Overview of the Immune System and Immunologic Disorders

T Lymphocytes

T lymphocytes undergo differentiation in the thymus. After originating in the bone marrow, prothymocytes pass from the cortex to the medulla of the thymus, during which time they undergo maturation. This involves a selection process such that self-reactive thymocytes are eliminated, while thymocytes that can recognize antigens through interactions with molecules of the major histocompatibility complex (MHC) are retained ( ; ). During maturation, they undergo genetic programming in which the gene for the T-cell antigen receptor (TCR) is rearranged to produce protein receptors that are invariant in their antigen specificity for the life span of that T lymphocyte as well as for all its descendant cells. T lymphocytes account for about 60% to 70% of all lymphocytes in the blood. They are also found in paracortical areas of lymph nodes and within periarteriolar lymphoid sheaths in the spleen.

A majority (>95%) of T lymphocytes have antigen receptors made of α- and β-subunits linked with disulfide bonds to form a molecular heterodimer that resides on the outer membrane of the cell in association with the CD3 molecular complex (CD3 is a pan–T-cell marker). The α- and β-subunit TCR proteins have variable, joining, and constant regions (α also contains a diversity region), with corresponding encoding regions in the TCR gene that undergo rearrangement, resulting in high specificity binding for a particular antigen. The CD3 proteins assist transduction of the signal to the interior of the cell when an antigen binds to the TCR on the lymphocyte surface ( ; ). A small percentage of T lymphocytes have a TCR composed of γ- and δ-subunits that similarly interact with CD3. These cells are generally found at mucosal surfaces of the gastrointestinal and respiratory tracts. T cell proliferations may be characterized as neoplastic (clonal) or benign (polyclonal) according to whether their DNA shows predominantly a single form of TCR gene rearrangement or a complete spectrum of such rearrangements, as normally occurs in a heterogeneous lymphocyte population.

Examination of T lymphocytes by flow cytometry focuses on a variety of surface markers. CD4 is found on about 60% of CD3 ⁺ cells; these are helper/inducer T cells that direct the functions of other cells of the immune system by secreting cytokines that stimulate various functions. Two distinct subpopulations of CD4 ⁺ helper cells have been identified: Th1 cells, which secrete interleukin (IL)-2 and interferon (IFN)-γ; and Th2 cells, which secrete IL-4 and IL-5. Th1 cells facilitate macrophage activation, delayed-type hypersensitivity, and the production of antibodies with opsonizing action. Th2 cells direct synthesis of other antibodies, such as IgE, and activate eosinophils. The marker CD8 is found on about 30% of T cells (thus, the normal ratio of CD4 ⁺ to CD8 ⁺ cells in the blood is typically 2:1). These CD8 ⁺ T cells exhibit cytotoxicity and suppressor activity in the immune response.

The mechanism of antigen recognition is different between CD4 ⁺ and CD8 ⁺ subsets of T lymphocytes. CD4 molecules bind to the MHC class II molecules on antigen-presenting cells, whereas CD8 molecules interact with MHC class I molecules. Accordingly, CD4 ⁺ T cells recognize antigens only in the context of MHC class II antigens, and CD8 ⁺ T cells recognize them only through MHC class I antigens. A subset of T helper cells termed, T regulatory (Treg) cells , are important for immune tolerance and prevention of autoimmune disorders (see Chapter 53 ). Treg cells have surface markers for CD4 and CD25 (IL-2 receptor); thus, they are driven by IL-2. The transcription factor FOXP3 plays a role in Treg function, and mutation in the foxp3 gene results in dysregulation of immune tolerance and progression to autoimmune diseases.

B Lymphocytes

B lymphocytes make up roughly 10% to 20% of peripheral lymphocytes in the blood. They also are found in the bone marrow, lymph nodes, spleen, and other lymphoid tissues. In the spleen and lymph nodes, they aggregate into lymphoid follicles. Differentiation of B lymphocytes occurs in the bone marrow, where both positive selection and negative selection take place, as well as at peripheral locations. Antigenic stimulation of B cells leads to the formation of plasma cells that secrete immunoglobulins—the basis of specificity in humoral immunity. The B-cell antigen receptor complex uses surface IgM as the antigen-binding component. The antigen specificity of immunoglobulins derives from a rearrangement process in which both heavy- and light-chain genes are realigned. The heavy-chain gene has variable, diversity, joining, and constant regions, whereas the light-chain gene has variable, joining, and constant regions. Maturation of an antibody response entails switching from IgM to another heavy-chain type (usually IgG) as the result of further gene rearrangement, although the light-chain type remains fixed ( ).

B cells have on their surfaces receptors for complement—CD21, which is also the receptor for Epstein-Barr virus (EBV), thus making these cells susceptible to EBV infection, and for the Fc region of immunoglobulins they have CD19 and CD20, which are frequently used for immunologic identification of B cells.

Antigen-Presenting Cells

Macrophages function as mononuclear phagocytes in inflammation. They also process ingested antigens and present them to immune effector cells in association with MHC molecules on their membranes ( Fig. 44.1 ). T cells are not activated by soluble antigens; thus, presentation of antigens in this manner is necessary for T-cell stimulation and induction of cell-mediated immunity ( ; ). Macrophages also secrete cytokines such as IL-1 for modulation of inflammatory processes. Macrophages can directly lyse tumor cells in their role of immunosurveillance and are effector cells for some types of cell-mediated immunity (e.g., delayed hypersensitivity).

Dendritic cells (found in lymphoid tissues and in interstitial regions of other organs) and Langerhans cells (found in the epidermis) have extensive dendritic cytoplasmic processes that are rich in MHC class II molecules. Consequently, they are very efficient at presenting antigens (although they probably are not phagocytic) and are considered to be extremely important in that task within the entire immune system ( ).

Natural Killer Cells

Natural killer (NK) cells constitute 10% to 15% of lymphocytes in the peripheral blood. They are neither T cells nor B cells and were formerly called null cells . NK cells have the function of lysing other cells without prior sensitization. They can attack tumor cells, cells infected with viruses, and others as well. Consequently, they form the initial defense against aberrant cells. NK cells are characterized by the surface markers CD16 and CD56, which are commonly used for their identification. CD16 is the Fc receptor for IgG; hence, NK cells are able to lyse selectively those cells that are coated with antibodies (antibody-dependent cell-mediated cytotoxicity, which is important in some hypersensitivity reactions). NK cells also secrete cytokines such as IFN-γ. It is interesting to note that NK cells are recognizable on examination of standard stained blood smears as large granular lymphocytes ( ).

Neutrophils and Eosinophils

Neutrophils are drawn to regions of inflammation by chemoattractants such as IL-8. They then release from their granules toxic substances and enzymes that digest cellular structures indiscriminately. Neutrophils also ingest cellular debris, as do eosinophils, and remove it from tissue sites.

Basophils and Mast Cells

Basophils (and their counterparts in tissues, the mast cells) have on their surfaces high-affinity Fc receptors that bind circulating IgE. Uptake of IgE onto the membranes of basophils apparently is not antigen dependent; instead, it is driven by mass action between the amount of total IgE and the available basophils. When the antigen (or allergen) comes into contact with basophil surface-bound IgE that recognizes it, those basophils become activated and release substances such as histamine, which mediate some hypersensitivity reactions. Thus, basophil specificity is directed by the particular IgE that is bound to its surface from the blood; theoretically, a basophil could have multiple different IgE molecules on its surface and, thus, could react with many different allergens.

Immunoglobulins

Antibody molecules can be bound to B-cell surfaces for stimulation of further immunoglobulin secretion. They also circulate in the blood and appear at mucosal surfaces of the respiratory and gastrointestinal tracts, where they are likely to come into contact with potentially pathogenic microorganisms. The major immunoglobulins in the blood are IgM, IgG, and IgA. These antibodies presumably arise following exposure to a multitude of foreign antigens and may remain for years with continued secretion to replace molecules that are lost through normal clearance of proteins from the circulation. At mucosal surfaces, the primary type of antibody is dimeric IgA, which is secreted at that site ( ) (see Chapter 47 ). The other immunoglobulins are IgD (which resides on B-cell surfaces, where it may be involved in immune signal transduction but does not achieve substantial concentrations as free molecules in the blood) and IgE (which functions by binding to surfaces of basophils and stimulates the release of vasoactive substances from those cells in the presence of specific allergens).

Immunoglobulins in the blood function by attaching to antigens on the surfaces of foreign cells, bacteria, viruses, and the like, and by facilitating their destruction through nonspecific effectors such as complement and NK cell activation. Disease monitoring by immunoglobulin testing includes qualitative analysis for clonal versus polyclonal detection (e.g., for diagnosis of multiple myeloma) and quantitative analyses both for overall concentrations of IgM, IgG, and IgA (to detect possible selective or combined deficiencies or overproduction of immunoglobulin classes) and for titers of specific antibodies against individual antigens (e.g., isohemagglutinins, Pneumococcus, Haemophilus , tetanus, and diphtheria).