Immunology. Richard Coico
The migration of lymphocytes between lymphoid and nonlymphoid tissue ensures that on exposure to an antigen, the antigen and lymphocytes expressing antigen‐specific receptors are sequestered in the lymphoid tissue, where the lymphocytes undergo proliferation and differentiation. This results in expansion of the antigen‐specific B‐cell population and the generation of circulating antibody‐secreting plasma cells as well as long‐lived, antigen‐specific memory B cells. The latter are disseminated throughout the secondary lymphoid tissues to ensure long‐lasting immunity to the antigen.
Figure 2.13. Scanning electron micrograph of macrophage with ruffled membrane and surface covered with microvilli (×5200).
Source: Reproduced with permission from J Clin Invest 117 [2007].
THE FATE OF ANTIGEN AFTER PENETRATION
The reticuloendothelial system is designed to trap foreign antigens that have penetrated the body and to subject them to ingestion and degradation by the phagocytic cells of the system. Also, there is constant movement of lymphocytes throughout the body, and this movement permits deposition of lymphocytes in strategic places along the lymphatic vessels. The system not only traps antigens but also provides loci (the secondary lymphoid organs) where antigen, macrophages, T cells, and B cells can interact within a very small area to initiate an immune response.
Figure 2.14. Circulation of lymph and fate of antigen following penetration through: (1) bloodstream, (2) skin, and (3) gastrointestinal or respiratory tract.
The fate of an antigen that has penetrated the physical barriers and the cellular and antibody components of the ensuing immune response are shown in Figure 2.14. Three major routes may be followed by an antigen after it has penetrated the interior of the body.
Antigens may enter the body through the bloodstream. In this case, they are carried through circulatory system to the spleen where they interact with APCs, such as DCs and macrophages. As discussed earlier, a major function of these APCs is to take up, process, and then present components of the antigen to the T cells that express the appropriate antigen‐specific TCR. This interaction, together with the other co‐stimulatory signals derived from cell–cell interaction, activates the T cells. Splenic B cells expressing antigen‐specific BCRs are also activated following exposure to antigen, a process facilitated by the cytokines produced by antigen‐activated T cells.
Antigens may lodge in the epidermal, dermal, or subcutaneous tissues to stimulate inflammatory responses. From these tissues, the antigen, either free or trapped by APCs, is transported through the afferent lymphatic channels into the regional draining lymph node. In the lymph node, the antigen, macrophages, DCs, T cells, and B cells interact to generate an immune response. Eventually, antigen‐specific T cells and antibodies, which have been synthesized in the lymph node, enter the circulation and are transported to the various tissues. Antigen‐specific T and B cells and antibodies also enter the circulation via the thoracic duct.
The antigen may enter the gastrointestinal or respiratory tract, where it lodges in the MALT or BALT, respectively. There it will interact with macrophages and lymphocytes. Antibodies synthesized in these organs are deposited in the local tissue. In addition, lymphocytes entering the efferent lymphatics are carried through the thoracic duct to the circulation and are thereby redistributed to various tissue.
Frequency of Antigen‐Specific Naïve Lymphocytes
It has been estimated that in a naïve (nonimmunized) animal, only one in every 103–105 lymphocytes is capable of recognizing a typical antigen. Therefore, the probability that an antigen will encounter these cells is very low. The problem is compounded by the fact that for synthesis of antibody to ensue, two different kinds of lymphocytes—the T lymphocyte and B lymphocyte, each with specificity against this particular antigen—must interact.
Statistically, the chances for the interaction of specific T lymphocytes with their particular antigen, and then with B lymphocytes specific for the same antigen, are very low. However, nature has devised an ingenious mechanism for bringing these cells into contact with antigen. The antigen is carried via the draining lymphatics to the secondary lymphoid organs, where the antigen is exposed on the surface of fixed specialized cells. Because both T and B lymphocytes circulate at a rather rapid rate, making the rounds every several days, some circulating lymphocytes with specificity for the particular antigen should pass by the antigen within a relatively short time. When these lymphocytes encounter the antigen for which they are specific, the lymphocytes become activated and the adaptive immune response, with specificity against this antigen, is triggered.
SUMMARY
1 The common lymphoid progenitor cell derived from the hematopoietic stem cell in the bone marrow gives rise to each of the lymphocyte populations.
2 The organs in which lymphocyte maturation, differentiation, and proliferation take place are divided into two categories: primary and secondary organs.
3 Primary lymphoid organs are sites where gene rearrangements occur to generate functional antigen‐specific BCRs and TCRs expressed by B and T cells, respectively.
4 Mature B cells differentiate to fully mature cells within the bone marrow.
5 T cells begin to develop within the bone marrow and undergo maturation to mature populations in the thymus.
6 Macrophages are functionally polarized into M1 or M2 macrophages. Such polarization is regulated by the cytokines and other molecules and conditions present in the local environment.
7 The secondary lymphoid organs include the spleen, lymph nodes, Peyer’s patches in the small intestine, the MALT, GALT, and BALT.
8 Secondary lymphoid tissues are highly efficient in trapping and concentrating foreign substances and are the main sites of production of antibodies and the induction of antigen‐specific T lymphocytes.
9 The lymphatic system is a network of lymphatic vessels that contain a clear fluid called lymph. All interstitial spaces are drained by the lymphatic system, ensuring that foreign antigens will be swept away and deposited within a draining lymph node where antigen‐presenting cells and antigen‐specific T and B cells can initiate an immune response.
10 T cell antigen engagement in secondary lymphoid tissues shapes the repertoire of antigen‐specific T cells, driving them to differentiate towards specific functional subsets including TH1, TH2, TH17, TReg, and TFH cells. Each subset displays characteristic cytokine and transcription factors.
11 Blood lymphocytes enter the lymph nodes through postcapillary venules and leave the lymph nodes through efferent lymphatic vessels, which eventually converge in the thoracic duct. The duct empties into the vena cava, the vessel that returns the blood to the heart, thus providing for the continual