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Home , Agranulocyte, Leukopoiesis, Pyknosis, White blood cell

Chapter 9 , Lymph, and 231

WHITE BLOOD CELLS All white blood cells develop in the marrow except Any nucleated normally found in blood is a white blood for some (they start out in but cell. White blood cells are also known as WBCs or leukocytes. develop elsewhere). At the beginning of all the When white blood cells accumulate in one place, they grossly immature white blood cells look alike even though they're appear white or cream-colored. For example, is an accu- already committed to a specific cell line. It's not until the mulation of white blood cells. Mature white blood cells are cells start developing some of their unique characteristics larger than mature red blood cells. that we can tell them apart. There are five types of white blood cells. They are neu- Function trophils, , , and lymphocytes (Table 9-2). The function of all white blood cells is to provide a defense White blood cells can be classified in three different ways: for the body against foreign invaders. Each type of white 1. Type of defense function has its own unique role in this defense. If all the • : , eosinophils, basophils, mono- white blood cells are functioning properly, an animal has a cytes good chance of remaining healthy. Individual white blood • production and cellular immunity: lympho- cell functions will be discussed with each cell type (see cytes Table 9-2). 2. Shape of nucleus In providing defense against foreign invaders, the white • Polymorphonuclear (multilobed, segmented nucleus): blood cells do their jobs primarily out in the tissues. The neutrophils, eosinophils, basophils (Figure 9-4) white blood cells use the peripheral blood to travel from • Mononuclear (single, rounded nucleus): lymphocytes their site of production (bone marrow) to their site of activ- • Pleomorphic (varying shapes, nonsegmented nucleus): ity (tissue). There is a constant flow of white blood cells out monocytes of marrow and into tissues in an attempt to control the mil- 3. Presence or absence of specific staining cytoplasmic lions of foreign invaders that attack a body every day. It's granules happening in us too. And as long as they do their job, we (presence of granules): neutrophils, don't even realize what's going on and we remain healthy. eosinophils, basophils • Agranuloctyes (absence of granules): lymphocytes, monocytes

Formation The general term for the formation of white blood cells is ~ TEST YOURSELF . leukopoiesis. All production starts out in the red bone marrow from the same pluripotent stem cell 1. List the five white blood cells and indicate if each one is (PPSC) population that produced red blood cells and mega- a or an . karyocytes. It is the stimuli that act upon the PPSCs that 2. What is the common function of all white blood cells? determine which cell type will be produced. Each type of 3. Which cell is the only white blood cell not capable of phagocytosis? white blood cell has its own stimulus for production.

TABLE 9-2 White Blood Cells

Name Cytoplasmic Granules Nuclear Shape Function Site of Action

Neutrophil Don't stain (usually Polymorphonuclear Phagocytosis Body tissues invisible) Stain red Polymorphonuclear Allergic reactions, , Body tissues phagocytosis Stain blue Polymorphonuclear Initiation of immune and allergic Body tissues reactions None Pleomorphic Phagocytosis and process Body tissues or blood () None Mononuclear Antibody production and Lymphoid tissue () None Mononuclear production and Lymphoid tissue and (lymphocyte) cell-mediated immunity other body tissues 232 Chapter 9 Blood, Lymph, and Immunity

Nucleus

:•~"':'r:;;-;':' • •...' ::::.::::..~ • • ..'..:::~~.~. ~' •••..~.. ~:o.::::' ~. -, ~:'::..":'~ :::". ;"::'@-:':':'. ;..··tI:: ~.:.. ;..... ' "1': .:"• :" Vi l?o0.,'. • • ::.~".: • : •• ' .'.:' • : " :. .: " ,,\\. " " .' ...... :W ." . '...., ~ " ~" .. ", : ...... : 0.. : " .. ",," ..: 0:: ...... : 0,,":" :""

Figure 9-4 Normal neutrophils showing polymorphonuclear characteristics.

he total white blood cell count and differential count are differential count, commonly referred to as "the diff." Because Tused to evaluate a patient for the diagnosis or prognosis you're counting 100 cells,the number of each celltype you see of an abnormal condition. For example,. if an is' can be expressed as a percentage. For example, if you count present in the body, there will be an increased need for neu- 100 cells and find that 20 of the cells are neutrophils and 80 trophils to killthe invading microorganisms. The bone marrow of the cells are lymphocytes, you would report you saw 20% responds to this need by releasing more neutrophils into the neutrophils and 80% lymphocytes. bloodstream that willtravel to the infected tissue. There are automated hematology analyzers that will The increased number of neutrophils in the blood will provide these numbers, but they won't pick up all cellular increase the total white blood cell count. The total white blood abnormalities. For this reason, you should always look at a cell count is equal to the sum of each of the individual white stained blood smear even if you're using an automated ana- blood cell counts. If one cell type increases or decreases, the lyzer. You don't have to complete a differential count; just total white blood cell count will increase or decrease accord- look for physical abnormalities. ingly. Sounds simple, doesn't it? Unfortunately, it's not always For every species of common domestic animal, there is a that simple. If one cell type increases and another cell type value range that represents a normal white blood cell count. decreases, the net effect could be a normal total white blood There is also a normal range for individual white blood cell cell count. That's the tricky part, so the total white blood cell types. For example, a dog willnormally have between 6 billion count is only one of a series of tests performed to evaluate and 17 billion white blood cells per liter of blood, and 60% the white blood cells. to 70% of these cells should be neutrophils. Cattle will have To find out which white blood cells are affecting the total between 4 billion and 12 billion white blood cells per liter and white blood cell count, we have to look at a stained smear of only 15% to 45% of the cells should be neutrophils. the blood. The usual method for evaluating the blood smear Taken together, the total white blood cell count and the is to count the first 100 white blood cells and keep track of the differential count can provide a lot of information about an number of each white blood cell type you see. This is called a animal's state of health.

Granulocytes II CLINICAL APPLICATION The granulocytes are the neutrophils, eosinophils, and baso- phils. They are named for the color of the granules in their :/.ld.r~~h!J!i!~~ti~2·;Z~'.!~;~.~i&z1~;i"~l0C~~;t~,.::.;;]cytoplasm when viewed on a stained blood smear (see an earlier discussion of stains in this chapter). Eosinophil gran- he word means "white blood." It is caused by ules pick up the acidic stain and appear red, basophil gran- Tan abnormal proliferation of one of the white blood cell ules pick up the basic stain and appear blue, and neutrophils types. In response to some unknown stimulus, the stem cells don't pick up either stain very well, so for the most part, the in the bone marrow start producing abnormal cells in one granules appear colorless or faintly violet on a cell line at an increased rate. These abnormal cells show up stained blood smear. in peripheral blood in large numbers, many times before they are mature, and cause the total white blood cellnumbers Formation. The production of all granulocytes is called to increase dramatically aeukocytosis}. are con- . In the bone marrow, early granulocytes are sidered a form of or and can be acute impossible to distinguish from one another. They are all or chronic. They are classified by the type of cell involved (e.g., lymphocytic leukemia, monocytic leukemia, eosino- large cells with lots of cytoplasm and large round nuclei. philic leukemia). Initially there are no cytoplasmic granules. As the granulo- cytes mature, a first set of granules is formed. Chapter 9 Blood, Lymph, and Immunity 233

These granules are the same in all three granulocytes and are called nonspecific granules. Gradually, the nonspecific granules are replaced by a new set of granules that is unique to each granulocyte type. These are called specific granules. The Golgi apparatus produces both nonspecific and specific granules. f a neutrophil nucleus in peripheral blood has more than The substances found in its granules determine the func- Ifive segments, it is called a hypersegmented nucleus (see tion of a granuloctye. For example, neutrophil granules figure). This indicates that the neutrophil has stayed in periph- contain chemicals called lysosomal enzymes, which aid in eral blood longer than normal, because hypersegmenting killing microorganisms that have been engulfed by the neu- usually takes place in tissue as part of the normal aging trophil. Neutrophils have therefore become a major factor process. The presence of hypersegmented neutrophils on a stained blood smear can be indicative of a pathological in preventing invading microorganisms from causing . condition that prevented neutrophils from leaving circulation, An early granulocyte has blue cytoplasm indicating that or it can mean the smear was made from old blood. Remem- it is a metabolically active cell. As it matures, the cytoplasm ber, blood is still living when it is removed from the animal, becomes less active and therefore doesn't stain as blue. and it will continue the aging process as long as it can. So Mature granulocytes in circulation contain almost colorless hypersegmented neutrophils may be just aging normally in cytoplasm containing the specific granules. In fact, if it the tube. weren't for the granules, the limits of the cell membrane Hypersegmented neutrophils are seen within a day after would be difficult to see, making it look like the nucleus was .dhe blood sample was drawn. For this reason, it is important pretty much floating around alone. This sometimes is just that a smear be made as soon as possible after the blood how neutrophils appear because of their colorless or faintly sample is drawn. stained granules. As a granulocyte matures, its nucleus transforms from a round structure to a segmented structure that takes on many Nucleus shapes (polymorphonuclear). Thin filaments connect these segments. The chromatin pattern of the nucleus starts out quite loose. As the nucleus squeezes itself down into seg- ments, the chromatin becomes more condensed. As the cell Cytoplasm ages and approaches , the segments break apart and lose all evidence of any chromatin pattern. This process is Hypersegmented nucleus. Can indicate an older cell than is called pyknosis, and it is an indication of a dead cell. normally found in peripheral blood.

Neutrophils. Neutrophils are also known as polymorpho- nuclear cells (because their nuclei have many shapes), PMNs (PolyMorphoNuclear leukocytes), and segs (because their nuclei are segmented). Even though eosinophil, basophil, pieces of nucleus but are joined by a thin strand of chroma- and monocyte nuclei can be polymorphonuclear, the neu- tin. Sometimes this strand of chromatin is difficult to see, trophil is the only cell that is commonly called a PMN. The so it looks like the segments are separated. If the neutrophil neutrophil is the most numerous white blood cell in circula- is released from the bone marrow before it is mature, it tion in the dog, horse, and cat. will have a horseshoe nucleus without any segmentation. This is called a band neutrophil. When band neutrophils are Formation. Neutrophils are produced in the bone marrow seen in peripheral blood, it is an indication that there is an and released into blood as needed, when neutrophils already increased demand for neutrophils beyond what the bone in circulation leave the bloodstream and enter tissue to kill marrow can supply in mature neutrophils. If the bone microorganisms or simply die of old age. It takes 3 to 6 days marrow runs out of band neutrophils and still hasn't met to produce a mature neutrophil under normal conditions, the body's demand, it will start releasing progressively more depending on the species of animal. If the body has a sudden immature cells. need for more neutrophils, this time can be shortened. function. Neutrophils are . That means they Characteristics: Neutrophil granules don't stain with engulf (phagocytize) microorganisms and other microscopic either the blue alkaline stain or the red acid stain, so they are debris in tissues. Neutrophils are part of the second line of said to be neutral. This means they are difficult to see on a defense, after the skin and/or mucous membranes, when stained smear; so identification of neutrophils is commonly invading microorganisms enter the body. based on nuclear morphology, rather than staining Neutrophils can respond very quickly. Their granules characteristics. contain digestive enzymes that are capable of destroying bac- A mature neutrophil in peripheral blood will have from teria and that have been engulfed. The neutrophil two to five nuclear segments. The segments aren't separate granules are organelles called . ;------~

234 . Chapter 9 Blood, Lymph, and Immunity

Endothelial Tissue ® cells ®

® Neutrophil ® . ~ Cytoplasmic ® Microorganrsms "'" granules ~~ ~ ••• • """'(Iysosomes)® ~ ?a.~<3>~~ ~•••• ® ® 0) ® ® ®~ ®@•••~ ® @® •• , ~ ® Figure 9-5 Diapedesis. 1, Neutrophil lying against vessel wall ®® 0~ begins to squeeze through the space between endothelial cells by flowing into pseudopod (false foot). 2, Pseudopod continues to push its way between cells. Rest of the cell cytoplasm flows along with it. 3, Pseudopod and the rest of the cell emerge on tissue side of blood Figure 9-6 Phagocytosis and destruction of microorganisms. vessel. 4, Neutrophil is off in search of foreign invaders to 1, Neutrophil membrane engulfs microorganisms. 2, Phagocytic phagocytize. ',. vacuole is formed. 3, Cytoplasmic granules (lysosomes) line up around phagocytic vacuole and empty their digestive enzymes into Neutrophils use blood as a transportation medium to vacuole. 4, Microorganisms are destroyed. take them to their site of action in tissue. Normally a neu- trophil will spend an average of 10 hours in circulation and to begin phagocytosis. The coating process is called before it enters the tissue. This circulation time is shorter opsonization. when there is an increased demand for neutrophils in the When the neutrophil recognizes a foreign microorgan- tissue. Once a neutrophil enters tissue it doesn't return to ism, its outer membrane flows around the invader and blood, so all circulating neutrophils need to be replaced encases it within a membrane-bound phagocytic vacuole about two and a halftimes a day. Under normal conditions, (Figure 9-6). If you've seen the 1950s sci-fi movie The Blob, they are replaced by mature neutrophils held in reservein then you've seen how a neutrophil operates: it flows around the bone marrow. anything in its way. (If you haven't seen the movie you Neutrophils leave the blood vessel by squeezing between should. It's a hoot.) The microorganism is surrounded by the cells of the in a process called diapedesis the neutrophil membrane, but isn't really inside the neutro- (Figure 9-5). Neutrophils are normally found in tissues that phil. Think of it as a hug. When you put your arms around are constantly exposed to microorganism invasion (e.g., something, you're encasing it but not taking it inside your the lungs and intestinal tract). Other neutrophils wander body. through tissue to the sites where they are needed. At this point, the neutrophil's cytoplasmic granules (lyso- Neutrophils stay in tissue until they die of old age or are somes) move to the edge of the vacuole that contains the destroyed by the microorganisms they are trying to destroy. microorganism, fuse with the membrane, and secrete their Dead or abnormal neutrophils are picked up and destroyed digestive contents into the vacuole. by tissue . (See the discussion of tissue macro- Neutrophils increase their metabolism of oxygen during phages in the section on monocytes.) Think of neutrophils ingestion of microorganisms to produce substances that are as garbage cans and tissue macrophages as garbage trucks. toxic to ingested . Hydrogen peroxide is the product of Neutrophils are attracted to a site of infection by chemo- oxygen metabolism that is the most important for the killing taxis, a process by which neutrophils and other cells activity of neutrophils. Hydrogen peroxide is capable of are attracted by inflammatory chemicals produced by the killing bacteria (bactericidal effect) all by itself, but its action interaction between microorganisms and the tissues they is enhanced by the enzyme , which is released are invading. Having arrived at the site invaded by the from neutrophil granules. Lysozyme from the granules also microorganisms, the neutrophil must recognize what enhances the bactericidal action of hydrogen peroxide and is to ingest. capable of destroying the cell walls of microorganisms. Detecting some microorganisms is not a problem for the neutrophils. Other microorganisms try to "hide" inside cap- Neutrophil Count in Peripheral Blood. The neutro- sules that make them difficult for neutrophils to recognize. phil count in peripheral blood is kept within a specific range To help make the microorganism more recognizable to the in a healthy animal. This number is controlled by three neutrophil, the encapsulated microorganism is coated with factors: a plasma protein, usually a specific antibody. (See the discus- l. Release of mature neutrophils from the storage pool in the sion of antibody production in the immunity section.) These bone marrow into the peripheral blood. In the bone marrow plasma proteins are called . Coating the micro- storage pool, there is usually a 5-day supply of mature organism enables the neutrophil to recognize it as foreign neutrophils. They are ready for immediate release if there Chapter 9 Blood, Lymph, and Immunity 235

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fthere is an increased demand for neutrophils in tissue, Ibone marrow willrelease its reserve stores of mature-and, eutrophils can move freely between the circulating and if necessary, immature-neutrophils into blood, so they can Nmarginal pools. At any given time in dogs, cattle, and be transported to the site where neutrophils are needed. Ifa horses, there is about a 50:50 ratio between the number of blood sample is drawn while these neutrophils are in transit, neutrophils in the circulating pool and the marginal pool. In there will be a higher than normal number of neutrophils in cats, the ratio is about a 30:70. the sample. This is called , and it is usually Cells can detach from the marginal pool and enter the detected during a differential cell count. circulating pool when an animal is experiencing some sort The increased number of neutrophils will also increase of physical or mental stress. Trauma, fear, and exercise are the total number of white blood cells in the sample. This is a few of the stresses that may lead to a temporary transfer called and usually is detected using an auto- of neutrophils from the marginal pool to the circulating mated blood analyzer or by looking at the thickness of the pool. This predictable neutrophil response is part of a larger in a tube. Leukocytosis with accom- physiological reaction called the stress response. panying neutrophilia can indicate an infection somewhere Splenic contraction also plays an important role in this in the body. ,•. movement of cells out of the marginal pool. The temporary movement of neutrophils into the circulating pool can arti- ficially elevate the total neutrophil count (neutrophilia) and the total white blood cell count (leukocytosis) because the normal values are based only on the number of cells nor- mally found in the circulating pool. These artificiallyelevated results can lead to a possible misdiagnosis. Remember this when you have to chase a horse around a pasture or wrestle with a cat to get a blood sample.

fan infection is out of control, all the reserves of neutro- t The administration of corticosteroid drugs, which are IphiIs can be used up faster than the bone marrow can similar to hormones (see Chapter 15) will replace them. If this happens, the number of neutrophils in cause the same response. This is one good reason circulation decreases, because the neutrophils are leaving for drawing a blood sample before medications are the bloodstream and entering tissue, and there are no cells administered. in the bone marrow to replace them. This condition is called . The total white blood cell count will also decrease. This is leukocytopenia. The prognosis is poor for phils from this pool. The normal range of neutrophil an animal that is clinicallyillwith accompanying neutropenia numbers in peripheral blood is based on the neutro- and leukocytopenia. It means the body is losing the war phils contained in this pool. against the invading microorganisms. 2. The marginal pool is composed of neutrophils that line the walls of small blood vessels mainly in the , lungs, and abdominal organs. These neutro- is a sudden drop in circulating numbers of neutrophils phils are not circulating and are not contained in caused by increased movement of neutrophils into tissue. blood samples obtained for laboratory analysis. 2. Rate of escape from peripheral blood into tissue. This rate depends on the need for neutrophils in the tissue. With Eosinophils. Eosinophils are named for the red granules a massive acute infection (e.g., coliform mastitis in in the cytoplasm of mature cells. The granules stain with the cattle), the total neutrophil population of the peripheral red eosin component of the blood stain. They make up 0% blood can enter the tissue in a matter of hours. to 5% of the total white blood cell count. 3. The entrance of increased numbers of pluripotent stem cells into the neutrophil production line. This is a slow method fonnation and Characteristics. Eosinophils are pro- of control because it takes 3 to 6 days for the neutrophils duced in the bone marrow from the same pluripotent stem to mature and be ready to be released. cells that give rise to all other blood cells. It takes 2 to 6 days to produce an eosinophil from a PPSc. The cytoplasmic Intravascular Pools of Neutrophils. In peripheral granules take up the acidic stain eosin and appear red when blood there are two pools of mature neutrophils: seen on a blood smear. Frequently the segmented nucleus 1. The circulating pool is contained in the blood as it has only two lobes. flows through the blood vessels. It is found toward the The granules are shaped differently in various species: center of the lumen of the vessel. Blood samples • Dogs: Granules are round. Their size varies from small obtained for laboratory analysis contain the neutro- to large within the same cell, and they stain very lightly. 236 Chapter 9 Blood, Lymph, and Immunity

Cats: Granules are small, rod-shaped, and numerous. Basophils. Basophils are named for the blue granules They stain darker than canine eosinophil granules. in the cytoplasm of mature cells. The granules stain with • Horses: Granules are very large, round or oval, and the basic component of the blood stain. They are the stain very intensely. white blood cell least often seen in circulation, and for • Cattle, sheep, and pigs: Granules are round and much this reason they are also the least understood white blood smaller than equine granules. They stain pink to red. cell. There is a good bone marrow reserve of eosinophils. There are also circulating and marginal pools of eosinophils Formation. Basophils are produced in the bone marrow in peripheral blood, like the neutrophil pools. Eosinophils from the same pluripotent stem cell as the other blood cells. don't stay in peripheral blood very long but migrate into Not much is known about the production and function of tissue in a few hours, where they spend the rest of their basophils. lives. In tissue they undergo the same aging process as neutrophils. Characteristics. The basophil granules are water soluble and are frequently washed out during the staining proce- function. The functions of eosinophils are not yet entirely dure, so they are not always readily visible on a stained understood, but like neutrophils, the functions are deter- smear. When they are seen, the basophil granules stain blue mined by the contents of their granules. regu- and fill the cytoplasm. A dog has fewer granules than the lates their entry into tissue. They don't re-enter circulation other common domestic species. Basophils most often have once they leave blood vessels. Large numbers of eosinophils-, a two- to three-lobed nucleus. are normally found in certain tissues in the body (e.g., skin, lung, small intestines). Three key functions are most often Basophils and Tissue Mast Cells. Basophils share some associated with eosinophils: characteristics with tissue mast cells, but some controversy • Anti-inflammatory response. Eosinophils are attracted to exists over the relationship between these two cells. Mast and inhibit local allergic and anaphylactic reactions. Their cells are normally found in tissue and don't migrate there granules contain anti-inflammatory substances that are from blood. Basophils are not commonly seen in tissue. released at the site of the allergic reaction. Mast cells are larger than basophils and have more cytoplas- • Immunity. Eosinophils can ingest substances associated mic granules that are not water-soluble. Mast cells have a with the humoral (e.g., - round nucleus that doesn't segment. antibody reaction complexes). Two theories currently exist regarding this relationship: • Phagocytosis. Eosinophils have minimal phagocytotic and 1. Mast cells and basophils are two different cell types bactericidal functions, but they are especially effective in with similar characteristics. They are produced in two the phagocytosis of large, pathogenic organisms, such as different areas of the body and don't give rise to one protozoa and some parasitic worms but are not protective another. against most bacterial . 2. Mast cells are tissue basophils. This theory is not as popular as the first theory. and Leukocytosis. Increased numbers of eosinophils in peripheral blood (eosinophilia) can be seen function. Not much is known about the function of baso- during allergic reactions and certain parasitic infections. The phils. They are the least phagocytic of the granulocytes. increased numbers are a response to a demand created by a Basophil granules contain and , which are pathological condition in the animal. An accompanying leu- responsible for at least part of basophil function in the fol- kocytosis may also occur, but because there are normally few lowing ways: eosinophils in circulation, the increased number may not be • Histamine helps initiate and acute aller- enough to elevate the white blood cell count beyond the gic reactions. normal range. Eosinophils are attracted to the site of an allergic reac- Eosinophilia can result from any of the following: tion by eosinophilic chemotactic factor released from the • Increased release of mature eosinophils from the storage basophil granules. pool in the bone marrow • Heparin acts as a localized anticoagulant to keep blood • Migration of eosinophils from the marginal pool to the flowing to an injured or damaged area. circulating pool • Increased production in the bone marrow Basophilia and Basopenia. Increased numbers of • Increased time spent in peripheral blood before enter- basophils in peripheral blood (basophilia) can be associated ing the tissue with an allergic or reaction in tissue. Some- times basophilia and eosinophilia are seen at the same Eosinopenia. Decreased numbers of eosinophils in periph- time. eral blood (eosinopenia) are difficult to detect and evaluate, Decreased numbers of basophils in peripheral blood because their numbers are normally low. (basopenia) are difficult to evaluate because basophils are so Chapter 9 Blood, Lymph, and Immunity 237 rarely seen in peripheral blood. In all of the common domes- • They ingest foreign substances. They have the same phago- tic species, basophils make up less than one percent of all cytic capabilities as neutrophils and then some. They are white blood cells in peripheral blood. They are not seen at larger than neutrophils, so they can engulf structures all on many blood smears. beyond the phagocytic capacity of neutrophils (e.g., fungi, protozoa, viruses, and dead neutrophils). Monocytes follow neutrophils into tissue by the process Agranulocytes are white blood cells that don't have specific of chemotaxis in response to tissue damage caused by trauma staining granules in their cytoplasm. They include mono- or invading microorganisms. Neutrophils respond more cytes and lymphocytes. quickly to the tissue damage, but monocytes stay around longer once they get to the damaged site and become tissue macrophages. Tissue macrophages have a longer life span Monocytes. Monocytes make up 5% to 6% of the cir- than neutrophils, so they are often associated with chronic culating white blood cells in all common domestic infections. species. Monocytes can also function in circulating blood to phagocytize damaged blood cells or microorganisms found Formation and Characteristics. Monocytes are formed in the blood, such as in the case of septicemia. in the bone marrow from pluripotent stem cells. They mature much faster than neutrophils (total monocyte Monocytosis. An increased number of monocytes in development time is 24 to 36 hours) and stay in the blood .,~peripheral blood is called monocytosis. It is often associ- longer (24 to 36 hours) than neutrophils. From peripheral ated with a chronic inflammatory condition, such as an blood, monocytes enter the tissue, where they do their infection. work. Monocytes are the largest white blood cells in circulation. Monocytopenia. A decreased number of monocytes in They have abundant cytoplasm that stains gray-blue and peripheral blood is called monocytopenia. It can be difficult may contain vacuoles of varying sizes. Sometimes the cyto- to evaluate because of the low numbers of monocytes nor- plasm takes on a fine granular appearance that is commonly mally found in circulation. referred to as a "ground glass" appearance. The nucleus can be round or any number of shapes (pleomorphic), but it Lymphocytes. Lymphocytes are normally the predomi- doesn't split up into distinct segments like a mature granu- - nant white blood cell in circulation in ruminants and pigs. locyte nucleus. They are the only white blood cell that has no phagocytic capabilities. Most of the lymphocytes in the body actually function. Monocytes are major phagocytic cells. When live in what are called lymphoid tissues and constantly recir- they enter tissue, they become known as tissue macrophages. culate between these tissues and blood. Monocytes in the bloodstream are less effective phagocytes than tissue macrophages. In fact, monocytes are considered Formation and function. Some controversy still exists as immature tissue macrophages. Tissue macrophages are to the origin and development of lymphocytes. It is most larger than monocytes and can be found in any tissue, but popularly believed that they arise from the same pluripotent are most prevalent in "filter" organs such as the liver, spleen, stem cells in the bone marrow as other blood cells. Before lung, and lymph nodes. These filter organs are responsible they begin to mature, some of the cells leave the bone marrow for removing or containing foreign invaders, damaged and to develop in other central lymphoid organs located through- old blood cells, and cellular debris. out the body before settling in their permanent home in Some tissue macrophages wander through tissue freely, peripheral lymphoid tissue. while others become fixed in specific tissues and remain there for the rest of their life span. Collectively the tissue Types of Lymphocytes. There are three different types macro phages and monocytes are known as the mononuclear of lymphocytes: T lymphocytes, B lymphocytes, and natural system (MPS). killer cells. Monocytes and tissue macrophages perform several specific functions: T lymphocytes (T cells). T lymphocytes are processed in the They clean up cellular debris that remains after an inflam- before going to peripheral lymphoid tissue. The pre- mation or infection clears up. T cells in the thymus are . Thymocytes multiply • They process certain antigens, making them more anti- rapidly, leave the thymus, and travel to specific T-dependent genic. Monocytes and tissue macrophages can ingest anti- zones in lymph nodes and the spleen. After they leave the gens and present them on their cell membranes to the thymus, thymocytes are known as T cells or T lymphocytes. lymphocytes that will then destroy them. This important T cells are responsible for cell-mediated immunity and for role in the immune response will be discussed in the activating B cells. Most of the lymphocytes in peripheral section of this chapter blood are T cells. 238 Chapter 9 Blood, Lymph, and Immunity

found in any tissue in the body, but are most numerous in tissues engaged in antibody formation (e.g., lymph nodes, spleen). Plasma cells are rarely found in peripheral ~D\) blood. Natural killer cells. Natural killer (NK) lymphocytes are neither T cells nor B cells. They don't have to be activated by a specific antigen, and they have the ability to kill some types of tumor cells and cells infected with various viruses. NK cells must come in direct contact with these cells before VWV they can destroy them. Every lymphocyte has surface markers that differentiate o Antigen o o Antibody B cells from T cells and subsets of each type of lymphocyte. These markers are not visible under light microscopy. We'll Figure 9-7 Antigens and . Every antigen has a uniquely shaped epitope on its cell membrane that will fit into a combining discuss the function of lymphocytes in more detail in the shape on an antibody. (Modified from the National Cancer Institute, immunity section of this chapter. NIH Publication No, 03-5423, September 2003.) Characteristics. The lymphocytes we see in circulation are '(., classified as either large or small. Large lymphocytes have more cytoplasm and are thought to be younger than small lymphocytes, They gradually develop into small lympho- B lymphocytes (B cells). The B means "bursa equivalent" cytes that have very little cytoplasm. and refers to bone marrow and other lymphoid tissue Lymphocytes contain no granules in their cytoplasm. The thought to be the equivalent of a bird called the bursa nucleus is round or oval and does not segment. Large lym- of Fabricius. Inactive B cells travel through lymph nodes, the phocytes have abundant sky-blue cytoplasm. Small lympho- spleen, and other lymphoid structures but rarely circulate cytes have such a scant amount of cytoplasm that it is in peripheral blood. B cells are ultimately responsible for , sometimes difficult to see. Small lymphocytes frequently antibody production. look like nuclei without cytoplasm. Or there may be just a Each B cell is preprogrammed to produce only one spe-- small amount of sky-blue cytoplasm visible on one side of cific antibody type against one specific antigen (foreign the nucleus. protein). On its cell surface, it has thousands of receptors shaped to fit only one antigen shape. Every antigen has a Memory Cells. Both T cells and B cells can become unique shape on its cell surface made up of amino acids. This memory cells. These cells are clones of an originallympho- area is called the epitope. The sequence of amino acids cyte. They don't participate in an initial immune response determines the shape of the epitope. And there is a B cell to a specific antigen but survive in lymphoid tissue waiting that has a complementary combining site or receptor that for a second exposure to that same antigen. When the animal fits the shape of the epitope (Figure 9-7). is exposed to the antigen for a second time, the memory When the B cell and antigen are joined, an antigen- cells are ready to respond. This response is much quicker antibody complex is formed. For example, there are certain and mounts a greater response than the initial immune B cells that are preprogrammed to receive only the canine response. distemper . If a dog is exposed to the distemper virus, only the B cells that are preprogrammed to recognize the and Leukocytosis. Lymphocytosis is an virus will respond by eventually making antibodies against increased number oflymphocytes in peripheral blood. It can the virus. All the other B cells will be unaffected. The amazing be the result of leukemia (a form of cancer of the lympho- thing is that the B cells are preprogrammed to produce anti- cytes), chronic infections, or epinephrine release (as part of bodies against antigens to which they have never been the fight-or-flight response). Lymphocytosis can be signifi- exposed. When B cells recognize an antigen, they transform cant enough to cause leukocytosis. into plasma cells that release antibodies. The can produce over 100 trillion (102°) antibodies, and there is Lymphopenia and . Lymphopenia is a no reason to think an animal can't do the same. This is called decreased number oflymphocytes in peripheral blood. It can humoral immunity. be the result of many factors, including decreased produc- Plasma cells are derived from B cells in response to an tion of lymphocytes, the presence of corticosteroids (drugs antigenic stimulus. The B cells that are activated by their similar to glucocorticoid hormones from the adrenal cortex), antigen multiply by mitosis in a process called blastic trans- immune deficiency , and acute viral diseases. In formation to become plasma cells. some animals, especially ruminants, in which lymphocytes Plasma cells produce, store, and release antibodies that are the primary white blood cell in circulation, lymphocyto- are also known as immunoglobins. Plasma cells can be penia can result in leukocytopenia.