Hematopoietic and Lymphoid Tissues

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Bone Marrow

Early in fetal life, hematopoiesis begins as red blood cell precursors appear in the yolk sac at 2 weeks gestation. In the first trimester, hematopoiesis can be found in the spleen, but in the late first trimester and throughout most of the second trimester and well into the third trimester, the major hematopoietic organ is the liver. This extramedullary hematopoiesis (blood cell production outside the marrow) is normal. Beginning in the late first trimester, the bones become large enough to have marrow cavities, and hematopoiesis becomes established in marrow, increasing there until, at term, the majority of hematopoiesis occurs in the marrow. However, at term and continuing for a month or more, extramedullary hematopoiesis can still be found in the liver. Under condition of fetal and neonatal stress, hematopoiesis can shift outside of the marrow (extramedullary hematopoiesis) to other organs.

Throughout childhood, many long bones contain red marrow, with hematopoietic elements, as well as the vertebral bone marrow, pelvis, ribs, and sternum. In adults, there is little red marrow in long bones, but mostly fatty marrow. An indicator of the reduction in mass of red marrow is the posterior iliac crest, the most common site for bone marrow biopsy. At age 50, the posterior iliac crest marrow is about 50% composed of hematopoietic elements, the rest fatty marrow. The cellularity decreases on average 10% per decade thereafter. In the elderly, most hematopoiesis is confined to vertebrae, ribs, and sternum. This is enough for normal circumstances, but in times of stress with blood loss and infection, for example, the demand for blood cell production can be increased, and the elderly (as well as infants) do not have a large reserve marrow capacity. When a bone marrow biopsy is performed, an aspirate of the marrow is also performed (and at some sites such as sternum, this is all that is done). The aspirate is made into bone marrow smears that are stained with Wright-Giemsa. It is easy to identify myelopoietic, erythroid, and megakaryocytic elements in the smears and count them to determine their relative numbers.

A differential count can be performed on the bone marrow to determine the relative numbers of the various elements. Below is an example generated by counting and classifying 1000 cells in a bone marrow smear:

Cell TypeCountNormal Range (%)
Myeloblast130.1 - 1.7
Promyelocyte291.9 - 4.7
Myelocyte1038.5 - 16.9
Metamyelocyte917.1 - 24.7
Band Neutrophil1169.4 - 15.4
Segmented Neutrophil1069.4 - 15.4
Lymphocyte1118.6 - 23.8
Monocyte60.0 - 0.6
Eosinophil141.1 - 5.2
Basophil20.0 - 0.2
Plasma Cell190.0 - 3.5
Nucleated RBC19415.0 - 36.2
Pronormoblast80.1 - 1.1
Basophilic Normoblast170.4 - 2.4
Polychromatophilic Normoblast14713.1 - 30.1
Orthochromatophilic Normoblast200.3 - 3.7
Megakaryocyte40.1 - 0.4
Myeloid-Erythroid Ratio2.51.1 - 3.5

The hematopoietic elements are present between the bone spicules. The marrow has a rich vascular supply, as well as sinusoids. The primordial cell that gives rise to all hematopoietic elements, as well as lymphoid cells, is the pleuripotential stem cell. A few of these cells circulate, but their job is to home in on marrow and establish cell lines for blood cell production. This pleuripotential stem cell gives rise to two cell lines:

  • Uncommitted lymphoid stem cell: this in turn give rise to the B stem cells and the T stem cells that establish populations of B lymphocytes and T lymphocytes.

  • Hematopoietic stem cell: from this line arise three additional subpopulations: the granulocyte-monocyte line, the megakaryocytic line, and the erythroid line. The granulocyte-monocyte line further differentiates into cell lines producing monocytes and granulocytes.

The marrow is principally populated by the cell lines that are involved with myelopoiesis (granulocytes), erythropoiesis (red blood cells), and megakaryopoiesis (platelets) which will circulate in the bloodstream.

The types of white blood cells that circulate include:

  • Neutrophils: these cells have prominent cytoplasmic granules that are lysosomes containing the enzymes released when neutrophils are recruited into inflammatory reactions. The neutrophils have multilobed nuclei. Circulating neutrophils last about 12 hours and, therefore, must constantly be replaced from the marrow.

  • Band neutrophils: a few of these slightly immature neutrophils circulate, and they have a crescent shaped nucleus that has not yet become lobated. They also have cytoplasmic granules.

  • Lymphocytes: both T and B cells circulate, with about 80% of the peripheral blood lymphocytes being T cells. These cells have a single large nucleus and scant blue cytoplasm. Lymphocytes can live for months to years.

  • Monocytes: these cells have a larger nucleus than lymphocytes, and it is folded. There is more cytoplasm than lymphocytes, and it is grey. Blood monocytes can migrate into tissues and become macrophages that persist for weeks to months.

  • Eosinophils: these specialized granulocytes are not numerous. They have prominent bright red cytoplasmic granules. They respond to allergic reactions and parasitic infections.

  • Basophils: these granulocytic cells have prominent dark purple cytoplasmic inclusions. They are the least numerous of circulating white blood cells.

A differential count is routinely performed with a complete blood count (CBC) to determine the relative numbers of the white blood cells in the peripheral blood. The peripheral blood smear is scanned and 100 white blood cells are counted. Below is an example:

Cell TypeCountNormal Range (%)
Segmented Neutrophil6145 - 79
Band Neutrophil20 - 5
Lymphocyte2416 - 47
Monocyte80 - 9
Eosinophil40 - 6
Basophil10 - 3

Megakaryocytes are the prominent large multinucleated cells scattered through the bone marrow. Platelets are the circulating fragments of megakaryocyte cytoplasm. The platelets are involved in coagulation. They are short-lived, only lasting a few days. Platelets have cytoplasmic granules, but no nucleus.

Lymphoid Tissues

The lymphoid tissues are distributed into the following major sites:

  • Lymph Nodes

  • Gastrointestinal Tract

  • Spleen

  • Thymus

  • Bone Marrow

The major cell types of lymphoid tissues include T cells and B cells, both derived from an uncommitted lymphoid stem cell. The designation "T" derives from the origin of many T cells in the thymus. The "B" cells are the "bursa equivalent" cells (so named because in birds, B cells are concentrated in a bursa of Fabricius next to the gut, and early studies were done in birds).

The B cells are responsible for production of globular proteins known as immunoglobulins that are directed against antigens. B cell markers include the CD19 and CD20 antigens. The immunoglobulins are, therefore, antibodies. The cells specialized to produce immunoglobulins are plasma cells. The plasma cells have an eccentrically placed nucleus with radially-arranged chromatin, a prominent Golgi apparatus next to the nucleus (the perinuclear "hof"), and abundant cytoplasmic endoplasmic reticulum for synthesizing immunoglobulin.

Plasma cells specialize in terms of antibody production. Different plasma cells can make immunoglobulin types G, A, M, D, and E. When the immune system responds to an infection, there are typically antibody responses to a variety of antigens, so that there are different types of immunoglobulin produced with specificities for the antigens. Such a response is called "polyclonal" because several clones of plasma cells, each producing a specific antibody, are stimulated to produce different immunoglobulins (mostly IgG, but the earliest production of antibody is of the IgM type). A neoplastic transformation of B cells that results in a proliferation of plasma cells causes a "monoclonal" production of immunoglobulin, because the neoplasm (called a myeloma) is a proliferation derived from a single clone.

The use of immunizations (e.g., to protect against childhood infections such as rubella or pertussis) is based upon the introduction of antigenic components of the infectious agent into the body that stimulate the immune system to produce specific antibodies. An encounter with the real infectious agent at a later date will result in quick production of antibodies against the infectious agent, because there are circulating antibodies as well as plasma cells in "storage" waiting to respond to the challenge.

The T cells are primarily involved in cell-mediated immune responses. They are identified by the presence of the CD3 antigen. In fetal life and childhood, the T cells arose in the thymus and then populated other lymphoid tissues. The major T cells are the "helper" cells that mark with the CD4 antigen and the "suppressor" cells that mark with the CD8 antigen. The recognition and stimulation of T cells is largely dependent upon recognition of major histocompatibility complex (MHC) antigens, also known as HLA antigens. Many cells of the human body express these antigens.

The T cells are often aided by macrophages, which phagocytize infectious agents, process the antigens, and present them to the T cells (and to B cells). Antibodies coating an invading micro-organism can lead to lysis by specialized lymphocytes called "natural killer" or NK cells./P>

Mast cells are specialized cells that have many cytoplasmic granules that can be released in response to inflammatory reactions, particularly type I hypersensitivity reactions. The granules contain mediators of the inflammatory process such as histamine.

Dendritic reticulum cells serve to assist in storing and transferring antigens to lymphoid cells which will respond to the antigens. The dendritic cells located in skin and mucous membranes are known as Langerhans cells. Within lymph nodes, they are known as follicular dendritic cells. These dendritic cells are named because of the long cell processes which catch antigens and "warehouse" them.

Lymph Nodes

The lymphatic channels of the body drain into groups of lymph nodes that are strategically placed to filter the lymph draining body regions and to provide immune surveillance based upon the antigen content of the lymph. The afferent lymphatic channels drain into the periphery of a lymph node in a region under the connective tissue capsule known as the subcapsular sinus. In the periphery of a lymph node is the paracortical region where lymphoid follicles are located. A follicle is a loosely arranged structure with an outer mantle of small T lymphocytes and a germinal center composed of B lymphocytes, follicular dendritic cells, and macrophages. The interfollicular zones between the follicles are populated mainly by T cells. From the periphery of the node, connective tissue trabeculae extend toward the hilum of the node. Sinuses drain toward the hilum and contain mainly macrophages. The medullary cords located near the hilum of the node contain mainly plasma cells and small lymphocytes. From the hilum, the efferent lymphatic channels egress.

The structure of a lymph node is diagrammed above:

  • A - Afferent lymphatic channels

  • B - Subcapsular sinus

  • C - Follicle

  • D - Sinuses

  • E - Paracortical region

  • F - Medullary cords

  • G - Efferent lymphatic channel

Gut Associated Lymphoid Tissue (GALT)

In the lamina propria and submucosal regions of the gastrointestinal tract from the tongue to the colon are collections of lymphoid tissue. In some areas, the lymphoid tissue is more prominent:

  • Lingual Tonsil: at the posterior tongue are larger collections of lymphoid tissue.

  • Pharyngeal Tonsil: these are the structures commonly called "tonsils" and comprise tissues functionally equivalent to lymph nodes.

  • Peyer's Patches: these are ovoid areas from 0.5 to 1.5 cm wide and 1 to 4 cm long located in the terminal ileum.

  • Appendix: the appendiceal submucosa contains abundant lymphoid tissue.


The spleen has a connective tissue capsule and has trabeculae of connective tissue running through the parenchyma. Arterial blood reaches the spleen through the splenic artery and drains out the splenic vein. The splenic parenchyma consists of red pulp and white pulp. The smaller arterial channels eventually become the central arterioles that run through the center of the nodules of white pulp, so named because this is where the lymphocytes are concentrated. From the arterioles, blood can be shunted directly to red pulp veins and out trabecular veins to the splenic vein. However, the filtering function of the spleen is accomplished by shunting some of the blood into the splenic cords. From there, the blood passes through slit-like channels in the splenic sinusoids into the red pulp veins.

Thus, the red pulp of the spleen is composed of thin-walled vascular sinusoids separated by fibrovascular splenic cords. These sinusoids are lined by a discontinuous epithelium, allowing passage of cells between the cords and the sinuses. The sinuses are lined with macrophages which are loosely connected by long dendritic processes, creating a filter through which the blood can seep. These sinuses act to trap red cell inclusions. These also act to trap older red blood cells (>120 days) for recycling, and to trap platelets. In a normal adult, up to 2 liters of blood per minute will filter through the spleen.

Of all the lymphoid organs in the body, the spleen is the only one with a preponderance of B cells rather than T cells. The lymphoid cells of the white pulp form a cylindrical cuff or sheath around splenic arterioles, and these are mainly T cells. At branch points of the arterioles, there may be expansion of this cylindrical sheath to form lymphoid nodules that contain B cells. With antigenic stimulation, the lymphoid follicles may be seen grossly The white pulp in spleen acts similarly to the lymphoid tissues in lymph nodes in initiating the immune reactions involving both cellular and humoral immunity.

The spleen also has a storage function. About 1/3 of the body pool of platelets is sequestered in the spleen. When the spleen enlarges (splenomegaly), too many platelets may be sequestered, leading to thrombocytopenia.


The thymus functions mainly in fetal life and early childhood. By puberty, the lymphoid tissues have largely been replaced by adipose tissue. The functional thymus is composed of two regions: the outer cortex and the inner medulla. Within the medulla are central structures known as Hassall's corpuscles that are composed of tight nests of epithelial cells. From the stem cells are derived pre-T cells that migrate from the cortex to the medulla, where they become functional CD4 and CD8 cells. The cortex is isolated from the thymic medulla by epithelial reticular cells. During development, about 98% of T cells in the cortex do not pass inspection for one reason or another (such as abnormal recognition of self-antigens) and are destroyed before reaching the thymic medulla, from which they are sent out to lymphoid regions throughout the body.

In the adult thymus, there is no defined cortex and medulla. It is atrophic and mainly replaced by adipose tissue, though some lymphocytes and Hassall's corpuscles remain.

Bone Marrow

Both lymphocytes and plasma cells are present in the marrow, though their numbers are not great. In older adults, there may be a few scattered small lymphoid nodules. Leukemias represent abnormal proliferations either the lymphoid or myeloid cell lines. A myeloproliferative disorder represents abnormal proliferation of cells that are derived from the hematopoietic stem cell line, so there can be greatly increased numbers of myeloid cells, erythroid cells, or megakaryocytes--or combinations of them.