The anatomy of the immune system

Lymphocytes are cells of the haemopoietic system and most derive ultimately from the haemopoietic stem cell in the bone marrow. The myeloid and lymphoid lineages diverge at an early time-point during differentiation, and this correlates with identification of a common myeloid progenitor (CMP) and common lymphoid progenitor cell (CLP). There are three classes of lymphocyte - B cells, T cells and NK cells - and these have different developmental pathways. T cells are generated in the thymus following the migration of prothymocytes from bone marrow to thymus followed by a complicated selection process involving negative and positive selection of thymocyte precursors. Over 95% of thymocytes die in the thymus, but the minority population emerges from the thymus as single positive CD4+ or CD8+ T cells and enter the lymphoid system as naive precursors that can survive for many years.

Most B cells are generated from within the bone marrow, the 'B' in their name referring to an obscure avian structure called the bursa of Fabricius in which the B cells of birds develop. Naive mature B cells enter the lymphoid circulation but, if triggered by antigen in the periphery, a proportion of cells will return to the bone marrow as long-lived plasma cells that secrete immunoglobulin. Natural killer (NK) cells similarly appear to develop from within the environment of the bone marrow.

The bone marrow and thymus are therefore the sites of lymphocyte development and are known as the primary lymphoid organs. However, immune responses are initiated when lymphocytes encounter antigen and this occurs primarily in secondary lymphoid tissues such as lymph nodes and the spleen.

Lymphocytes circulate around the body tissues via the blood and lymphatic vasculature. Lymphatic vessels drain extravascu-lar spaces and lymph nodes are collections of lymphoid tissue in lymphatic vessels, which are organized to optimize encounters between lymphocytes and antigen. Afferent lymph drains into the lymph nodes, bringing circulating lymphocytes and populations of antigen-loaded dendritic cells from regional tissue. Efferent lymph returns lymphocytes to the bloodstream, where naive cells continue this circulatory pattern in a continuing quest for antigenic encounter. Antigen-experienced lymphocytes migrate to a variety of tissues in order to mediate their effector functions. The pattern of homing is largely determined by the chemokine receptor profile on the lymphocyte.

Lymphocytes

B lymphocytes are the precursors of antibody-producing cells. Each B cell produces and expresses on its surface immunoglubu-lin (Ig) with a distinct specificity for antigen. The specificity of the Ig is determined by the way the Ig variable-region genes are rearranged during B lymphopoiesis. B cells that bind antigen through their surface Ig have to obtain accessory signals if they are to proliferate and differentiate into antibody-secreting cells. These can be provided by helper T cells, which recognize antigen that has been taken up and presented by the B cell.

T cells are functionally diverse. Their receptors for antigen -the T-cell receptor (TCR) - exist only as cell-surface molecules and are not secreted. T cells function by: (i) providing signals that help induce T cells and B cells to proliferate and differentiate; (ii) specifically deleting virally infected cells or foreign cells; and (iii) activating macrophages to enhance cellular cytotoxicity.

NK cells are able to kill cells that fail to express major histocompatibility complex (MHC) class I molecules on their surface. Many intracellular viral infections are able to downregulate surface MHC class I expression as a mechanism of immune evasion. Surface expression is also frequently reduced on malignant cells.

The nature of the antigen-specific receptors on T and B cells

Figure 20.1 The structure of the antigen-specific receptor of B cells (BCR). Antibody (Ig) molecules on the surface of B cells provide their antigen-specific receptors. The green structures are the heavy (H) chains and the orange the light (L) chains. The antigen-combining - variable - regions are shown as open circles; the locations of the antigen-combining sites are indicated by arrows. The binding of antigen by B cells through their surface Ig can lead to antigen being internalized and can result, indirectly, in proliferation by the B cell and its differentiation to become an antibody-secreting cell or a memory cell. Signals delivered to the B cell when the surface Ig binds antigen are delivered through the a and P CD79 transmembrane signalling molecules and other surface Ig-associated molecules, including the complex of CD21 and CD19 with TAPA. CD21 binds the complement component C3d, which is derived from C3, and attaches to bacterial and other cell membranes; when CD21 and the surface immunoglobulin are cross-linked the stimulus for B-cell activation is considerably more than that delivered through the surface Ig alone. All B-cell surface Ig, such as plasma IgG and IgA, has two heavy and two light chains per molecule; IgA secreted from the body is a dimer and most IgM found in body fluids a pentamer of this basic four-chain structure.

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