Lymphocyte Origin And Function

The lymphocytic series is distinctive in its presentation and function. In contrast to most other white cells, which are derived solely from the bone marrow, lymphocytes are derived from two locations. The primary lymphoid organs are the bone marrow and thymus. The secondary lymphoid organs are the spleen, lymph nodes, Peyer's patches of the gastrointestinal tract, and the tonsils. Additionally, the lymphatic system plays an essential role in lymphocyte development, differentia-

Figure 9.11 Large lymphocyte. Oval nucleus with looser, more transparent chromatin pattern.

tion, and function. More than 100 lymph nodes form a nexus known as the lymphatic system, which runs from the cervical lymph nodes of the neck to the inguinal lymph nodes in the groin area (Fig. 9.12). The lymphatic system plays an important role in blood filtration, fluid balance, antibody generation, and lymphopoiesis.6 A major part of this system is lymph, a clear, thin fluid derived from plasma that bathes the soft tissues. Once an injury has occurred and fluid is accumulated through swelling, the lymphatic system moves fluid from the affected area back to the circulation through the capillaries of the lymph nodes. Because the lymphatic system has no pumping mechanism like the heart, it derives its circulatory ability from respiration, muscle movement, and pressure from nearby blood vessels. Excess fluid is transported to two large vessels:

^^Submaxillary nodes

Mammary plexus

Right lymphatic duct

Cubital nodes

^^Submaxillary nodes

Cervical nodes

Mammary plexus

Right lymphatic duct

Cubital nodes

Popliteal nodes

— Iliac nodes Inguinal nodes

Cervical nodes

Left subclavian vein Thoracic duct Axillary nodes

Spleen

Cisterna chyli Mesenteric nodes

— Iliac nodes Inguinal nodes

Popliteal nodes

Figure 9.12 The lymphatic system.

136 Part III • White Cell Disorders the thoracic duct near the left subclavian vein and the right thoracic duct near the right subclavian vein.

The primary function of lymphocytes is immuno-logic: recognizing what is foreign, non-self; forming antibodies; and securing immunity. Non-self or foreign substances may appear as bacteria, cell substances, proteins, or viruses.

Lymphocyte Populations

There are two general subpopulations of lympho-cytes—B lymphocytes and T lymphocytes—which appear morphologically similar on peripheral smear. Yet their derivation and function are quite different. B lymphocytes comprise 10% to 20% of the total lymphocyte population, while T lymphocytes comprise 60% to 80%. A third minor population, natural killer (NK) lymphocytes, constitute less than 10% of the total lymphocyte population (Fig. 9.13).

B lymphocytes are derived from bone marrow stem cells. The pluripotent stem cell is activated by interleukin (IL)-1 and IL-6 to differentiate into the lymphocyte stem cell (LSC). In general, the LSC gives rise to the progression of the pre-B cell, the lymphoblast, the B cell, and the terminal cell, the plasma cell. The plasma cell is responsible for antibody production and humoral immunity, antibodies to a specific antigen. T cells arise from the LSC, which migrates to the thymus. The thymus, a gland located above the heart, gives rise to the prothymocyte, T lymphoblast, and T cell responsible for cell-mediated immunity. This gland, although highly active in infants and children, is not functional in adults. Determining lymphocyte life span is difficult. Long-lived lymphocytes product cytokines, whereas short-lived lymphocytes produce antibodies. Plasma and tissue environmental influences either promote or delay longevity. There has been speculation that some lymphocytes may live up to 4 years.7

T and B cells are dependent on their interaction with their microenvironment: bone marrow versus thymus, versus lymph nodes, versus peripheral blood. Their specific derivation is defined from the surface membrane markers they possess and their stimulation toward a particular immune response. Classification of stages of T and B cells is complex and dominated by which CD markers or surface antigens they possess.

The Travel Path of Lymphocytes

Lymphocytes may originate in the bone marrow, the thymus, and the lymphatic system. Because the lymphatic system is a network of tissues, the travel path of lymphocytes from blood to thymus to lymphatics is less than straightforward. Most white cells proliferate and mature in the bone marrow and are released into peripheral circulation. From the circulation, they may either migrate to tissues or wind their way through circulation until they degenerate. Lymphocytes travel two paths. They either travel between areas of inflammation, or they move from the bone marrow to the thymus and then into secondary lymphoid tissue, the lymphatic system. Mature lymphocytes primarily move back and forth the between the lymphatic system, while imma-

Figure 9.13 Subpopulations of lymphocytes.

ture lymphocytes move from the bone marrow to the thymus and then into the lymphatic system. Because the lymphocyte is a highly mobile cell, it will interact with the endothelial cells of blood vessels as it migrates to tissues. This migration is carefully orchestrated through a series of receptors and cytokines from the endothelial network. Lymphocytes spend far more time in travel through tissues than the marrow or circulation.8 Extensive transit is meant to increase their opportunities to become exposed to foreign antigenic stimuli and mount an appropriate response.

Lymphocytes and the Development of Immunocompetency

Initially, lymphocytes that are developing and maturing in the bone marrow and thymus are not responsive to provocative antigens. It is only when they reach the lymphatic system that they begin to develop a response to antigenic stimulation and become immunocompe-tent. Migration through the lymphatic system is carefully orchestrated through a series of receptors, and chemokines on the endothelial network of blood vessels surrounding lymphatic tissue.8 Immunoblasts are large activated lymphocytes capable of mustering an immune response. Antigenic presentation to lymphocytes may take many forms from altered cells to the body or foreign antigens or proteins. When a foreign antigen is presented to the body, it is usually phagocytized and destroyed by the macrophages of the lymph nodes or tissues. If this mechanism is not complete and some part of the invading mechanism is left behind, then an immune response begins to take place. Lymphocytes become activated and proceed to "battle" foreign antigens with many immune capabilities. Activated lymphocytes take on many roles and proliferate in the first few days after recognition of a foreign antigen or anti-genic products. B cells begin to synthesize antibodies to the particular antigen as a primary response. Once the antigen is presented to T cells by macrophages or B cells, then T cells respond by participating in cell-mediated immunity activities. These include:

• Delayed hypersensitivity

• Tumor suppression

• Resistance to intracellular organisms

In addition to each of these responses, T cells release lymphokines, which activate B lymphocytes and assist in humoral immunity and the production of plasma cells. Therefore, T cells play a vital role in cellmediated and humoral response and are essential to immune development.

The Response of Lymphocytes to Antigenic Stimulation

Once resting lymphocytes respond to antigenic stimulation, they begin to synthesize receptors, signals, or antigenic markers. T cells, which represent 60% to 85% of total lymphocytes, can be subdivided into two populations: T helper (CD4) or T cytotoxic/sup-pressor (CD8). T helper cells interact with macrocytes and macrophages, secrete cytokines, and promote humoral immunity. T-cytotoxic cells promote memory cells and help to eliminate non-self by promoting enzyme activity, which can significantly alter the cell membrane. B cells, which represent 10% to 20% of total lymphocytes, differentiate into plasma cells. This transformation takes place as T cells recognize antigens and release lymphokines. Lymphokines assist B lymphocytes in transforming into plasma cells, detecting antigens, and producing antibodies. NK cells represent a small subpopulation of lymphocytes with a highly specific function. These cells are non-T or non-B in origin and do not need antigenic stimulation to function. Originating in the bone marrow, they play a role primarily in resisting bacteria, viruses, and fungi.

Lymphocyte Cell Markers and the Cluster Designation (CD)

Before 1980, lymphocytes were demarcated by surface and cytoplasmic immunoglobulins, HLA markers, and terminal deoxynucleotidyl transferase (tDt) antigens. For a listing of CD markers in the unstimulated B and T cells, see Table 9.1. At present, most lymphocyte subpopulations are recognized by their CD markers. CD refers to cluster designation, a series of monoclonal antibodies manufactured by public and private companies to identify surface antigens on the many lymphocyte subsets. Lymphocytes can now by identified at successive stages in their maturation by their pattern of reaction to monoclonal antibodies. Most lymphocytes have several CD designations that they may initially possess and then lose or may carry with them throughout their maturation sequence.

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