Cellular Defenses
In a healthy individual, immune cells patrol blood vessels to detect and respond to danger through molecules frequently found on pathogens called PAMPs, and molecules that are released by damaged cells, DAMPs. [1] [2] Immune cells involved in intravascular surveillance are neutrophils, monocytes, invariant natural killer T cells, kupffer cells, platelets, and mast cells. [1] [2] These cells express particular receptors such as toll-like receptors and proteins like CD36 that allow them to recognize and respond to danger signals. [2] Endothelial cells lining the vasculature are also a part of the intravasculature's cellular defense system. They express molecules such as, CD14, TLR2, TLR4, TLR9, MD2, and MyD88, to detect bacteria in the blood. [2]
These molecules can be referred to as small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast array of different types of molecules can serve as PAMPs, including glycans and glycoconjugates.
Damage-associated molecular patterns (DAMPs), also known as danger-associated molecular patterns, danger signals, and alarmin, are host biomolecules that can initiate and perpetuate a noninfectious inflammatory response. In contrast, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response. DAMPs may be nuclear or cytosolic proteins, which when released from the cell or exposed on its surface – following tissue injury – move from a reducing to an oxidizing environment, resulting in their denaturation. Following necrosis, tumor cell DNA is released, with the potential to be recognised as a DAMP.
Neutrophils are the most abundant type of granulocytes and the most abundant type of white blood cells in most mammals. They form an essential part of the innate immune system. Their functions vary in different animals.
Leukocytes move through blood vessels using protein-protein interactions between cells and are also assisted by blood flow. [2] Circulating immune cells behave differently in the presence and absence of an infection. For example, in the absence of an invader, monocytes migrate randomly throughout the microvasculature, cerebral vessels, and mesentery vessels. However, in the presence of an invader, monocytes emigrate to the infected area. [2] Similarly, neutrophils use a rolling mechanism to counteract the blood flow and localize to the infected area. [4] [2] In a healthy state, neutrophils have been observed to exhibit a similar but brief crawling mechanism. The function and precise mechanism is not yet known. [2]
Hemodynamics or hæmodynamics is the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms, such as hydraulic circuits are controlled by control systems. Hemodynamic response continuously monitors and adjusts to conditions in the body and its environment. Thus hemodynamics explains the physical laws that govern the flow of blood in the blood vessels.
Leukocyte extravasation, less commonly called diapedesis, is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.
A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to prevent bleeding, but can be harmful in thrombosis, when clots obstruct blood flow through healthy blood vessels.
Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.
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 also influence the process of adaptive immunity. There are at least three subclasses of monocytes in human blood based on their phenotypic receptors.
Microangiopathic hemolytic anemia (MAHA) is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels. It is identified by the finding of anemia and schistocytes on microscopy of the blood film.
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel. It is the first stage of wound healing. This involves coagulation, blood changing from a liquid to a gel. Intact blood vessels are central to moderating blood's tendency to form clots. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with nitric oxide and prostacyclin. When endothelial injury occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor which initiate the maintenance of hemostasis after injury. Hemostasis has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a fibrin clot. These processes seal the hole until tissues are repaired.
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes or polymorphonuclear neutrophils because of the varying shapes of the nucleus, which is usually lobed into three segments. This distinguishes them from the mononuclear agranulocytes. In common parlance, the term polymorphonuclear leukocyte often refers specifically to "neutrophil granulocytes", the most abundant of the granulocytes; the other types have lower numbers. Granulocytes are produced via granulopoiesis in the bone marrow.
Acute-phase proteins (APPs) are a class of proteins whose plasma concentrations increase or decrease in response to inflammation. This response is called the acute-phase reaction. For acute-phase reaction is characteristic fever, acceleration of peripherals leukocytes, circulating neutrophils and their precursors. The terms acute-phase protein and acute-phase reactant (APR) are often used synonymously, although some APRs are polypeptides rather than proteins.
A schistocyte or schizocyte is a fragmented part of a red blood cell. Schistocytes are typically irregularly shaped, jagged, and have two pointed ends.
Leukocyte adhesion deficiency (LAD), is a rare autosomal recessive disorder characterized by immunodeficiency resulting in recurrent infections. LAD is currently divided into three subtypes: LAD1, LAD2, and the recently described LAD3, also known as LAD-1/variant. In LAD3, the immune defects are supplemented by a Glanzmann thrombasthenia-like bleeding tendency.
The innate immune system is one of the two main immunity strategies found in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and it is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.
Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first-line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs. NETs allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells. Upon in vitro activation with the pharmacological agent phorbol myristate acetate (PMA), Interleukin 8 (IL-8) or lipopolysaccharide (LPS), neutrophils release granule proteins and chromatin to form an extracellular fibril matrix known as NETs through an active process.
The platelet plug, also known as the hemostatic plug or platelet thrombus, is an aggregation of platelets formed during the earlier stage of hemostasis in response to blood vessel wall injury. After platelets are recruited and begin to accumulate around the breakage, their “sticky” nature allows them to adhere to each other. This forms a platelet plug, which prevents more blood from leaving the body as well as any outside contaminants from getting in. The plug provides a temporary blockage of the break in the vasculature. As such, platelet plug formation occurs after vasoconstriction of the blood vessels but before the creation of the fibrin mesh clot, which is the more permanent solution to the injury. The result of the platelet plug formation is the coagulation of blood. It can also be referred to as primary hemostasis.
