The immune system consists of a network of circulating blood cells, lymphoid tissues, and organs, which respond to foreign material by producing soluble antibodies (humoral response) or activated lymphocytes and macrophages (cellular response). Lymphoid tissue is composed of primary and secondary lymphoid organs. The bone marrow and thymus are considered primary lymphoid organs. The spleen, lymph nodes, and tonsils are regarded as secondary organs; the submucosa of the lung and intestine are also important secondary lymphoid organs. To accommodate these organs into a classification scheme, these organs are called the bronchiole-associated lymphoid tissue (BALT) and the gut-associated lymphoid tissue (GALT). Together, these sites comprise the mucosal-associated lymphoid tissue (MALT). Lymphocytes and macrophages are the major effector cells in immunologic reactions.

Hematopoiesis

Hematopoiesis refers to the development or maturation of red blood cells, white blood cells, and platelets. In the third month of gestation, hematopoietic stem cells migrate to the fetal liver. Later in gestation, stem cells localize in the spleen, where they undergo maturation. After birth, most stem cells are found in the bone marrow. Marrow is found in tubular, flat, and long bones and consists of a connective tissue framework, called stroma, which supports red or yellow pulp. Red pulp, which is the major source of hemopoietic stem cells, is found in flat bones such as the hip bone, breast bone, ribs, and vertebrae. The cancellous material at the epiphyseal plate of long bones contains red pulp. Yellow pulp is the major marrow constituent in long tubular bones and is comprised of aggregated fat cells.

Stem cells from red pulp produce four major cell lineages: (1) erythrocytes, (2) platelets, (3) myeloid cells (polymorphonuclear leukocytes, basophils, eosinophils, monocyte/macrophages), and (4) lymphocytes. These lineages undergo maturation in the bone marrow before being released into blood.

Blood

Blood contains red and white cells. Red cells are responsible for carrying oxygen to tissues, and white blood cells play a key role in fighting infections.

White Blood Cells

Peripheral blood contains red blood cells, white blood cells, and platelets. Based on the presence or absence of cytoplasmic granules, white blood cells can be defined as granulocytes and nongranulocytes. Granulocyte subsets include polymorphonuclear leukocytes, eosinophils, and basophils. Monocytes and small lymphocytes are generally considered nongranulocytic. However, a small subpopulation of lymphocytes, called large granular lymphocytes (LGLs), does contain granules.

Polymorphonuclear Neutrophils

Polymorphonuclear neutrophils (PMN) (also referred to as polymorphonuclear leukocytes [PML]) constitute 50% to 70% of the white blood cells in peripheral blood. Their main function is to ingest and destroy foreign protein and bacteria. PMNs have a multi-lobed nucleus, which is usually divided into three or more segments (Figure 1-1).

The cytoplasm contains four distinct types of granules: (1) primary or azurophilic granules, (2) secondary granules, (3) gelatinase granules, and (4) secretory vesicles.

Primary Granules

These granules contain myeloperoxidase and lysozyme, which play major roles in the destruction of intracellular bacteria. Myeloperoxidase converts hydrogen peroxide into hypochlorous acid, which reduces pH and initiates the destruction of the bacterial cell wall. Lysozyme is an enzyme that disrupts the structural integrity of bacterial cell walls by breaking polymeric β 1-4 linkages.

Secondary Granules

Secondary granules contain additional enzymes such as apolactoferrin and collagenase, which prevent bacterial growth and increase PMN mobility. Apolactoferrin binds free iron and prevents the bacterial synthesis of heme-containing proteins such as cytochromes.

Tertiary Granules

Tertiary and secretory granules also play a role in immunity and host defense. Tertiary granules contain lysozyme and gelatinase. Gelatinase degrades ground substances between cells and increases PMN mobility. Secretory vesicles excrete N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP), which is a chemoattractant and activating agent for PMNs.

PMNs are produced in the bone marrow and undergo a 9-day to 2-week, seven-step maturation process from myeloblasts to mature cells. Mature cells entering the blood may remain in circulation (circulating pool) or marginate (marginating pool) by attaching to the endothelial lining of the vessels in capillary beds. Cells in capillary beds express certain molecules, called selectins, which preferentially attach PMNs to the vessel wall.

In response to infection or inflammation, PMNs “demarginate” and enter the blood circulation. At the same time, the bone marrow releases large numbers of immature neutrophils, called neutrophilic “bands,” into the circulation. The influx of immature band cells, commonly referred to by physicians as a left shift in blood cells, is indicative of an acute infection. The half-life of PMNs is 1 day in blood and 5 days in tissue.

Eosinophils

Eosinophils comprise 2% to 5 % of the circulating white blood cells. They are characterized by bi-lobed nuclei and the presence of large reddish-orange (eosin staining) granules and refractive crystals in the cytoplasm (Figure 1-2).

Figure 1-2 A, The internal structures of an eosinophilic granule are shown in this electron micrograph. B, An eosinophil in a blood smear (x1000). Note the reddish-orange granules. (From Carr J, Rodak B: Clinical hematology atlas, ed 3, St Louis, 2009, Saunders.)

Eosinophils migrate to inflammatory sites and extrude granules into the external environment. The contents of these granules include major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). Extruded granules are a useful alternative for killing large extracellular pathogens that cannot be ingested by phagocytic cells. The proteins in granules have the following functions:

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MBP	• Cytotoxic to helminth larvae
MBP	• Releases histamine and other preformed mediators from basophils
ECP	• Cytotoxic by pore formation in cell walls
EPO	• Neuronal and axonal damage in the cerebellum and spinal cord

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Basophils

Basophils constitute less than 1% of circulating leukocytes. They are small cells that have multi-lobed, heterochromatic nuclei and are easily stained with acidic or basophilic dyes (Figure 1-3). Basophils are one of the major effector cells in skin allergic reactions and termination of helminth infections. Cytoplasmic granules contain histamine, heparin, and tryptase.

Figure 1-3 A, A basophil with an obscured nucleus. B, An electron micrograph of a basophil (x28,750). (A, from Rodak B, Fritsma G, Doig K: Hematology: Clinical principles and applications, ed 3, St Louis, 2007, Saunders. B, from Carr J, Rodak B: Clinical hematology atlas, ed 3, St Louis, 2009, Saunders.)

Mast Cells

Mast cells are distributed beneath the epithelial linings of the skin and of the respiratory, intestinal, and genitourinary tracts. Although they have similar morphologies, mast cells are not basophils (Figure 1-4). They are derived from a different progenitor, have a different natural history, and express different cell surface markers.

Cytoplasmic granules are normal constituents of mast cells and contain the same inflammatory mediators as basophils. When released from mast cells, the inflammatory mediators facilitate allergic reactions in the respiratory tract and the intestine.

Monocytes

Monocytes comprise approximately 2% to 6% of the circulating white blood cells. They are the largest white blood cells in peripheral blood and contain large, indented nuclei, as well as abundant cytoplasm and azurophilic granules (Figure 1-5). As part of the immune response, monocytes degrade foreign material and present it to lymphocytes. Monocytes also produce reactive oxygen metabolites and the tumor necrosis factor (TNF), which has tumoricidal activity. In blood, monocytes have a half-life of 3 days.

Macrophages

Some circulating monocytes migrate into tissue to become fixed macrophages. Generally, these macrophages are located in certain anatomic areas, that is, bone, liver, brain, and connective tissue, where microbes are most likely to enter tissue. Tissue macrophages are usually named for their locations. For example, osteoclasts are found in bone, microglial cells are localized in the brain, and histiocytes are restricted to connective tissue.

The different types of tissue macrophages are presented in Table 1-1. Tissue macrophage populations are renewed every 6 to 16 days by an influx of monocytes or by the proliferation of tissue progenitor cells.

Table 1-1

Nomenclature for Tissue-Bound Macrophages

Location	Name
Connective tissue	Histiocytes
Bone	Osteoclasts
Liver	Kupffer cells
Neural tissue	Microglial cells

Lymphocytes

Between 20% and 45% of circulating white blood cells are lymphocytes. On the basis of size and staining patterns, lymphocytes are classified as small lymphocytes or large granular lymphocytes (Figure 1-6). Small lymphocytes have large, dark-staining nuclei, little cytoplasm, and no granules. Most small lymphocytes are localized in secondary lymphoid tissue (e.g., spleen or lymph nodes). Only 2% of these cells circulate in peripheral blood at any point in time. Large granular lymphocytes (LGLs), which arise in bone marrow, have large nuclei, plentiful cytoplasm, and multiple azurophilic granules. LGLs function as NK cells, which induce apoptosis in virus-infected cells and tumor cells. Lymphocytes have a half-life of several weeks to years.

Figure 1-6 1, The small lymphocyte has no granules, a round nucleus, and a high N:C ratio. 2, The large granular lymphocyte *(LGL)* has a lower N:C ratio, indented nucleus, and azurophilic granules in the cytoplasm. Giemsa stain (Courtesy of Dr. A. Stevens and Professor J. Lowe.). 3, An electron micrograph of a lymphocyte (x30,000). In general, the distinction between what is a large granule lymphocyte and what is a small lymphocyte is determined by the amount of cytoplasm within the cell. (From Carr J, Rodak B: Clinical hematology atlas, ed 3, St Louis, 2009, Saunders.)

Subdivision of Small Lymphocytes

Small lymphocytes are divided into T and B cells on the basis of differentiation in the thymus (T cells) or in bone marrow (B cells). T cells are involved in the apoptosis of tumor cells, inflammatory responses to intracellular bacteria, and immuneregulation. B cells differentiate into plasma cells that produce soluble, protein antibodies directed toward foreign protein, carbohydrates, and extracellular microbial pathogens called antigens.

T and B cells cannot be distinguished by light microscopy, since all small lymphocytes have the same morphology. The presence of surface glycoproteins and glycolipids, called cluster of differentiation (CD) markers, is used to identify T and B cells. All T cells express CD3, which is part of a TCR that interacts with antigenic fragments. Each lymphocyte has only a single TCR type and recognizes only one antigen.

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Cells and Organs of the Immune System

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