In mammalian immunologic development, the precursors of lymphocytes arise from progenitor cells of the yolk sac and liver (Fig. 1). Later in fetal development, and throughout the life cycle, the bone marrow becomes the sole provider of undifferentiated progenitor cells, which can further develop into lymphoblasts. Continued cellular development and proliferation of lymphoid precursors occur as the cells travel to the primary and secondary lymphoid tissues.

Fig1. Development of immunologic organs.  The anatomy of the human fetus illustrates the development of the mammalian immune system. Cells of the  pharyngeal pouches migrate into the chest and form  the thymus. Precursors of lymphocytes originate early  in embryonic life in the yolk sac and eventually migrate  to the bone marrow via the spleen and liver.

Primary Lymphoid Tissue

 In mammals, both the bone marrow (and/or fetal liver) and thymus are classified as primary or central lymphoid organs (Fig. 2). Thymus. Early in embryonic development, the stroma and nonlymphoid epithelium of the thymus are derived from the third and fourth pharyngeal pouches. The characteristics of the thymus gland change with aging. Older persons are immunologically challenged because aging causes a reduction in the production of naïve T cells by the thymus. Intrinsic defects in mature T cell function, alterations in the life span of naïve T cells and in naïve or memory T cell ratios in the peripheral lymphoid tissues, occur as the result of the decline of the T cell response in older persons.

Fig2. Human primary and secondary tissues. (Adapted from Turgeon ML: Clinical hematology: theory and procedures, ed 4, Philadelphia, 2005, Lippincott Williams & Wilkins.)

The thymus, located in the mediastinum, exercises control over the entire immune system. It is believed that the development of diversity occurs mainly in the thymus and bone mar row, although clonal expansion can occur anywhere in the peripheral lymphoid tissue.

Progenitor cells that migrate to the thymus proliferate and differentiate under the influence of the humoral factor, thymosin. These lymphocyte precursors with acquired surface mem brane antigens are referred to as thymocytes.

The reticular structure of the thymus allows a significant number of lymphocytes to pass through it to become fully immunocompetent (able to function in the immune response), thymus-derived T cells. The thymus also regulates immune function by the secretion of multiple soluble hormones.

Many cells die in the thymus and apparently are phagocytized, a mechanism to eliminate lymphocyte clones reactive against self. It is estimated that approximately 97% of the cortical cells die in the thymus before becoming mature T cells. Viable cells migrate to the secondary tissues. The absence or abnormal development of the thymus results in a T lymphocyte deficiency.

Involution of the thymus is the first age-related change occur ring in the human immune system. In postnatal life, the thymus is the primary organ that produces naïve T cells for the peripheral T cell pool but production of cells declines as early as 3 months of age. The thymus gradually loses up to 95% of its mass during the first 50 years of life (Fig. 3). The accompanying functional changes of decreased synthesis of thymic hormones and the loss of ability to differentiate immature lymphocytes are reflected in an increased number of immature lymphocytes within the thymus and as circulating peripheral blood T cells. Most changes in immune function, such as dysfunction of T and B lymphocytes, elevated levels of circulating immune complexes, increases in autoantibodies, and monoclonal gammopathies are correlated with involution of the thymus. Immune senescence may account for the increased susceptibility of older adults to infections, autoimmune disease, and neoplasms.

Fig3. Thymic development.  Histology of the thymus changes with  age. The main feature of these changes  is a loss of cellularity with increasing  age.

Bone Marrow. The bone marrow is the source of progenitor cells. These cells can differentiate into lymphocytes and other hematopoietic cells (e.g., granulocytes, erythrocytes, mega karyocyte populations). In mammals, the bone marrow also supports eventual differentiation of mature T and B lymphocytes, probably from a common lymphoid cell progenitor. It is believed that the bone marrow and gut-associated lymphoid tissue (GALT) may also play a role in the differentiation of progenitor cells into B lymphocytes.

Secondary Lymphoid Organs

 Secondary lymphoid organs provide a unique microenvironment for the initiation and development of immune responses. The secondary lymphoid tissues include lymph nodes, spleen, GALT, thoracic duct, bronchus-associated lymphoid tissue (BALT), skin-associated lymphoid tissue, and blood. Mature lymphocytes and accessory cells (e.g., antigen-presenting cells) are found throughout the body, although the relative percent ages of T and B cells vary in different locations (Table1).

Table1. Approximate Percentage of Lymphocytes in Lymphoid Organs

The highly sophisticated structure of secondary lymphoid organs allows migration and interactions between antigen- presenting cells, T and B lymphocytes, and follicular dendritic cells (FDCs) and other stromal cells. The cooperative activities of lymphoid cells within secondary organs dramatically increase the probability of interactions of rare B, T, and APCs that results in effective generation of humoral immune responses.

Tumor necrosis factor (TNF) and lymphotoxin are essential to the formation and maintenance of secondary organs. These cytokines are produced by B and T lymphocytes. Proliferation of the T and B lymphocytes in the secondary or peripheral lymphoid tissues (Fig. 4) is primarily dependent on antigenic stimulation.

Fig4. A, Lymph node (×90). B, Enlargement of cortical nodule seen in A (×450). (From Anthony CP, Thibodeau GA: Textbook of anatomy and physiol ogy, ed 12, St Louis, 1987, Mosby.)

The T lymphocytes or T cells populate the following:

 1. Perifollicular and paracortical regions of the lymph nodes

2. Medullary cords of the lymph nodes

3. Periarteriolar regions of the spleen

4. Thoracic duct of the circulatory system

The B lymphocytes or B cells multiply and populate the following:

 1. Follicular and medullary (germinal centers) of the lymph nodes

 2. Primary follicles and red pulp of the spleen

 3. Follicular regions of GALT

4. Medullary cords of the lymph nodes

Lymph Nodes. Lymph nodes act as lymphoid filters in the lymphatic system. Lymph nodes respond to antigens introduced distally and routed to them by afferent lymphatics (Fig. 5). Generalized lymph node reactivity can occur after systemic antigen challenge (e.g., serum sickness).

Fig5. Structure of a lymph node. Several valved afferent lym phatics bring lymph to the node. An efferent lymphatic leaves the  node at the hilus. Note that the artery and vein enter and leave at the  hilus. (Adapted from Anthony CP, Thibodeau GA: Textbook of anatomy and physiology, ed 12, St Louis, 1987, Mosby.)

Spleen. The spleen acts as a lymphatic filter within the blood vascular tree. It is an important site of antibody production in response to IV particulate antigens (e.g., bacteria). The spleen is also a major organ for the clearance particles.

Gut-Associated Lymphoid Tissue. GALT includes lymphoid tissue in the intestines (Peyer’s patches) and the liver. GALT features immunoglobulin A (IgA) production and involves a unique pattern of lymphocyte recirculation. Pre–B cells develop in Peyer’s patches and, after meeting antigen from the gut, many enter the general circulation and then return back to the gut. GALT is also important for the development of tolerance to ingested antigens.

Thoracic Duct. The thoracic duct lymph is a rich source of mature T cells. Chronic thoracic duct drainage can cause T cell depletion and has been used as a method of immunosuppression.

Bronchus-Associated Lymphoid Tissue. BALT includes lymphoid tissue in the lower respiratory tract and hilar lymph nodes. It is mainly associated with IgA production in response to inhaled antigens.

Skin-Associated Lymphoid Tissue. Antigens introduced through the skin are presented by epidermal Langerhans cells, which are bone marrow–derived accessory cells. These epidermal cells then interact with lymphocytes in the skin and in draining lymph nodes.

Blood. The blood is an important lymphoid organ and immunologic effector tissue. Circulating blood has enough mature T cells to produce a graft-versus-host reaction. In addition, blood transfusions have been responsible for inducing acquired immunologic tolerance in kidney allograft patients.

Blood is the most frequently sampled lymphoid organ. It is assumed that what is found in blood samples represents what is present in other lymphoid tissues. Although this may be a true representation, it is not always accurate.

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