"The immune system is a complex "network" of organs, cells and molecules. The following discussion presents a more technical explanation of the major immune system elements and their inter-relationships."

The bone marrow and the thymus are the primary lymphoid organs in mammals. The bone marrow is the source of stem cells which in the appropriate microenvironment and in the presence of colony stimulating factors proliferate and differentiate into erythroid, myeloid, and lymphoid cells. The bone marrow is also the site of differentiation of lymphoid cells into B lymphocytes.

The thymus provides the microenvironment and local hormones necessary for the differentiation of thymic (T) lymphocytes from lymphoid cells derived from the bone marrow. Thereafter, the mature T cells leave the thymus, circulate in the blood and lymphatic vessels, and colonize peripheral lymphoid organs.

Peripheral (Secondary) Lymphoid Organs

The lymph nodes and spleen are encapsulated organs whose connective tissue framework contains lymphocytes (functionally separated into T cells and B cells), macrophages, and dendritic cells that localize and process antigens from the lymph and blood stream. The B cell areas of lymph nodes are located in the outer cortex and include lymphoid follicles and germinal centers. The germinal centers enlarge greatly in secondary antibody responses. They have a central role in the proliferation, mutation, and maturation of B cells into plasma cells and memory cells.

T cells are found mainly in the medulla and paracortical regions of lymph nodes. Antibody-secreting plasma cells occur separately or intermixed with other lymphoid cells. The lymphoid tissue of the spleen forms the white pulp and is divided into T cell areas along the periarteriolar sheaths and B cell areas analogous to those of lymph nodes.

Mucosa-associated lymphoid tissue which is found in the alimentary (Peyer's patches, appendix, tonsils), respiratory, and genitourinary tracts also contains T and B cell areas, the latter forming lymphoid follicles and sometimes prominent germinal centers.

T Cells

T cells differentiate in the thymus from lymphoid stem cells derived from bone marrow and, when mature, leave the thymus, circulate in blood and lymph, and spread to peripheral lymphoid organs. Resting lymphocytes are small round cells, and resting T and B cells are indistinguishable by ordinary light microscopy. Following mitogenic or antigenic stimulation, resting T cells are transformed into blast cells capable of division. In normal subjects, about 80% of peripheral blood lymphocytes are T cells and 10-20% are B cells.

Stimulated by IL-2, activated T cells proliferate, undergo clonal expansion, and differentiate into functional classes: cytotoxic/suppressor T cells and helper/inducer T cells. Helper and suppressor T cells are regulator cells which, mainly through the secretion of cytokines, modulate the function of B cells and other T cells. Cytotoxic T cells are effector cells which kill virus-infected host cells and histoincompatible transplanted cells.

By labeling and counting techniques using monoclonal antibodies (produced against cell-surface molecules of T cells) and fluorescence microscopy or flow cytometry, surface markers have been characterized for developing and mature T cells and their functional classes. These markers or molecules are designated by the prefix CD (cluster designation). Most useful in clinical immunology, CD3 is present on all mature T cells, CD4 is a marker for helper/inducer T cells, and CD8 is a marker for cytotoxic/suppressor T cells. In normal adult subjects, the peripheral blood CD4 T cell count is at least 800/cumm, about 60% of peripheral T cells are CD4+, approximately 30% are CD8+, and the CD4/CD8 ratio is about 2.

B Cells

B cells differentiate from lymphoid stem cells in the bone marrow, circulate in the blood, and localize in peripheral lymphoid organs. The B cell receptor for antigen is surface membrane Ig. Surface membrane Ig is one marker for B cells which are identified by fluorescence labeling techniques using fluorescence microscopy or flow cytometry. Normally, about 10-20% of peripheral blood lymphocytes are B cells.

The initial step in the activation of B cells is the specific binding of antigen to the surface membrane Ig. In the presence of a second signal (T and B cell contact) and growth factors (IL-4, -5, -6) released by helper T cells, B cells proliferate, undergo clonal expansion, form germinal centers, and at full maturity differentiate into antibody-secreting plasma cells. Mature plasma cells are characterized by cytoplasmic and secretory Ig and morphologically by basophilic cytoplasm and an eccentric single, or sometimes double, nucleus often with a "cart wheel" pattern of dense chromatin.

Natural Killer (NK) Cells

NK cells, which are lymphoid cells found in the blood and peripheral lymphoid organs, are capable of killing virus-infected cells or tumor cells in the absence of prior immunization. NK cells are also described as "large granular lymphocytes" or as "null" cells because of the absence of surface markers characteristic of T or B cells. NK cells are able to target cells by direct contact with them, have surface receptors and kill target cells which are coated with specific antibody.

Macrophages

Tissue macrophages are derived from blood monocytes and belong to the widely distributed mononuclear phagocytic (reticulo- endothelial) system. Macrophages mediate critical functions both in inate immunity (non-specific phagocytosis and destruction of pathogens) and in the initiation of specific immunity (antigen processing and presentation). They secrete many biologically active products, among them, IL-1 which promotes the differentiation of T cells and B cells and mobilizes other host defenses. Macrophages in turn are activated by interferon-gamma secreted by activated T cells. Macrophages secrete tumor necrosis factor (TNF) and kill some tumor cells.
Dendritic and Langerhans' Cells

Dendritic cells (DCs) are 'professional' antigen presenting cells whose activation is an important step in inate immunity and in initiating acquired, lymphocyte-mediated, immune responses. DCs have elongated cytoplasmic processes; bind and localize antigen; process and present to T-cells and B-cells immunogenic peptide fragments; and express ligands and co-stimulatory signals required for T-cell and B-cell activation. DCs can migrate from non-lymphoid to lymphoid locations, are present in skin (Langerhans¹ cells) and other locations and in T-cell areas of lymphoid tissue.

Cytokines

This is a generic term for messenger molecules (polypeptides) which are secreted by lymphoid and non-lymphoid cells and form a mediator network regulating the growth, differentiation, and function of cells involved in immunity, hematopoiesis, and inflammation. Cytokines secreted by lymphocytes are also called lymphokines, and those secreted by monocytes/macrophages are known as monokines. An interleukin (IL) is a cytokine which carries a message between leukocytes. Cytokines involved in the regulation of T cells, B cells, and macrophages were mentioned previously and are summarized in Table-1 and Figure 1 below.

Table 1

CD 4+ helper T cells are now divided into two subsets based upon cytokine profile and predominant function:
Type 1 (TH1) cells produce IFN-gamma, TNF-alpha and gamma, and IL-2 (but not IL-4, IL-5, IL-10) and regulate classical delayed (type IV) hypersensitivity reactions centered around macrophage activation and T cell-mediated immunity;

Type 2 (TH2) cells elaborate IL-4, IL-5, IL-6, and IL-10 and participate in immediate (type 1) hypersensitivity reactions and B-cell antibody-mediated immunity


Proinflammatory cytokines, such as TNF (alpha and beta) and IL-1 produced by activated macrophages, mediate local and systemic effects, including the induction of the acute-phase reactions of inflammation.
Chemokines (chemotactic cytokines) belong to a family of low-molecular weight proteins that are secreted by monocytes, macrophages, and T cells that influence leukocyte motion, and that attract leukocytes to sites of tissue inflammation or infection.

Figure 1

Symbols: IL - Interleukin; IFN - Interferon; TNF - Tissue necrosis factor.