The functions and activities of the macrophage

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First and foremost, all humans have a relatively complex and versatile defence system used to protect them from disease-causing microorganisms. Since there's no finite amount of these pathogens in our surroundings, it is imperative to have a dynamic immune system to identify and destroy them. Due to the fact there are so many pathogenic species in the bacteria kingdom alone, this means that they all have genetic variation and thus have different protein structures on a molecular level. In order to kill them, the immune system generates many types of cells that can distinguish between these foreign microorganisms from each other and also from our own cells. These are: lymphocytes, monocytes, mast cells, erythrocytes, megakaryocytes and granulocytes (Goldsby et al., 2003).

Many people argue that macrophages, classed as mononuclear phagocytes (monocytes), are the most important cells in the immune system. This is because of the roles they have mainly in innate immunity which is to ingest, kill and digest pathogenic microorganisms. They are also used in acquired immunity.

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Macrophages are simply mature monocytes found in tissues. Like all blood cells, they arise from self-renewing hematopoietic stem cells in the bone marrow (Goldsby et al., 2003). Some of these develop into myeloid progenitors, which first differentiate into granulocyte-monocyte progenitors, then promonocytes. After entering the bloodstream, they enlarge, become mature and can finally settle into their specific tissues as mature macrophages where they constitute the mononuclear phagocyte system (Delves et al., 2006). After settling, they become 'resident' macrophages and need activating by various stimuli to function at their maximum potential during an immune response. Many of them are macrophage activating factors like interferon gamma (IFNÆ´), GM-CSF, TNF and lymphotoxins secreted by activated Th1 cells (Delves et al., 2006). Phagocytising specific antigens activate macrophages in its own right.

The functions of activated macrophages are what make them arguably the most important cells in the immune system. Along with neutrophils, they provide the major line of defence against pathogens, should they pass the anatomic and physiological barriers. They are more useful than resting macrophages because they have a better ability to ingest, kill, secrete inflammatory mediators, and activate T cells. They can also perform better as antigen-presenting cells because they express lots of class II MHC molecules (Goldsby et al., 2003). Although their mode of action is non-specific, they can target a wide range of potential pathogens such as tumour cells, intracellular bacteria and virus-infected cells because they are able to secrete cytotoxic proteins after phagocytosis; which destroys their chemical structure and hinder them useless. For example, IFNÆ´, TNF and lymphotoxins all induce 2'-5' (A) synthetase, a protein which is needed for a virus's protection. This will indirectly block the virus from gaining access to the cells replicative machinery (Delves et al., 2006). These mechanisms are either classed as oxygen-dependant or oxygen-independent.

In oxygen-dependant killing mechanisms, many reactive oxygen and nitrogen intermediates are produced by activated macrophages which are lethal to ingested microorganisms. Many of these molecules are formed as a result of the respiratory burst process. Free radicals, such as superoxide anions get converted into compounds that can be found in household bleach like hypochlorite and hydrogen peroxide. Other free radicals are also made which react with almost anything. They are all extremely effective antimicrobial agents. Recent studies have shown that it is in fact nitric oxide and its derivatives; nitrogen dioxide and nitrous acid, which are the best at eliminating bacteria, fungi, parasitic worms and protozoa (Goldsby et al., 2003). Nitric oxide can be produced by a relatively straight forward process of using nitric oxide synthetase to convert L-arginine, an amino acid in abundance in the cytoplasm, to L-citrulline. One of the by-products is nitric oxide. The reason why it is so effective in my opinion is because of the fact the nitric oxide is in a gas form. This allows easy entry through a microorganism's cell membrane via protein channels because the molecules are more segregated and thus smaller.

Oxygen-independent killing mechanisms use enzymes, cytokines and other compounds secreted by activated macrophages to stop microbial activity, without the use of oxygen. A common group of molecules that are secreted are defensins, which create ion-permeable channels in bacterial cell membranes (Goldsby et al., 2003). This allows antimicrobial agents to enter. They can eliminate lots of bacteria such as Escherichia coli and Streptococcus pnumoniae. In innate immunity, one of the last lines of defence is the inflammatory barrier and so an inflammatory response usually occurs. This includes seepage of vascular fluid and an influx of phagocytic cells into the specific area. Activated macrophages can secrete factors such as TNF-α, IL-1, IL-6, and complement proteins, which promote inflammatory responses (Goldsby et al., 2003). These factors among many others have lots of different functions that are all beneficial in the elimination of pathogens. For example, GM-CSF promotes the rate of haematopoiesis so that more phagocytic cells are produced.

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http://lpi.oregonstate.edu/infocenter/macrophage.jpg

(Linus Pauling Institute, 2010)

The structure of macrophages are specialised for their function, which is to initiate phagocytosis. From the diagram, it shows that they have many internal systems. All microorganisms have pathogen-associated molecular patterns (Linus Pauling Institute, 2010), which are detected by the macrophages receptors. Opsonins, like for example antibodies, help bind the antigen more tightly to these receptors. The cell membrane is flexible which allows it to engulf microorganisms and ingest them into a phagosome. This is then combined with lysosomes to form a phagolysosome, the bacteria is then broken down by an enzyme and antimicrobial agents. Lastly, the dead matter is exocytosed. Macrophages cytoplasms are full of different substances such as enzymes, lysosomes, Golgi apparatus, phagosomes, SER, RER. All these work seamlessly together to carry out the function of phagocytosis and/or the synthesis and secretion of pro-inflammatory cytokines.

Cytokines help gather and activate lymphocytes, which begins to start the slow acquired immunity response. Therefore it is macrophages which trigger the acquired immunity response. This implies that both innate and acquired immunity are not independent of each other, and it is macrophages (and dendrites) that connect the two together. Acquired immunity is concerned with immunological memory, so that if a host body were to experience a foreign molecule encountered previously, the initial response will be enhanced. The main components are the B and T-cells; lymphocytes that can recognise and inactivate foreign molecules (Campbell et al., 2008). During an immune response, foreign antigens become detected by specific B and T- cells. Macrophages play an important role as antigen presenting cells. This is because there may be a very limited amount of T-cells and B-cells that are complementary to the antigen, and therefore would require a lot of time to identify them. Every time a macrophage eliminates one of these foreign microorganisms, its antigen fragments are pushed to the surface of the macrophage, where they are displayed with the help of Class II MHC molecules. Thus more copies of the antigen are exposed. This helps decrease time delays so that the immune response can initiate quicker. To summarise the immune response, once an antigen has been identified by the T-cells, these lymphocytes divide mitotically so that there's a clonal expansion. T-cells differentiate into T-helper cells, T-killer cells, or T-memory cells. On the other hand B-lymphocytes differentiate into either plasma cells or B memory cells. All these cells are very specific to the antigen and generally speaking, they create antibodies, stimulate phagocytosis by releasing cytokines, and act as the immunological memory so that the immune response is faster if encountered with the epitope again. The point is, these processes are what gives organisms acquired immunity and it is essential they occur otherwise organisms will more likely to be infected with potentially pathogenic microorganisms. Macrophages play an important role in allowing acquired immunity to occur in the first place.

Nonetheless, other people will argue that there are more important cells than macrophages in the immune system such as T-cells and B-cells. This is because macrophages are not specific and so many foreign microorganisms can infect host cells and it is only after there's an immune response by the B and T-cells where the pathogens can be killed. However, if for example macrophages did not exist, then there would be no cytokines secreted from them activating the lymphocytes of a foreign invasion. They would have to rely on other cells such as neutrophils. Also, there would be no antigen-presenting macrophages, so there may be a longer delay of the immune response. By this time, the pathogens may have already infected all host cells. Even though macrophages are not as specific when compared to for example T-cells, they are still able to destroy the majority of foreign microorganisms. Therefore from my point of view, although all cells of the immune system are essential, the most important ones are the macrophages.

However, looking at it from a different angle completely, the most important cell of the immune system would be the hematopoietic stem cell, where all white blood cells are derived from.