The Immunological Apparatus

The immune system is comprised of various continuously circulating cells (T and B lymphocytes, and antigen-presenting cells present in various tis­sues). T and B cells develop from a common stem cell type, then mature in the thymus (Tcells) or the bone marrow (B cells), which are called primary (or central) lymphoid organs. An antigen-specific differentiation step then takes places within the specialized and highly organized secondary (or per­ipheral) lymphoid organs (lymph nodes, spleen, mucosa-associated lym­phoid tissues [MALT]). The antigen-specific activation of B and/or T cells in­volves their staggered interaction with other cells in a contact-dependent manner and by soluble factors.

B cells bear antibodies on their surfaces (cell-bound B-cell receptors). They secrete antibodies into the blood (soluble antibodies) or onto mucosal surfaces once they have fully matured into plasma cells. Antibodies recognize the three-dimensional structures of complex, folded proteins, and hydro­carbons. Chemically, B-cell receptors are globulins (“immunoglobulins”) and comprise an astounding variety of specific types. Despite the division of immunoglobulins into classes and subclasses, they all share essentially the same structure. Switching from one Ig class to another generally requires T-cell help.

T cells recognize peptides presented on the cell surface by major histo­compatibility (gene) complex (MHC) molecules. A T-cell response can only be initiated within organized lymphoid organs. Naive T cells circulate through the blood, spleen, and other lymphoid tissues, but cannot leave these com­partments to migrate through peripheral nonlymphoid tissues and organs unless they are activated. Self-antigens (autoantigens), presented in the thy­mus and lymphoid tissues by mobile lymphohematopoietic cells, induce T-cell destruction (so-called negative selection). Antigens that are expressed only in the periphery, that is outside of the thymus and secondary lymphoid or­gans are ignored by T cells; potentially autoreactive T cells are thus directed against such self antigens. T cells react to peptides that penetrate into the organized lymphoid tissues. New antigens are first localized within few lym­phoid tissues before they can spread systemically. These must be present in lymphoid tissues for three to five days in order to elicit an immune response. An immune response can be induced against a previously ignored self antigen that does not normally enter lymphoid tissues if its entry is induced by cir­cumstance, for instance, because of cell destruction resulting from chronic peripheral infection. It is important to remember that induction of a small number of T cells will not suffice to provide immune protection against a pathogen. Such protection necessitates a certain minimum sum of activated T cells.

The function of the immunological apparatus is based on a complex series of interactions between humoral, cellular, specific, and nonspecific mechan­isms. This can be better understood by examining how the individual com­ponents of the immune response function.

The human immunological system can be conceived as a widely dis­tributed organ comprising approximately 10¹² individual cells, mainly lym­phocytes, with a total weight of approximately 1 kg. Leukocytes arise from pluripotent stem cells in the bone marrow, then differentiate further as two distinct lineages. The myeloid lineage constitutes granulocytes and mono­cytes, which perform important basic defense functions as phagocytes (“scavenger cells”). The lymphoid lineage gives rise to the effector cells of the specific immune response, T and B lymphocytes. These cells are con­stantly being renewed (about 10⁶ new lymphocytes are produced in every minute) and destroyed in large numbers. T and B lym­phocytes, while morphologically similar, undergo distinct maturation pro­ cesses (Table 1, Fig. 1). The antigen-independent phase of lymphocyte differentiation takes place in the so-called primary lymphoid organs: T lymphocytes mature in the thymus and B lymphocytes in the bursa fabric! (in birds). Although mammals have no bursa, the term B lymphocytes (or B cells) has been retained to distinguish these cells, with their clearly distinct functions and maturation in the bone marrow, from T lymphocytes, which mature in the thymus (Table 1). B cells mature in the fetal liver as well as in fetal and adult bone marrow. In addition to their divergent differentia- tion pathways, T and B cells differ with respect to their functions, receptors, and surface markers. They manifest contrasting response patterns to cyto­kines, and display a marked preference to occupy different compartments of lymphoid organs. T and B cells communicate with each other, and with other cell types, by means of adhesion and accessory molecules or in response to soluble factors, such as cytokines, which bind to specific receptors and induce the activation of intracellular sig­naling pathways. The antigen-dependent differentiation processes which leads to T and B cell specialization, takes place within the secondary lym­phoid organs where lymphocytes come into contact with antigens. As a general rule the secondary lymphoid organs contain only mature T and B cells, and comprise encapsulated organs such as the lymph nodes and spleen, or non-encapsulated structures which contain lymphocytes and are associated with the skin, mucosa, gut, or bronchus (i.e. SALT, MALT, GALT, and BALT). Together, the primary and secondary lymphoid organs ac­count for approximately 1-2% of body weight.

Fig. 1 All lymphoid cells originate from pluripotent stem cells present in the bone marrow which can undergo differentiation into B or T cells. Stem cells that remain in the bone marrow develop into mature B cells via several anti­gen-independent stages; including the k5Vpre-B cell stage, and pre-B cells with a special k5 precursor chain. Antigen contact within secondary lymphoid or­gans can then activate these cells, finally causing them to differentiate into anti­body-secreting plasma cells.

Tcells mature in the thymus; pTa is a precursor a chain associated with TCRb chain surface expression. The pTa chain is later replaced by the normal TCRa chain. Immature CD4+ CD8+ double-positive thymocytes are localized within the cortical region of the thymus; some autoreactive T cells are deleted in the cortex, whilst some are deleted in the medulla as mature single-positive T cells. The remaining T cells mature within the medulla to become CD4+ CD8^- or CD4^- CD8+ T cells. From here, these single positive T cells can emigrate to peripheral secondary lymphoid organs, where they may become activated by a combination of antigen contacts, secondary signals, and cytokines.     

Table.1 Distribution of Lymphocyte Subpopulations and APCs in Various Organs (% of All Mononuclear Cells)

References

Zinkernagel, R. M. (2005). Medical Microbiology.  Thieme.