Immunology. Richard Coico
hundreds of lymph nodes located deep inside the body. They are close to major junctions of the lymphatic channels, which are connected to the thoracic duct. The thoracic duct transports lymph and lymphocytes to the vena cava, the vessel that carries blood to the right side of the heart (see Figure 2.14), from where it is redistributed throughout the body.
Lymph nodes are composed of a medulla, with many sinuses, and a cortex, which is surrounded by a capsule of connective tissue (Figure 2.5A). The cortical region contains primary lymphoid follicles. After antigenic stimulation, these structures enlarge to form secondary lymphoid follicles with germinal centers containing dense populations of lymphocytes (mostly B cells) that are undergoing mitosis (Figure 2.5B). In response to antigen stimulation, antigen‐specific B cells proliferating within these germinal centers also undergo a process known as affinity maturation to generate clones of cells with higher affinity receptors (antibody) for the antigenic epitope that triggered the initial response (see Chapter 9). The remaining antigen‐nonspecific B cells are pushed to the outside to form the mantle zone. The deep cortical area or paracortical region contains T cells and dendritic cells. Antigens are brought into these areas by dendritic cells, which present antigen fragments (peptides) to T cells, events that result in activation of the T cells. The medullary area of the lymph node contains antibody‐secreting plasma cells that have traveled from the cortex to the medulla via lymphatic vessels.
MAJOR HEMATOPOIETIC CELLS
In Chapter 1, we illustrated the developmental pathways of the major hematopoietic cells derived from stem cells in the bone marrow (see Figure 1.1). Cell populations emerging from these pathways include the granulocytes, lymphocytes, erythrocytes, monocytes, macrophages, dendritic cells, and megakaryocytes Our focus here will be those cells responsible for adaptive and innate immune responses which mainly derive from the common lymphoid progenitor cells and myeloid progenitor cells, respectively.
Lymphoid Lineage Cell Populations
We begin our discussion of cells of the immune system by focusing on cells derived from common lymphoid progenitors (CLPs) (see Figure 1.1). These cells, broadly called lymphocytes, represent the principal cell players in adaptive immune responses while, in the case of some cell types, they have the ability to bridge innate and adaptive immunity. Figure 2.6 illustrates the major lymphoid populations of cells derived from CLPs.
B Lymphocytes.
Antibody‐producing B lymphocytes (B cells) get their name from the organ site where they were first identified and shown to develop in birds, namely the bursa of Fabricius. As discussed in Chapter 1, in mammals, the major site of B cell maturation is the bone marrow where hematopoietic stem cells differentiate into CLPs which further differentiate into different lymphocyte populations (see Figure 2.6). B cells develop in a clonal fashion and fully mature within the bone marrow environment. Ultimately, each B‐cell clone differentiates to generate antigen receptors (antibody) composed of immunoglobulin molecules that get expressed as transmembrane molecules. A typical antibody molecule is composed of four polypeptide chains: two identical heavy chains and two identical light chains (Figure 2.7) (see also Figure 1.2 and Chapter 6).
Mature B cells entering the periphery are endowed with hundreds of thousands of antigen‐specific immunoglobulin (Ig) molecules anchored within their plasma membranes. These are closely associated with signaling molecules (Igα and Igβ) to enable the B cell to communicate with the nucleus when the B cell binds to its specific antigen. Together, the plasma membrane‐bound immunoglobulin and Igα/Igβ) molecules make up the B cell receptor (BCR) complex (Figure 2.8). B‐cell signaling following antigen activation is discussed in Chapter 9.
Figure 2.4. (A) Overall and section views of the spleen. (B) Section of spleen. The yellow arrow indicates red pulp. The green arrow points to white pulp showing a splenic nodule with a germinal center.
Source: Photograph by Dr Susan Gottesman, SUNY Downstate College of Medicine, New York.
The molecular mechanisms associated with the generation of these multichain polypeptide are discussed in Chapter 9. In short, the genes encoding the antigen receptors are formed by recombination of DNA segments during B‐cell maturation resulting in the generation of millions of uniquely recombined receptor genes encoding protein chains that associate with each other to create BCRs. Once B cells fully mature, they clonally express these BCRs to manifest a highly diverse repertoire of antigen specificities. Individual B cells within a given clone (with millions of cells per clone) all express identical BCRs and, hence, they share the same antigen specificity.
Figure 2.5. (A) Section of lymph node. Arrows show flow of lymph and lymphocytes. (B) Section through a lymph node showing T‐cell zone, mantle zone, and germinal center.
At this stage, the mature B cells exit the bone marrow and enter the periphery. B cells mainly populate the lymphoid organs (spleen, lymph nodes, and mucosal lymphoid tissue) but they also migrate to other anatomical sites including the skin, respiratory and gastrointestinal tracks, and the blood. Within the periphery, contact with antigens that bind to the specific BCRs which they express activates B cells, causing them to proliferate and further differentiate resulting in (1) an expansion of the B cell clone and secretion of antibody, (2) generation of plasma cells that become a permanent source of secreted antibody, and (3) a population of long‐lived B memory cells poised to rapidly respond to future exposure to the same antigen. Collectively, this response is responsible for humoral immunity (Figure 2.9).
Antigen activation of B cells is a team effort due, in particular, to the need for T‐cell help (see Chapter 9) to optimally stimulate B cells. Most B‐cell responses to antigen are, therefore, T cell dependent. B‐cell activation also results in the generation of an even more diverse population of B cells due to a process called class switching in which the antibodies produced preserve their antigen specificity while displaying nonantigen‐binding regions that impart functional properties of the antibody molecules that differ from the