Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 4: Cells of the Innate Immune System

I. OVERVIEW

White blood cells or leukocytes serve as sentinels and defenders against infection by patrolling the tissues and organs of the body. They move around the body via the lymphatic and blood circulatory systems and can leave and reenter the circulation to move through body tissues. As “soldiers” of the immune system, leukocytes have specialized roles in defense of the body. Leukocytes are classified by morphology, including the number of lobes that their nuclei possess and the presence or absence of microscopically visible granules in their cytoplasm (Fig. 4.1). Histologic structure is often a helpful clue to the cell’s function. Some leukocytes may combat invasive organisms directly; others produce soluble molecules that serve as deterrents to microbial invasion throughout the body. Some leukocytes are autonomous, wielding lethal blows against invaders without intervention from other cells. Others are poised for “combat,” awaiting “orders” from their superiors. Still others serve as field marshals by regulating the assault. Leukocytes may be found as individual cells throughout body, as accumulations within lymphoid organs (e.g., spleen, lymph nodes) and at sites of infection or inflammation. Knowledge of the role that each leukocyte plays is important to understanding immune function.

All bloodborne cells ultimately derive from pluripotent hematopoietic stem cells. They are called pluripotent because each stem cell has the capacity to produce all leukocytes as well as red blood cells (erythroid lineage) and platelets (thrombocytic lineage). Pluripotent stem cells resident in the bone marrow are the source of lymphocytes and plasma cells; macrophages, monocytes, and dendritic cells; and granulocytes (neutrophils, eosinophils, and basophils). Cells of the myeloid lineage, especially those containing cytoplasmic granules (eosinophils, basophils, and neutrophils), together with agranular phagocytic cells (monocytes, macrophages, and dendritic cells) are involved in innate defenses. Other myeloid lineage–derived cells are involved in transport of oxygen and carbon dioxide (erythrocytes or red blood cells) and in blood clotting (platelets). Most of the cells derived from the lymphoid lineage (lymphocytes and plasma cells) are responsible for adaptive immune responses (see Unit III). Other cells (natural killer or NK cells and the phagocytes) bridge both innate and adaptive immune systems.

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Figure 4.1

Types of leukocytes. White blood cells or leukocytes may be broadly classified by the absence (agranular) or presence (granular) of cytoplasmic inclusions or granules. A. Lymphocytes include T, B, and natural killer (NK) cells. B. B cells that enlarge and differentiate into immunoglobulin secretors are known as plasma cells. C. Monocytes are phagocytic cells in the circulation and are called macrophages when they enter tissues. D. Dendritic cells are phagocytic cells that bear treelike cytoplasmic processes. E. Neutrophils have multilobed nuclei and cytoplasmic granules that stain with neutral (pH) dyes. F. Basophils have bilobed nuclei and cytoplasmic granules that stain with basic (pH) dyes. G. Eosinophils have bilobed nuclei and cytoplasmic granules that stain with acidic (pH) dyes.

II. AGRANULAR LEUKOCYTES

White blood cells that have multilobed nuclei and contain conspicuous cytoplasmic granules are known as granulocytes. Others with a single, unlobed nucleus and cytoplasm that contains few or no granules are known as agranular leukocytes. Agranular leukocytes derive from lymphoid or myeloid lineage precursors and account for approximately 35% to 38% of the leukocytes in circulation.

A. Lymphoid lineage cells

Cells that differentiate along one of several of the lymphocytic pathways are known as lymphocytes (see (Fig. 4.2). B lymphocytes or B cells reside in the bone marrow and are able to synthesize immunoglobulin molecules. In fact, B cells and their further differentiated progeny, plasma cells, are the only cells that are capable of immunoglobulin synthesis. Other lymphoid lineage cells of bone marrow origin migrate to, differentiate, and are vetted within the environment of the thymus. Those cells (thymocytes) that exit the thymus are known as thymus-derived lymphocytes or T lymphocytes (T cells). We will address the differentiation and function of B cells, plasma cells, and T cells and their roles in adaptive immune function in Chapters 7 to 21.

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Figure 4.2

Hematopoietic lineages. Pluripotent stem cells within the bone marrow give rise to all the cells found in the blood. Cells of the myeloid lineage differentiate further into platelets, erythrocytes, eosinophils, basophils (and mast cells), neutrophils, monocytes/macrophages, and some dendritic cells. Cells of the lymphoid lineage differentiate further into T and B lymphocytes, NK cells, and some dendritic cells.

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Figure 4.3

Lymphocytes. Except for differing in size (4- to 15-μm range), lymphocytes generally look alike although they may vary functionally.

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Figure 4.4

Monocytes. Circulating mononuclear phagocytes are called monocytes. When they leave the circulation and enter tissues they are called macrophages.

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Figure 4.5

Dendritic cells. As professional phagocytes, dendritic cells use their cytoplasmic extensions to sample their environment.

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Figure 4.6

Neutrophil development. Neutrophils are the most numerous leukocytes and play a vital role in policing the body against microbial invasion. They require about 2 weeks to mature from metamyelocytes through intermediate stages and become mature-segmented neutrophils.

A third lymphoid lineage cell distinct from B and T cells, and their progeny is the natural killer (NKcell. These large, nonphagocytic, granular lymphocytes are named for their ability to kill abnormal (e.g., infected or malignant) host cells (Fig. 4.3). They account for 5% to 10% of all lymphocytes in the circulation.

B. Monocytic lineage cells

Mononuclear cells that differentiate from myeloid precursors are known as monocytes in the circulation or macrophages once they leave the circulation and enter the tissues. These cells are the scavengers of the body. They phagocytize or pick up cellular debris, foreign cells, and particles and degrade them enzymatically. Another group of phagocytic cells with both myeloid and lymphoid origins is collectively known as dendritic cells, so named for their branchlike cytoplasmic projections.

1. Monocytes and macrophages: Monocytes are large mononuclear cells and account for approximately 5% to 7% of the leukocytes in the peripheral blood (Fig. 4.4). Monocytes spend 1 to 2 days in the circulation (their half-life is approximately 8.4 hours), then cross the endothelium to enter tissues throughout the body, where they reside for up to several months as macrophages. Both monocytes and macrophages actively sample their environment by phagocytosis and serve as scavengers to remove cellular debris. Ingested materials are enzymatically degraded.

2. Dendritic cells: Found throughout the body but predominantly in potential portals of microbial entry (e.g., skin, lung, gastrointestinal tract), these cells are named for their branchlike cytoplasmic projections (Fig. 4.5). Like other phagocytes, dendritic cells actively engulf cells and particles in their environment by phagocytosis (see Chapter 20). In addition, dendritic cells sample copious quantities of extracellular fluids by macropinocytosis, in which their cytoplasmic projections encircle and engulf tissue fluids, and the molecules, and particles contained within. Dendritic cells may arise from either myeloid or lymphoid (also called plasmacytoid) lineage cells. As actively phagocytic cells, dendritic cells are important in innate immune defenses.

III. GRANULAR LEUKOCYTES

Leukocytes that contain conspicuous cytoplasmic granules are known as granulocytes. These cells have multilobed nuclei and cytoplasmic granules that contain amines (stained by basic dyes), basic proteins (stained with acidophilic or eosinophilic dyes), or both (neutral staining).

A. Neutrophils

Comprising approximately 60% of the peripheral blood leukocytes, neutrophils are the most numerous leukocyte population. They are also called polymorphonuclear (PMN) cells because of their variable number of nuclear segments (two to five). With a half-life of approximately 7 hours, more than 100 billion neutrophils enter the circulation daily in normal adults. It takes about 2 weeks for metamyelocytes (an intermediate stage neutrophil with a kidney-shaped nucleus) to differentiate from the juvenile or band form (with an elongating nucleus), to the staff or stab (German, meaning “staff”) form, and then to the segmented or mature stage (Fig 4.6). Neutrophils are very effective at killing bacteria. An increase in the number of peripheral blood neutrophils is often an indication of acute infection. As reserves of PMNs within the bone marrow become exhausted during an infectious disease, several metamyelocytes and juvenile forms increase in the circulation.

B. Basophils and mast cells

The acidic cytoplasmic granules of basophils contain vasoactive amines (e.g., histamine) that cause smooth muscle contraction and are readily stained with “base-loving” dyes (Fig. 4.7). These bilobed cells are found in low numbers in the peripheral blood (0% to 1%) or in their tissue resident form, known as mast cells. Both basophils and mast cells are important in allergic reactions of the adaptive immune response (discussed in Chapter 14).

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Figure 4.7

Basophils. Release of their cytoplasmic granules (degranulation) disseminates vasoactive amines and other molecules associated with allergic reactions.

C. Eosinophils

So named because of their “eosin-loving” granules (eosin is a dye used in histology), eosinophils are bilobed granulocytes with cytoplasmic granules that contain basic proteins. Although they comprise 0% to 5% of the peripheral blood leukocytes, eosinophils are active participants in innate and adaptive immune responses to parasitic helminth (worm) infections (Fig. 4.8).

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Figure 4.8

Eosinophils. Release of cytoplasmic granules by eosinophils provides molecules that are potent weapons against parasitic worms.

Chapter Summary

• All bloodborne cells ultimately derive from pluripotent hematopoietic stem cells that have the capacity to produce all leukocytesred blood cells, and platelets.

• Cells of the myeloid lineage (eosinophilsbasophilsneutrophilsmonocytesmacrophages, and some dendritic cells) are involved in innate immune defenses.

• Many of the cells derived from the lymphoid lineage (lymphocytes and plasma cells) are responsible for adaptive immune responses.

• Agranular leukocytes derive from lymphoid or myeloid lineage precursors and account for approximately 35% to 38% of the leukocytes in circulation.

• B cells and plasma cells are the only cells capable of immunoglobulin synthesis.

• Mononuclear cells (monocytes and macrophages) are the scavengers of the body. They phagocytize; that is, they pick up cellular debris, foreign cells, and particles and degrade them enzymatically.

• Mast cells are similar to basophils but reside in connective tissues.

• Natural killer cells are large, nonphagocytic, granular lymphocytes that kill abnormal (e.g., infected or malignant) host cells and account for 5% to 10% of all lymphocytes in the circulation.

• Sixty percent of the peripheral blood leukocytes are neutrophils. These cells are very effective at killing bacteria.

Study Questions

4.1. Which of the following types of cells are notable for their presence at the sites of helminth infections?

A. Basophils

B. Eosinophils

C. Lymphocytes

D. Monocytes

E. Neutrophils

The answer is B. Eosinophils contain cytoplasmic granules that serve as potent agents against infection by parasitic worms (helminths). Basophils do not migrate to the site of an infection. Although lymphocytes, monocytes, and neutrophils will migrate to infection sites, eosinophils uniquely migrate to sites of parasitic worm infection.

4.2. Natural killer cells are members of which of the following families of leukocytes?

A. Basophils

B. Eosinophils

C. Lymphocytes

D. Monocytes

E. Neutrophils

The answer is C. Natural killer (NK) cells are lymphocytes and are often described as large, granular, non-T, non-B lymphocytes. Although they do contain cytoplasmic granules, these are considerably less prominent than those found in granulocytes (basophils, eosinophils, and neutrophils). Nor are NK cells members of the monocyte family.

4.3. A 16-year-old boy has acute appendicitis (infection of the appendix). Which of the following blood cells is most likely to increase in number as a result of his condition?

A. Basophils

B. Eosinophils

C. Lymphocytes

D. Monocytes

E. Neutrophils

The answer is E. A marked increase in blood neutrophils is a hallmark of infection. Basophils and eosinophils are rarely seen in the circulation in numbers that exceed 5% of the bloodborne leukocytes. Monocytes and lymphocytes increase in notable numbers usually only in chronic disorders.

4.4. Which of the following cells are important effector cells in allergic reactions?

A. Basophils

B. Dendritic cells

C. Lymphocytes

D. Monocytes

E. Neutrophils

The answer is A. Bloodborne basophils and tissue resident mast cells are responsible for allergic responses caused by the release of vasoactive amines within their cytoplasmic granules. Dendritic cells, lymphocytes, and monocytes all play roles in adaptive immune responses but are not the actual effector cells in allergic reactions. Neutrophils actively destroy invasive bacteria.

4.5. Which of the following cells sample their extracellular environment by macropinocytosis?

A. Basophils

B. Dendritic cells

C. Eosinophils

D. Macrophages

E. Neutrophils

The answer is B. Dendritic cells use two mechanisms to sample their extracellular environment. One, phagocytosis, internalizes by endocytosis molecules and cells that are bound to the cell’s surface receptors. The other, macrophagocytosis, involves the engulfment of extracellular fluids by cytoplasmic projections. Basophils, eosinophils, macrophages, and neutrophils do not use macrophagocytosis.

4.6. Red blood cells are derived from

A. granulocytic lineage cells.

B. lymphocytic lineage cells.

C. monocytic lineage cells.

D. myeloid lineage cells.

E. thrombocytic lineage cells.

The answer is D. Erythrocytes or red blood cells derive from myeloid lineage cells. Erythrocytes play a unique role in the blood in the transport of gases to and from lungs to the tissues. None of the other cells derived from granulocyte (basophils, eosinophils, and neutrophils), lymphocytic (B and T lymphocytes, NK cells, and plasma cells), monocytic (monocytes, macrophages, and dendritic cells), and thrombocytic (platelets) lineages produce cells responsible for gas exchange.

4.7. A subset of which of the following of these undergoes further differentiation within the thymus?

A. Basophils

B. Eosinophils

C. Lymphocytes

D. Monocytes

E. Neutrophils

The answer is C. Thymus-derived or T cells are a subset of lymphocytes. None of the other cell types differentiate within the thymus.

4.8. Three days ago, an otherwise healthy 17-year-old boy sustained a skin laceration during a lacrosse match. Yesterday, he complained of mild “flulike” symptoms. This morning, he became suddenly ill with a fever, general muscle aches, and dizziness; then he lost consciousness. On arrival in the emergency department, he had a temperature of 37.8°C and a heart rate of 136 beats per minute. His blood leukocyte count was 22,000 cells per μl (reference range: 4,500 to 12,500 per μl). The predominant cell type(s) in this patient’s blood is/are most likely

A. B lymphocytes.

B. juvenile and mature neutrophils.

C. monocytes and macrophages.

D. natural killer cells.

E. T lymphocytes.

The answer is B. Numbers of circulating neutrophils (mostly segmented form) quickly increase on an acute infection. Such numbers are recruited that some juvenile forms are pressed into the circulation prior to their maturation. B and T lymphocytes, natural killer (NK) cells, and monocytes and macrophages do not show the same rate of increase.

4.9. Lymphoid lineage cells

A. are the most numerous leukocyte population.

B. consist of B, T, and NK cells.

C. contain conspicuous cytoplasmic granules.

D. differentiate from myeloid cell precursors.

E. phagocytize debris and foreign cells.

The answer is B. Lymphocytes including bone marrow–derived (B cells), thymus-derived (T cells), and natural killer (NK) cells derive from lymphoid lineage cells. They account for fewer than 40% of blood leukocytes; neutrophils are the most numerous. Lymphoid lineage cells are agranular leukocytes and are also poorly phagocytic.