Cells Cells Cells!

The immune system is the host defense system against foreign pathogens. It is an extremely adept system comprised of the innate immune system and the adaptive immune system, as well as complement. For more information on those two systems as a whole, review part one of the immune system.

This part of the immune system overview will focus on the leukocytes or granulocytes of the innate immune system.

The most abundant leukocyte is the neutrophil. It comprises about 40-70% of the white cells an individual has. The maturation of the neutrophil is myeloblast, promyelocyte, myelocyte, metamyelocyte, band neutrophil, segmented neutrophil. The cytokine responsible for stimulating neutrophil production in the bone marrow is G-CSF (granulocyte colony stimulating factor). There are three pools in the bone marrow, the stem cell pool, consisting of HSCs, the proliferative pool, full of mitotic cells, and the maturation (storage) pool. Full of metamyelocytes, bands, and PMNs. During the proliferative pool stage GM-CSF, G-CSF and IL-3 are all used as growth factors to help the neutrophil differentiate and mature. Granulocyte release from the bone marrow is stimulated by G-CSF. Once in circulation neutrophils are divided randomly into either a circulating pool and a marginated pool. The neutrophils in the marginated pool are loosely localized to the walls of capillaries in tissues. Neutrophils can move freely between the two pools. Integrins and selectins are important as they allow neutrophils to marginate and allow them to move into the tissues by using diapedesis. Diapedesis is the extravasation of blood cells through intact vessel walls.

In response to inflammatory mediators and chemoattractants the neutrophil is activated and it results in reorganization of the actin cytoskeleton, membrane ruffling, adhesion and motility. In basic terms, when an infection is ongoing, the surrounding cells and tissue release cytokines and inflammatory mediators that attract neutrophils specifically to come to the site and help control the infection. Chemotaxis is the term for this. The neutrophil attaches to the substratum (endothelial surface) which allows extensions of pseudopods to attach through integrins. Contraction allows the cell body to be pulled forward (still attached). Release of the neutrophil at the back allows the cell to move forward.

Once the neutrophil has reached the site of infection it aids in fighting the infection or pathogen by phagocytosis. Phagocytosis occurs when a neutrophil surface receptor recognizes an antigen either through direct recognition, or to recognize an opsonized antigen. An opsonized antigen remember is when particular cellular processes, such as complement, present pathogenic antigens to these neutrophils to aid in phagocytosis so the neutrophil doesn’t have to search for the pathogen. With recognition comes attachment and engulfment. Cytoplasmic pseudopodia surround the particle forming a phagosome within the neutrophil cytoplasm. The formation of the phagosome allows the NADPH oxidase complex to form which leads to the generation of reactive oxygen species (ROS) such as hydrogen peroxide which is converted to hypochlorite by myeloperoxidase. (O2 dependent). A series of metabolic changes can occur like the changing of the pH and that allows primary or secondary granules within the neutrophil to release numerous bactericidal molecules into the phagosome. (O2-Independent). Bactericidal molecules aid in the killing of foreign pathogens. There is a third mechanism to which neutrophils are able to fight off foreign invader and its by using NETS. Neutrophils can generate an extracellular net that consists of chains of nucleosomes from unfolded nuclear chromatin. These structures have enzymes from neutrophil granules and can trap and kill some gram positive and gram negative bacteria, and fungi. NETs are generated at the time neutrophils die.

Monocyte development is similar to that of neutrophilic maturation because they are both derived from the granulocyte monocyte progenitor. M-CSF (macrophage colony stimulating factor) is the major cytokine responsible for the growth and differentiation of monocytes. Once in the tissue, monocytes differentiate into macrophages, depending on the tissue that the monocytes migrate too, for example, in the lymph nodes they differentiate into dendritic cells, and in the liver, they differentiate into Kupffer cells.

Eosinophils make up 1-3% of the cells in the bone marrow. Eosinophil granules are full of synthesized proteins, cytokines, chemokines, growth factors and cationic proteins. Degranulation can occur in multiple ways; by classic exocytosis, granules move to and fuse with the plasma membrane and the granules secrete into the ECS (Extracellular Space). By compound exocytosis, the granules fuse in the cytoplasm before moving to the plasma membrane. Piecemeal degranulation is when vesicles remove specific proteins from the secondary granules and then migrate to the plasma membrane and then emptying into the ECS. Eosinophils play a role in immune regulation. Eosinophils secrete major basic protein (MBP) which is the cause of mast cell degranulation and cytokine production. Eosinophils are implicated in both type 1 and type 2 immune response, primarily being infectious diseases. Eosinophils are primarily implicated in parasitic infections and are the hallmark characteristic of helminth infections. They help drive antibody production and suppress phagocytosis by secreting arylsufatase which inactivated leukotrienes and secrete antihistamine which counteracts the action of mast cells and basophils.

Basophils and Mast cells are usually grouped together, although basophils are a true WBC because they mature in the bone marrow and circulate in the blood with granules. Mast cell precursors leave the bone marrow and migrate to a tissue where they mature. Basophils and mast cells have membrane bound IgE on their surface. When activated by an antigen causes degranulation (histamine and heparin, which leads to an inflammation causing vasodilation and edema. They also secrete cytokines that activate B and T cells. Basophils are capable of releasing large quantities of subtype 2 helper T cell cytokines such as IL-4, and IL-13 that regulate the TH2 immune response. Mast cells function in chronic allergic reactions, Basophils are the initiators of allergic inflammation through the release of preformed cytokines. Basophils can play a rule in angiogenesis through the release of VEGF and its receptors.

To recap everything that has been learned with this article; neutrophils are the most abundant leukocyte encountered and play a huge role in the innate immune system. They are often the first to a site of infection or inflammation and use multiple mechanics of phagocytosis to control the situation. Monocytes circulate and settle into a tissue where they become resident macrophages. Macrophages also phagocytize foreign antigens when it comes into contact with the tissue they reside in. Eosinophils are active in infections, particularly of parasitic origin. Eosinophilia is a common finding in helminth infections. Basophils and mast cells work in conjunction with IgE to mediate hypersensitivity allergic reactions. They are the ones to thank for making your nose run.


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