through the endothelium of a blood vessel, a process known as leukocyte extravasation, it undergoes a series of changes to become a macrophage. Monocytes are attracted to a damaged site by chemical substances through chemotaxis, triggered by a range of stimuli including damaged cells and cytokines released by macrophages at the site. At some sites such as the testis, macrophages have been shown to populate the organ through proliferation. Unlike short-lived neutrophils, macrophages survive longer in the body, up to several months. Macrophages are professional phagocytes and are specialized in removal of dying or dead cells and cellular debris; this role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophils, which are ingested by macrophages if they come of age. The neutrophils are at first attracted to a site, where they proliferate, before they are phagocytized by the macrophages.
When at the site, the first wave of neutrophils, after the process of aging and after the first 48 hours, stimulate the appearance of the macrophages whereby these macrophages will ingest the aged neutrophils. The removal of dying cells is, to a greater extent, handled by fixed macrophages, which will stay at strategic locations such as the lungs, neural tissue, bone and connective tissue, ingesting foreign materials such as pathogens and recruiting additional macrophages if needed; when a macrophage ingests a pathogen, the pathogen becomes trapped in a phagosome, which fuses with a lysosome. Within the phagolysosome and toxic peroxides digest the pathogen. However, some bacteria, such as Mycobacterium tuberculosis, have become resistant to these methods of digestion. Typhoidal Salmonellae induce their own phagocytos
A megakaryocyte is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes, which are necessary for normal blood clotting. Megakaryocytes account for 1 out of 10,000 bone marrow cells in normal people, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte. In general, megakaryocytes are 10 to 15 times larger than a typical red blood cell, averaging 50–100 μm in diameter. During its maturation, the megakaryocyte grows in size and replicates its DNA without cytokinesis in a process called endomitosis; as a result, the nucleus of the megakaryocyte can become large and lobulated, under a light microscope, can give the false impression that there are several nuclei. In some cases, the nucleus may contain up to 64N DNA, or 32 copies of the normal complement of DNA in a human cell; the cytoplasm, just as the platelets that bud off from it, contains dense bodies.
Megakaryocytes are derived from hematopoietic stem cell precursor cells in the bone marrow. They are produced by the liver, kidney and bone marrow; these multipotent stem cells live in the marrow sinusoids and are capable of producing all types of blood cells depending on the signals they receive. The primary signal for megakaryocyte production is thrombopoietin or TPO. TPO is sufficient but not necessary for inducing differentiation of progenitor cells in the bone marrow towards a final megakaryocyte phenotype. Other molecular signals for megakaryocyte differentiation include GM-CSF, IL-3, IL-6, IL-11, chemokines. and erythropoietin. The megakaryocyte develops through the following lineage: CFU-Me → megakaryoblast → promegakaryocyte → megakaryocyte; the cell reaches megakaryocyte stage and loses its ability to divide. However, it is still able to continue development, becoming polyploid; the cytoplasm continues to expand and the DNA complement can increase up to 64N in human and 256N in mouse.
Many of the morphological features of megakaryocyte differentiation can be recapitulated in non-hematopoietic cells by the expression of Class VI β-tubulin and they provide a mechanistic basis for understanding these changes. Once the cell has completed differentiation and become a mature megakaryocyte, it begins the process of producing platelets; the maturation process occurs via endomitotic synchronous replication whereby the cytoplasmic volume enlarges as the number of chromosomes multiplies without cellular division. The cell ceases its growth at 4N, 8N or 16N, becomes granular, begins to produce platelets. Thrombopoietin plays a role in inducing the megakaryocyte to form small proto-platelet processes. Platelets are held within these internal membranes within the cytoplasm of megakaryocytes. There are two proposed mechanisms for platelet release. In one scenario, these proto-platelet processes break up explosively to become platelets. Alternatively, the cell may form platelet ribbons into blood vessels.
The ribbons are formed via pseudopodia and they are able to continuously emit platelets into circulation. In either scenario, each of these proto-platelet processes can give rise to 2000–5000 new platelets upon breakup. Overall, 2/3 of these newly produced platelets will remain in circulation while 1/3 will be sequestered by the spleen. Thrombopoietin is a 353-amino acid protein encoded on chromosome 3p27. TPO is synthesized in the liver but can be made by kidneys, testes and bone marrow stromal cells, it has high homology with erythropoietin. It is essential for the formation of an adequate quantity of platelets. After budding off platelets, what remains is the cell nucleus; this crosses the bone marrow barrier to the blood and is consumed in the lung by alveolar macrophages. Cytokines are signals used in the immune system for intercellular communication. There are many cytokines. Certain cytokines such as IL-3, IL-6, IL-11, LIF, thrombopoietin all stimulate the maturation of megakaryocytic progenitor cells.
Other signals such as PF4, CXCL5, CXCL7, CCL5 inhibit platelet formation. Megakaryocytes are directly responsible for producing platelets, which are needed for the formation of a thrombus, or blood clot. There are several diseases that are directly attributable to abnormal megakaryocyte function or abnormal platelet function. Essential thrombocytosis known as essential thrombocythemia, is a disorder characterized by elevated numbers of circulating platelets; the disease occurs in 1–2 per 100,000 people. The 2016 WHO requirements for diagnosis include > 450,000 platelets/μL of blood and a bone marrow biopsy. Some of the consequences of having such high numbers of platelets include thrombosis or clots throughout the body. Thrombi form more in arteries than veins, it seems ironic that having platelet counts above 1,000,000 platelets/μL can lead to hemorrhagic events. Recent evidence suggests that the majority of ET cases are due to a mutation in the JAK2 protein, a member of the JAK-STAT pathway. Evidence suggests that this mutation renders the megakaryocyte hypersensitive to thrombopoietin and causes clonal proliferation of megakaryocytes.
There is a significant risk of transformation to leukemia with this disorder. The primary treatment consists of hydroxyurea to lower platelet levels. Congenital amegakaryocytic thrombocytopenia is a rare inherited disorder; the primary manifestations are thrombocytopenia and megakaryocytopenia, i.e. low numbers of platelets and megakaryo
Blood is a body fluid in humans and other animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells. In vertebrates, it is composed of blood cells suspended in blood plasma. Plasma, which constitutes 55% of blood fluid, is water, contains proteins, mineral ions, carbon dioxide, blood cells themselves. Albumin is the main protein in plasma, it functions to regulate the colloidal osmotic pressure of blood; the blood cells are red blood cells, white blood cells and platelets. The most abundant cells in vertebrate blood are red blood cells; these contain hemoglobin, an iron-containing protein, which facilitates oxygen transport by reversibly binding to this respiratory gas and increasing its solubility in blood. In contrast, carbon dioxide is transported extracellularly as bicarbonate ion transported in plasma. Vertebrate blood is bright red when its hemoglobin is oxygenated and dark red when it is deoxygenated.
Some animals, such as crustaceans and mollusks, use hemocyanin to carry oxygen, instead of hemoglobin. Insects and some mollusks use a fluid called hemolymph instead of blood, the difference being that hemolymph is not contained in a closed circulatory system. In most insects, this "blood" does not contain oxygen-carrying molecules such as hemoglobin because their bodies are small enough for their tracheal system to suffice for supplying oxygen. Jawed vertebrates have an adaptive immune system, based on white blood cells. White blood cells help to resist parasites. Platelets are important in the clotting of blood. Arthropods, using hemolymph, have hemocytes as part of their immune system. Blood is circulated around the body through blood vessels by the pumping action of the heart. In animals with lungs, arterial blood carries oxygen from inhaled air to the tissues of the body, venous blood carries carbon dioxide, a waste product of metabolism produced by cells, from the tissues to the lungs to be exhaled.
Medical terms related to blood begin with hemo- or hemato- from the Greek word αἷμα for "blood". In terms of anatomy and histology, blood is considered a specialized form of connective tissue, given its origin in the bones and the presence of potential molecular fibers in the form of fibrinogen. Blood performs many important functions within the body, including: Supply of oxygen to tissues Supply of nutrients such as glucose, amino acids, fatty acids Removal of waste such as carbon dioxide and lactic acid Immunological functions, including circulation of white blood cells, detection of foreign material by antibodies Coagulation, the response to a broken blood vessel, the conversion of blood from a liquid to a semisolid gel to stop bleeding Messenger functions, including the transport of hormones and the signaling of tissue damage Regulation of core body temperature Hydraulic functions Blood accounts for 7% of the human body weight, with an average density around 1060 kg/m3 close to pure water's density of 1000 kg/m3.
The average adult has a blood volume of 5 litres, composed of plasma and several kinds of cells. These blood cells consist of erythrocytes and thrombocytes. By volume, the red blood cells constitute about 45% of whole blood, the plasma about 54.3%, white cells about 0.7%. Whole blood exhibits non-Newtonian fluid dynamics. If all human hemoglobin were free in the plasma rather than being contained in RBCs, the circulatory fluid would be too viscous for the cardiovascular system to function effectively. One microliter of blood contains: 4.7 to 6.1 million, 4.2 to 5.4 million erythrocytes: Red blood cells contain the blood's hemoglobin and distribute oxygen. Mature red blood cells lack a nucleus and organelles in mammals; the red blood cells are marked by glycoproteins that define the different blood types. The proportion of blood occupied by red blood cells is referred to as the hematocrit, is about 45%; the combined surface area of all red blood cells of the human body would be 2,000 times as great as the body's exterior surface.
4,000–11,000 leukocytes: White blood cells are part of the body's immune system. The cancer of leukocytes is called leukemia. 200,000 -- 500,000 thrombocytes: Also called platelets. Fibrin from the coagulation cascade creates a mesh over the platelet plug. About 55% of blood is blood plasma, a fluid, the blood's liquid medium, which by itself is straw-yellow in color; the blood plasma volume totals of 2.7–3.0 liters in an average human. It is an aqueous solution containing 92% water, 8% blood plasma proteins, trace amounts of other materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, fatty acids, removes waste products, such as carbon dioxide and lactic acid. Other important components include: Serum albumin Blood-clotting factors Immunoglobulins lipoprotein particles Various
Anatomical terms of microanatomy
Anatomical terminology is used to describe microanatomical structures. This helps describe the structure and position of an object, minimises ambiguity. An internationally accepted lexicon is Terminologia Histologica. Epithelial cells line body surfaces, are described according to their shape, with three principal shapes: squamous and cuboidal. Squamous epithelium has cells. Cuboidal epithelium has cells whose height and width are the same. Columnar epithelium has cells taller. Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall, it is a thin layer of single-layered, squamous cells called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells. Epithelium can be arranged in a single layer of cells described as "simple", or more than one layer, described as "stratified".
By layer, epithelium is classed as either simple epithelium, only one cell thick or stratified epithelium as stratified squamous epithelium, stratified cuboidal epithelium, stratified columnar epithelium that are two or more cells thick, both types of layering can be made up of any of the cell shapes. However, when taller simple columnar epithelial cells are viewed in cross section showing several nuclei appearing at different heights, they can be confused with stratified epithelia; this kind of epithelium is therefore described as pseudostratified columnar epithelium. Transitional epithelium has cells that can change from squamous to cuboidal, depending on the amount of tension on the epithelium. A mucous membrane or mucosa is a membrane that lines various cavities in the body and covers the surface of internal organs, it consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is of endodermal origin and is continuous with the skin at various body openings such as the eyes, inside the nose, inside the mouth, the urethral opening and the anus.
Some mucous membranes a thick protective fluid. The function of the membrane is to stop pathogens and dirt from entering the body and to prevent bodily tissues from becoming dehydrated; the submucosa consists of a dense and irregular layer of connective tissue with blood vessels and nerves branching into the mucosa and muscular layer. It contains the submucous plexus, enteric nervous plexus, situated on the inner surface of the muscular layer; the muscular layer consists of two layers of the inner and outer layer. The muscle of the inner layer is arranged in circular rings around the tract, whereas the muscle of the outer layer is arranged longitudinally; the stomach has an inner oblique muscular layer. Between the two muscle layers are the myenteric or Auerbach's plexus; this controls peristalsis. Activity is initiated by the pacemaker cells; the gut has intrinsic peristaltic activity due to its self-contained enteric nervous system. The rate can of course be modulated by the rest of the autonomic nervous system.
The layers are not longitudinal or circular, rather the layers of muscle are helical with different pitches. The inner circular is helical with a steep pitch and the outer longitudinal is helical with a much shallower pitch. Serosa / Adventitia -- these last two tissue types differ in form and function according to the part of the gastrointestinal tract they belong to; the hollow inner part of a body organ or tube is called the lumen. The side of a cell facing the lumen is called the apical surface.
Monocytes are a type of leukocyte, or white blood cell. They are the largest type of leukocyte and can differentiate into macrophages and myeloid lineage dendritic cells; as a part of the vertebrate innate immune system monocytes influence the process of adaptive immunity. There are at least three subclasses of monocytes in human blood based on their phenotypic receptors. Monocytes are amoeboid in appearance, have a granulated cytoplasm. Containing unilobar nuclei, these cells are one of the types of mononuclear leukocytes which shelter azurophil granules; the archetypal geometry of the monocyte nucleus is ellipsoidal. Contrast to this classification occurs in polymorphonuclear leukocytes. Monocytes compose 2% to 10% of all leukocytes in the human body and serve multiple roles in immune function; such roles include: replenishing resident macrophages under normal conditions. In an adult human, half of the monocytes are stored in the spleen; these change into macrophages after entering into appropriate tissue spaces, can transform into foam cells in endothelium.
There are at least three types of monocytes in human blood: The classical monocyte is characterized by high level expression of the CD14 cell surface receptor The non-classical monocyte shows low level expression of CD14 and additional co-expression of the CD16 receptor. The intermediate monocyte with high level expression of CD14 and low level expression of CD16. While in humans the level of CD14 expression can be used to differentiate non-classical and intermediate monocytes, the slan cell surface marker was shown to give an unequivocal separation of the two cell types. Ghattas et al. state that the "intermediate" monocyte population is to be a unique subpopulation of monocytes, as opposed to a developmental step, due to their comparatively high expression of surface receptors involved in reparative processes as well as evidence that the "intermediate" subset is enriched in the bone marrow. After stimulation with microbial products the CD14+CD16++ monocytes produce high amounts of pro-inflammatory cytokines like tumor necrosis factor and interleukin-12.
Said et al. showed that activated monocytes express high levels of PD-1 which might explain the higher expression of PD-1 in CD14+CD16++ monocytes as compared to CD14++CD16- monocytes. Triggering monocytes-expressed PD-1 by its ligand PD-L1 induces IL-10 production which activates CD4 Th2 cells and inhibits CD4 Th1 cell function. In mice, monocytes can be divided in two subpopulations. Inflammatory monocytes, which are equivalent to human classical CD14++ CD16− monocytes and resident monocytes, which are equivalent to human non-classical CD14low CD16+ monocytes. Resident monocytes have the ability to patrol along the endothelium wall in the steady state and under inflammatory conditions. In man a monocyte crawling behavior, similar to the patrolling in mice, has been demonstrated both for the classical and the non-classical monocytes. Monocytes are produced by the bone marrow from precursors called monoblasts, bipotent cells that differentiated from hematopoietic stem cells. Monocytes circulate in the bloodstream for about one to three days and typically move into tissues throughout the body where they differentiate into macrophages and dendritic cells.
They constitute between eight percent of the leukocytes in the blood. About half of the body's monocytes are stored as a reserve in the spleen in clusters in the red pulp's Cords of Billroth. Moreover, monocytes are the largest corpuscle in blood. Monocytes which migrate from the bloodstream to other tissues will differentiate into tissue resident macrophages or dendritic cells. Macrophages are responsible for protecting tissues from foreign substances, but are suspected to be important in the formation of important organs like the heart and brain, they are cells that possess a large smooth nucleus, a large area of cytoplasm, many internal vesicles for processing foreign material. In vitro, monocytes can differentiate into dendritic cells by adding the cytokines granulocyte macrophage colony-stimulating factor and interleukin 4. Monocytes and their macrophage and dendritic-cell progeny serve three main functions in the immune system; these are phagocytosis, antigen presentation, cytokine production.
Phagocytosis is the process of uptake of microbes and particles followed by digestion and destruction of this material. Monocytes can perform phagocytosis using intermediary proteins such as antibodies or complement that coat the pathogen, as well as by binding to the microbe directly via pattern-recognition receptors that recognize pathogens. Monocytes are capable of killing infected host cells via antibody-dependent cell-mediated cytotoxicity. Vacuolization may be present in a cell that has phagocytized foreign matter. Many factors produced by other cells can regulate other functions of monocytes; these factors include most chemokines such as monocyte chemotactic protein-1 and monocyte chemotactic protein-3.
A band cell is a cell undergoing granulopoiesis, derived from a metamyelocyte, leading to a mature granulocyte. It is characterized by having a curved but not lobular nucleus; the term "band cell" implies a granulocytic lineage. Band neutrophils are an intermediary step prior to the complete maturation of segmented neutrophils. An increase in band neutrophils means that the bone marrow has been signaled to release more WBCs and increase production of WBCs known as a "left shift". Most this is due to infection or inflammation in the body. Blood reference ranges for neutrophilic band cells in adults are 3 to 5% of white blood cells, or up to 0.7 x109/L. An excess may sometimes be referred to as bandemia. Pluripotential hemopoietic stem cell Histology image: 01807loa – Histology Learning System at Boston University - "Bone Marrow and Hemopoiesis: bone marrow smear, neutrophil series" Histology at KUMC blood-blood11 Histology image: 75_07 at the University of Oklahoma Health Sciences Center Histology at okstate.edu Slide at hematologyatlas.com - "Neutrophil band" visible in second row Interactive diagram at lycos.es
Granulocyte-macrophage colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor known as colony-stimulating factor 2, is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of occurring GM-CSF are called sargramostim and molgramostim. Unlike granulocyte colony-stimulating factor, which promotes neutrophil proliferation and maturation, GM-CSF affects more cell types macrophages and eosinophils. GM-CSF is a monomeric glycoprotein that functions as a cytokine — it is a white blood cell growth factor. GM-CSF stimulates stem cells to produce monocytes. Monocytes exit the circulation and migrate into tissue, whereupon they mature into macrophages and dendritic cells. Thus, it is part of the immune/inflammatory cascade, by which activation of a small number of macrophages can lead to an increase in their numbers, a process crucial for fighting infection. GM-CSF has some effects on mature cells of the immune system.
These include, for example, inhibiting neutrophil migration and causing an alteration of the receptors expressed on the cells surface. GM-CSF signals via signal transducer and activator of transcription, STAT5. In macrophages, it has been shown to signal via STAT3; the cytokine activates macrophages to inhibit fungal survival. It induces deprivation in intracellular free zinc and increases production of reactive oxygen species that culminate in fungal zinc starvation and toxicity. Thus, GM-CSF promotes defense against infections. GM-CSF plays a role in embryonic development by functioning as an embryokine produced by reproductive tract; the human gene has been localized in close proximity to the interleukin 3 gene within a T helper type 2-associated cytokine gene cluster at chromosome region 5q31, known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. GM-CSF and IL-3 are separated by an insulator element and thus independently regulated. Other genes in the cluster include those encoding interleukins 4, 5, 13.
Human granulocyte-macrophage colony-stimulating factor is glycosylated in its mature form. GM-CSF was first cloned in 1985, soon afterwards three potential drug products were being made using recombinant DNA technology: molgramostim was made in Escherichia coli and is not glycosylated, sargramostim was made in yeast, has a leucine instead of proline at position 23 and is somewhat glyocylated, regramostim was made in Chinese hamster ovary cells and has more glycosylation than sargramostim; the amount of glycosylation affects how the body interacts with the drug and how the drug interacts with the body. At that time, Genetics Institute, Inc. was working on molgramostim, Immunex was working on sargramostim, Sandoz was working on regramostim. Molgramostim was co-developed and co-marketed by Novartis and Schering-Plough under the trade name Leucomax for use in helping white blood cell levels recover following chemotherapy, in 2002 Novartis sold its rights to Schering-Plough. Sargramostim was approved by the US FDA in 1991 to accelerate white blood cell recovery following autologous bone marrow transplantation under the trade name Leukine, passed through several hands, ending up with Genzyme which subsequently was acquired by Sanofi.
Leukine is now owned by Partner Therapeutics. GM-CSF is found in high levels in joints with rheumatoid arthritis and blocking GM-CSF as a biological target may reduce the inflammation or damage; some drugs are being developed to block GM-CSF. In critically ill patients GM-CSF has been trialled as a therapy for the immunosuppression of critical illness, has shown promise restoring monocyte and neutrophil function, although the impact on patient outcomes is unclear and awaits larger studies. CFU-GM Granulocyte-macrophage colony-stimulating factor receptor Filgrastim Pegfilgrastim Official gentaur web site Official Leukine web site Granulocyte-Macrophage+Colony-Stimulating+Factor at the US National Library of Medicine Medical Subject Headings