shifts to the liver between the third and fourth months of gestation, and finally shifts to the bone marrow. During times of exceptional demand for blood cells (e.g., hemorrhage) or when the bone marrow is injured, the liver and spleen become sites of extramedullary hematopoiesis.
As shown in Figure 1.1, the HSC gives rise to common lymphoid progenitor cells and myeloid progenitors. The former then differentiates into lymphocyte populations (B and T cells) in a process known as lymphopoiesis. Lymphoid progenitor cells also give rise to a subpopulation of dendritic cells as well as natural killer (NK) cells and innate immune cells (ILC). Myeloid progenitor cells ultimately differentiate into neutrophils, eosinophils, basophils, erythrocytes (red blood cells), and monocytes which further differentiate into macrophages and dendritic cells. Myeloid progenitors also give rise to megakaryocytes which undergo an intricate series of remodeling that results in the release of thousands of platelets from a single megakaryocyte. In later chapters, we will discuss in more detail the major characteristics of each of the hematopoietic cells as well as the major steps of lymphocyte development.
Figure 1.1. Self‐renewing hematopoietic stem cells differentiate into lymphoid and myeloid progenitors. These cells differentiate along lineage‐specific lines in the bone marrow. Most of these cells mature there and then travel to peripheral organs via the blood. Mast cells and macrophages undergo further maturation outside the bone marrow. T cells develop into mature T‐cell subsets in the thymus before entering the periphery.
The immune system has evolved to exploit each of the hematopoietic cell populations. As we have already pointed out, it is convenient to discuss the major arms of the immune system beginning with elements of the innate immune system followed by the adaptive immune system. But it is important to underscore the interrelationship of these two arms of our immune system. Clearly, they are interrelated developmentally due to their common hematopoietic precursor, the hematopoietic stem cell. A classic example of their functional interrelationship is illustrated by the roles played by innate immune cells involved in antigen presentation. These so‐called antigen‐presenting cells (APCs) do just what their name implies: they present antigens (e.g., pieces of phagocytized bacteria) to T cells within the adaptive immune system. As will be discussed in great detail in subsequent chapters, T cells must interact with APCs that display antigens for which they are specific in order for the T cells to be activated to generate antigen‐specific responses.
CLONAL SELECTION THEORY
A turning point in immunology came in the 1950s with the introduction of a Darwinian view of the cellular basis of specificity in the immune response. This was the now universally accepted clonal selection theory proposed and developed by Jerne and Burnet (both Nobel Prize winners) and by Talmage. The clonal selection theory had a truly revolutionary effect on the field of immunology. It dramatically changed our approach to studying the immune system and stimulated research carried out during the last half of the twentieth century. This work ultimately provided us with knowledge regarding the molecular machinery associated with activation and regulation of cellular elements of the immune system. The essential postulates of this theory are summarized below.
As we have discussed earlier, the specificity of the immune response is based on the ability of B and T lymphocytes to recognize particular foreign molecules (antigens) and respond to them in order to eliminate them. The process of clonal expansion of these cells is highly efficient, but there is always the rare chance that errors or mutations will occur, resulting in the generation of cells bearing receptors that bind poorly or not at all to the antigen, or, in a worse‐case scenario, cells that have autoreactivity. Under normal conditions, nonfunctional cells may survive or be aborted with no deleterious consequences to the individual. In contrast, the rare self‐reactive cells are clonally deleted or suppressed by other regulatory cells of the immune system charged with this role, among others. If such a mechanism were absent, autoimmune responses might occur routinely. It is noteworthy that during the early stages of development, lymphocytes with receptors that bind to self‐antigens are also produced, but fortunately they are also eliminated or functionally inactivated. This process gives rise to the initial repertoire of mature lymphocytes that are programmed to generate antigen‐specific responses with a relatively minute population functionally benign, albeit potentially autoreactive cells (Figure 1.2). The circumstances and predisposing genetic conditions that may lead to the latter phenomenon are discussed in Chapter 12.
Figure 1.2. Clonal selection theory of B cells leading to antibody formation.
As we have already stated, the immune system is capable of recognizing innumerable foreign substance serving as antigens. How is a response to any one antigen accomplished? In addition to the now proven postulate that self‐reactive clones of lymphocytes are functionally inactivated or aborted, the clonal selection theory proposed the following.
T and B lymphocytes of myriad specificities exist before there is any contact with the foreign antigen.
Lymphocytes participating in an immune response express antigen‐specific receptors on their surface membranes. As a consequence of antigen binding to the lymphocyte, the cell is activated and releases various products. In the case of B lymphocytes, these receptors, so‐called B‐cell receptors (BCRs), are the very molecules that subsequently get secreted as antibodies following B‐cell activation.
T cells have receptors denoted as T‐cell receptors (TCRs). Unlike the B‐cell products, the T‐cell products are not the same as their surface receptors but are other protein molecules, called cytokines, that participate in elimination of the antigen by regulating the many cells needed to mount an effective immune response.
Each lymphocyte carries on its surface receptor molecules of only a single specificity, as demonstrated in Figure 1.2 for B cells, and which also holds true for T cells.
These postulates describe the existence of a large repertoire of possible specificities formed by cellular multiplication and differentiation before there is any contact with the foreign substance to which the response is to be made. The introduction of the foreign antigen then selects from among all the available specificities those with specificity for the antigen, enabling binding to occur. The scheme shown in Figure 1.2 for B cells also applies to T cells; however, T cells have receptors that are not antibodies and secrete molecules other than antibodies.
The remaining postulates of the clonal selection theory account for this process of selection by the antigen from among all the available cells in the repertoire.
Immunocompetent lymphocytes combine with the foreign antigen, or a portion of it termed the epitope or antigenic determinant, by virtue of their surface receptors. They are stimulated under appropriate conditions to proliferate and differentiate into clones of cells with the corresponding epitope‐specific receptors.
With B‐cell clones, this will lead to the synthesis of antibodies
