5. Development of the Immune Response System
Before we examine lymphocyte development and function in greater detail, we must initially review concepts such as the unique structure of molecules (especially proteins), the characteristics of cell surfaces (membranes and envelopes), the ways that genes are expressed, immune recognition, and identification of self and nonself. Ultimately, the shape and function of protein receptors and markers protruding from the surfaces of certain white blood cells are the result of genetic expression, and these molecules are responsible for specific immune recognition and, thus, immune reactions.
Figure 2. Overview of the origins and events of adaptive immune responses.
6. Cooperation in Immune Reactions to Antigens
The basis for most immune responses is the encounter between antigens and white blood cells. Microbes and other foreign substances enter most often through the respiratory or gastrointestinal mucosa and less frequently through other mucous membranes or the skin. Antigens introduced intravenously become localized in the liver, spleen, bone marrow, kidney, and lung. If introduced by some other route, antigens are carried in lymphatic fluid and concentrated by the lymph nodes. The lymph nodes and spleen are important in concentrating the antigens in areas where they will come in contact with antigen-presenting cells (APCs) and lymphocytes. APCs and lymphocytes can subsequently circulate into fluid compartments to seek out the antigens for which they are specific.
7. The Role of Antigen Processing and Presentation
In most immune reactions, the antigen is in a “raw” state and must be further acted upon by antigen-presenting cells (APCs) before it is presented to T cells. Three different cells can serve as APCs: macrophages, dendritic cells (dendritic Gr. dendron , branching like a tree), and B cells. Antigen-presenting cells modify the antigen so that it will be more immunogenic and recognizable. After processing is complete, the antigen is moved to the surface of the APC and bound to an MHC class II receptor to make it readily accessible to T cells during presentation (figure 3).
Before a T cell can respond to APC-bound antigens, certain conditions must be met. T-cell-dependent antigens, usually proteinbased, require recognition steps between the APC, antigen, and lymphocytes. The fi rst cells on the scene to assist in activating B cells and other T cells are a special class of T helper cells (TH ). The T cell receptor (TCR) of this class of T cell will bind simultaneously with the class II MHC receptor on the APC and with the antigen (figure 3). A second interaction involves the binding of the T-cell CD4 receptor to the MHC of the APC. Once this identification has occurred, a cytokine, interleukin-1 (IL-1), produced by the APC, activates this T helper cell. The T H cell, in turn, produces a different cytokine, interleukin-2 (IL-2), that stimulates a general increase in activity of committed B and T cells. The manner in which B and T cells subsequently become activated by the APC–T helper cell complex and their individual responses to antigen are addressed in the next two sections.
Figure 3. Interactions between antigen-presenting cells (APCs) and T helper (CD4) cells required for T-cell activation.
A few antigens can trigger a response from B lymphocytes without the cooperation of APCs or T helper cells. These T-cell-independent antigens are usually simple molecules such as carbohydrates with many repeating and invariable determinant groups. Examples include lipopolysaccharide from the cell wall of Escherichia coli, polysaccharide from the capsule of Streptococcus pneumoniae, and molecules from rabies and Epstein-Barr virus. Because so few antigens are of this type, most B-cell reactions require assistance from T helper cells.
Figure 4. Events in B-cell activation and antibody synthesis. *Only key receptors for these reactions are shown.
8. B-Cell Responses: Activation of B Lymphocytes: Clonal Selection, Expansion, and Antibody Production
The immunologic activation of most B cells requires a series of events (figure 4).
1. Clonal selection and binding of antigen. In this case, a precommitted B cell of a particular clonal specificity picks up the antigen on its Ig receptors and processes it into small peptide determinants. The antigen is then bound to the MHC II receptors on the B cell. The MHC/Ag receptor on the B cell is bound by a TH cell.
2. Instruction by chemical mediators. The B cell receives developmental signals from macrophages and T cells (interleukin-2 and interleukin-6) and various other growth factors, such as IL-4 and IL-5.
3. The combination of these stimuli on the membrane receptors causes a signal to be transmitted internally to the B-cell nucleus.
4. These events trigger B-cell activation. An activated B cell called a lymphoblast undergoes an increase in size and DNA and protein synthesis, in preparation for entering the cell cycle and mitosis.
5–6. Clonal expansion. A stimulated B cell multiplies through successive mitotic divisions and produces a large population of genetically identical daughter cells. Some cells that stop short of becoming fully differentiated are memory cells, which remain for long periods to react with that same antigen at a later time. This reaction also expands the clone size, so that subsequent exposure to that antigen provides more cells with that specificity. This expansion of the clone size is one factor in the increased memory response. The most numerous progeny are large, specialized, terminally differentiated B cells called plasma cells.
7. Antibody production and secretion. The primary action of plasma cells is to secrete into the surrounding tissues copious amounts of antibodies with the same specificity as the original receptor (figure 4). Although an individual plasma cell can produce around 2,000 antibodies per second, production does not continue indefinitely. The plasma cells do not survive for long and deteriorate after they have synthesized antibodies.