Lymphocytes

T CellS *( representative sample)

B cells

CD4+ T Cell CD4+ T Cell CD8+Tcell y/S b cell Plasma cell

Fig. 1.4. Cells of the immune system. Cells of the innate immune system and the adaptive immune system are illustrated. Note that there are several types of cells in the various categories.

Phagocytes

Phagocytes are cells whose function is primarily phagocytosis. Phagocytosis is a defense mechanism by which microorganisms, especially bacteria and other extracellular microbes are engulfed and destroyed by phagocytes. Predominant phagocytes include neutrophils and monocytes/macrophages (Figs. 1.1, 1.4). The neutrophil is the dominant type of circulating polymorphonuclear granulocyte. The term monocyte refers to immature macrophages. Monocytes are typically found in circulation and have a limited capacity for phagocytosis. When monocytes migrate to different tissues, they mature into macrophages. Mature macrophages exist in tissues and are named according to the particular area of the body in which they reside (Table 1.2). In addition to its role in phagocytosis, the macroph-1 age serves as a link between innate and adaptive immunity by delivering antigen to distinct lymphocytes, a process termed antigen presentation (see below).

Antigen presenting cells

Antigen presenting cells (APC) are cells that endocytose antigen, process it into fragments (peptides), and then display various fragments on the cell surface. For effective presentation antigen fragments must be expressed on the APC surface, cradled within the groove of special molecules termed, class II major histocompatibility proteins (class II MHC). These cell surface complexes of peptide/ class II MHC represent the form of antigen that is recognized by a subset of lymphocytes, T lymphocytes. Antigen presenting cells include dendritic cells, macrophages, and B cells (Figs. 1.1, 1.4). B cells are lymphocytes that function as antigen presenting cells in addition to their role in adaptive immunity.

Natural killer cells

The main role of natural killer (NK) cells is destruction of virally infected autologous (self) cells. There is evidence that natural killer cells also destroy some tumor cells (Figs. 1.1, 1.4). Exposure to certain small molecules termed cytokines (e.g., interleukin-2 and interleukin-12), enhances the ability of NK cells to kill their targets. In the presence of high concentrations of interleukin-2, NK cells differentiate to lymphokine activated killer cells (LAK cells). LAK cells are cytotoxic and are more potent killers than the NK cells.

Inflammatory cells

Inflammatory cells include mast cells, basophils, and eosinophils (Figs. 1.1, 1.4). Basophils are the circulating counterpart of the tissue mast cells. Eosinophils are found primarily in tissues, and in smaller numbers, in the circulation. These inflammatory cells play a role in the development and/or maintenance of the inflammatory response, which is an integral part of immunity.

Mast cells are present in gut, lung, and in most tissues (including connective tissue) adjoining blood cells. Mast cells express high affinity receptors for differ-

Table 1.2 Phagocytic cell nomenclature

Tissue

Phagocytic Cell Nomenclature

Blood

Monocyte

Bone Marrow

Monoblasts

Central Nervous System

Microglial Cells

Kidney

Kupffer Cells

Synovium

Synoviocytes

Lung

Alveolar Macrophages

Lymph Node and Spleen

Macrophages

ent molecules, all of which (when crosslinked) can trigger the degranulation of mast cells and release of inflammatory mediators present in the granules. The 1 granules contain histamine, and the leukotrienes LTC4, LTD4, and LTE4, eosinophil chemotactic factor of anaphylaxis (ECF-A) and platelet activating factor (PAF). The leukotrienes, LTC4, LTD4, and LTE4 were previously collectively referred to as slow releasing substance of anaphylaxis (SRS-A). Because mast cells are present in tissues they are activated early in the response. Some of the molecules secreted at the site of tissue injury serve as chemotactic factors for other cells, including basophils and eosinophils. Molecules secreted by eosinophils include major basic protein (MBP), and eosinophil cationic protein (ECP), both of which play a role in the destruction of some parasites (e.g., helminths).

Cells That Function in Adaptive Immune Responses

Cells that function in adaptive immunity are lymphocytes (Figs. 1.2, 1.4). There are two broad classes of lymphocytes, B lymphocytes and T lymphocytes. Each cell type has a distinct function and mode of activation. In addition, subsets of cells within each class of lymphocytes have distinct roles. Lymphocytes possess unique antigen recognizing receptors, which endows them with the ability to interact with one antigen, but not another.

B lymphocytes

B lymphocytes express cell surface antigen receptors termed antibodies or immunoglobulins. These cell surface antibodies are the instruments by which B cells recognize and interact with antigen. In the presence of specific antigen, and appropriate costimulatory molecules, B cells will clonally expand and differentiate into antibody secreting plasma cells. For protein antigens, B-cell differentiation requires stimulation with cytokines secreted by T cells, as well as cognate interaction with a subset of T lymphocytes.

T lymphocytes

T lymphocytes are cells that express antigen recognizing receptors termed T cell receptors. T cells express one of two types of T-cell receptor, alpha/beta receptors or gamma/delta receptors. This designation refers to the polypeptides that make up the receptor. Most of the T cells in the body express alpha/beta receptors. Unless otherwise specified, the term T cell in this book refers to T cells expressing alpha/beta T-cell receptors. Alpha/beta T-cell receptors recognize, and interact with, antigen fragments that are displayed in the groove of proteins expressed on the surface of cells. The proteins that display antigen fragments are termed either class I MHC or class II MHC.

There are two major subsets of T lymphocytes, defined by the presence of protein markers, CD4 and CD8, on the cell surface. The CD4+ subset of T cells recognize antigen fragments presented in association with class II MHC expressed on the surface of antigen presenting cells. T cells expressing the CD4 marker are also referred to as T helper (Th) cells, because they secrete cytokines required for both innate and adaptive immunity. Th cell subsets secrete distinct patterns of cytokines which can be used to define the subsets, Th1 and Th2. Th1 cells secrete 1 Type 1 cytokines; Th2 cells secrete Type 2 cytokines. The activities of different components of the immune system are altered in the presence of Type 1 or Type 2 cytokines.

T cells expressing the CD8 marker are termed CD8+ T cells or cytotoxic T cells (CTL). Cytotoxic T cells are capable of destroying autologous cells expressing an antigen fragment in the groove of a class I MHC molecule. These autologous cells are commonly referred to as target cells (not antigen presenting cells). CD8+ T cells are also capable of destroying allogenic cells, as occurs in the context of tissue and/or organ transplantation.

Tissues of the Immune System: General Features

Immune tissues are broadly classed according to their role in the immune system. Tissues that serve as developmental sites for lymphocytes are termed primary immune tissues, while those tissues that serve as activation sites are termed secondary immune tissues. Primary immune tissues include the bone marrow and thymus. Although there is evidence for the development of lymphocytes outside these primary tissues, the sites have not been identified. Secondary immune tissues include the lymph nodes, tonsils and adenoids, spleen, and mucosa-associ-ated lymphoid tissue. The bone marrow and liver (the latter particularly in conditions of lympho-hematopoietic stress) can also be considered secondary lymphoid tissue.

Tissues of the Immune System: Primary Lymphoid Organs

Bone marrow

In the early stage of embryogenesis, blood cells arise from the yolk sac, and later from the liver and spleen. During the later stages of embryogenesis, and after birth, the bone marrow is the hematopoietic tissue that gives rise to most mature nonlymphoid blood cells including monocytes, granulocytes, eosinophils, basophils, erythrocytes, and platelets. These blood cells have a relatively short life span and are replaced continuously by progeny of self-renewing pluripotent stem cells, a process termed hematopoiesis. Under the influence of cytokines, and other factors produced by bone marrow stromal cells, blood cells go through distinct stages of differentiation and maturation before being released into the blood. Soluble mediators that have been shown to play a role in hematopoiesis include c-kit ligand, interleukin-3 (IL-3), interleukin-7 (IL-7), and the colony stimulating growth factors (CSF): G-CSF, M-CSF, and GM-CSF (G = granulocyte, M= monocyte).

Pluripotent stem cells also give rise to precursor lymphoid cells. Under the influence of the local microenvironment some of the lymphoid precursors will give rise to mature B cells, while other precursors will leave the bone marrow and migrate to the thymus. The bone marrow is, therefore, the site of B-cell development and maturation. B-cell development occurs prior to antigen exposure and is often referred to as antigen-independent B-cell maturation. B-cell maturation was initially shown to occur in the chicken's Bursa of Fabricius, and the human site of B-cell maturation is often referred to as the "bursa equivalent". The fundamental event of B-cell development is the expression of a unique B-cell antigen receptor (antibody) on its cell surface. This receptor is the instrument by which B cells will recognize antigen. Expression of any given B-cell antigen receptor is a random event, and some of the receptors expressed on B cells will recognize self-proteins and be potentially autoreactive. The cells expressing receptors that recognize self-molecules undergo tolerance induction, a process in which potentially autoreactive cells are deleted or inactivated (anergized). B-cell maturation is also characterized by the expression of cell surface proteins that play a role in subsequent B-cell activation, while other expressed proteins serve as phenotypic B-cell markers. These mature naive B cells leave the bone marrow and seed the periphery.

Thymus

The thymus is the site of T-cell maturation. At puberty the thymus weighs 3040 grams. Thereafter, it undergoes progressive involution and extensive fatty infiltration. Whether the remaining thymic rudiment is responsible for adult T-cell maturation and selection, or whether an extra thymic source exists for these adult functions, is not known. The thymus is a bi-lobed organ, with each lobe further subdivided into lobules. Each lobule has a cortex and a medulla (Fig. 1.5). A blood-thymus barrier prevents the passage of molecules from the blood to the thymic cortex. In contrast, the blood vessels of the thymic medulla have no such barrier.

By analogy with B cells, the most significant event of T-cell maturation is the cell surface expression of a unique antigen receptor, the T-cell receptor. Expression of a specific T-cell receptor is a random event, which results in the expression of some T-cell receptors that are of no value to the host, as well as some which are potentially autoreactive. During thymic maturation, processes termed respectively

Fig. 1.5. Site of T-cell development: the thymus. The thymus is the site of T-cell maturation. It is a bi-lobed organ, with each lobe being divided into lobules. Each lobule has a cortex and a medulla. T-cell maturation occurs primarily in the cortex, while the medulla serves as a site for final screening, and elimination of autoreactive cells.

Fig. 1.5. Site of T-cell development: the thymus. The thymus is the site of T-cell maturation. It is a bi-lobed organ, with each lobe being divided into lobules. Each lobule has a cortex and a medulla. T-cell maturation occurs primarily in the cortex, while the medulla serves as a site for final screening, and elimination of autoreactive cells.

death by neglect and negative selection delete these two types of T cell. Approxi-I mately, 50 million precursor cells enter the thymus daily with only approximately one million surviving the selection process. T cells that survive the selection process are said to have been positively selected and will undergo lineage commitment. Lineage commitment refers to a phenotypic change such that either a CD4 or a CD8 molecule is on the cell surface (not both). Because the expression of CD4 or CD8 determines the role of the T cell in the periphery, lineage commitment determines the biological function of the T cell. Thymocytes migrate from the cortex to the medulla where they undergo a second screening process to further ensure that selfreactive T cells are destroyed before leaving the thymus.

Tissues of the Immune System: Secondary Lymphoid Tissues

Secondary lymphoid tissues include the lymph nodes, tonsils and adenoids, spleen, and mucosa-associated lymphoid tissues (MALT). These tissues are the major sites of adaptive immune responses, though the actual site where the initial immune response occurs is determined by the mode of antigen entry (Fig. 1.6). If antigen is carried via the lymphatics, the initial site of the adaptive immune response is the lymph node; if antigens are blood-borne, the initial site of the adaptive immune response is the spleen; and if antigens enter via mucosal tissue, MALT serves as the initial site of the adaptive immune response.

Lymph nodes

Lymph nodes are encapsulated organs strategically located along lymphatic channels throughout the body. Afferent lymphatics penetrate the connective tissue that encapsulates the lymph node (Fig. 1.7) and empty their contents into the subcapsular sinuses. The sinuses are lined with tiny apertures that allow lymph

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Blood

Mucosal Tissue

Spleen

Lymph

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