insufficiency, mucocutaneous infections, and hypopara­ thyoridism, these patients can manifest diabetes, Sjögren’s syndrome, vitiligo, and uveitis.21

B cells

B cells make up the second broad arm of the lymphocyte immune response. Originating from the same pluripotential stem cell in the bone marrow as the T cell, the maturational process and role of the B cell are quite different. The term B cell originates from observations obtained from work with chickens, in which it was noted that antibody-producing cells would not develop if the bursa of Fabricius, a uniquely avian structure, was removed. The human equivalent appears to be the bone marrow. The B cell, under proper conditions, will develop into a plasma cell that is capable of secreting immunoglobulin. Therefore, its role is to function as the effector cell in humoral immunity. The unique characteristic of these cells is the presence of surface immunoglobulin on their cell membranes.

B-cells begin as a group of cells originating from stem cells designated as proor pre-B cells. The maturation process leading to a B cell is complex and not fully understood. What is clear is that various gene regions that control the B-cell’s main product, immunoglobulins, are not physically next to each other. Through a process of translocation these genes align themselves next to each other, excising intervening genes. IL-7 is an important factor in the maturation process. B cells can be activated by their interaction with CD4+ T cells that express on their surface class II MHC antigens and CD40 ligand. B-cell activation will cause these cells to divide, usually in the context of T-cell interaction and cytokines elaborated by the T cell, including IL-4, IL-5, IL-6, IL-17 and IL-2.

Subgroups of B cells have been described. Naive, conventional (B2) B cells are found. Another type, memory B cells, live for long periods, are readily activated, and will produce immunoglobulin (Ig) isotypes other than IgM (see next section). These cells presumably play an important role in the anamnestic response of the organism. This is the very rapid antigen-specific immune response that occurs when the immune system encounters an antigen to which it has already been sensitized. Another subgroup consists of B1 (CD5+) lymphocytes, whose characteristics overlap with those of other B cells but which appear to be derived from a separate lineage and are very long-lived. These cells produce IL-10 and have been associated with autoantibody production. Chronic lymphocytic leukemias often derive from B1 cells.

B cells initially express surface IgM and IgD simultaneously, with differentiation occurring only after appropriate activation. Five major classes of immunoglobulin are identified on the basis of the structure of their heavy chains: α, γ, µ, δ, and ε, corresponding to IgA, IgG, IgM, IgD, and IgE (Table 1-5). The structure of the immunoglobulin demonstrates a symmetry, with two heavy and two light chains uniformly seen in all classes except IgM and IgA (Fig. 1-6). The production of immunoglobulin usually requires T-cell participation. Many ‘relevant’ antigens are T-cell dependent, meaning that the addition of antigen to a culture of pure B cells will not induce immunoglobulin production. However, polyclonal B-cell activators, such as lipopolysaccharide,

Elements of the immune system

From Allansmith M. Unpublished data 1987. Used with permission.

Hypervariable region: antigen binding

VH

VL

Heavy Light chain chain

CH1

CL

Hinge region

Complement binding region

CH2

CH3

Fc portion

Cellular attachment

Figure 1-6.  Structure of human IgG molecule.

9

pokeweed mitogen, dextran, and the Epstein–Barr virus (as well as other viruses), have the capacity to directly induce B-cell proliferation and immunoglobulin production. For a primary immune response B cells will produce IgM, which binds complement. With time – and if they encounter these antigens again – B cells will switch immunoglobulin production to IgG, usually during the primary response. This immunoglobulin class switching, which requires a gene re­ arrangement, is inherent in the B cell and is partly controlled by lymphokines. IL-4 has been associated with a switch to express IgG (in mouse IgG1, in human IgG4) and IgE, whereas IFN-γ controls a switch to IgG2a and TGF-β to IgA.

Classes of Immunoglobulin

More IgA is made than any other immunoglobulin, much in the gut. IgG is the major circulating immunoglobulin class found in humans: it is synthesized at a very high rate and makes up about 75% of the total serum immunoglobulins. Plasma cells that produce IgG are found mainly in the spleen and the lymph nodes. Four subclasses of IgG have been identified in humans (G1–G4). G1 and G3 fix complement readily and can be transmitted to the fetus. The production of these subclasses is not random but reflects the antigen to which the antibody is being made. When doing tests in the serum or the chambers of the eye (aqueous or vitreous), we usually look at IgG production.

IgM is a pentamer made up of the typical antibody structure linked by disulfide bonds and J chains (Fig. 1-7). Only about one-fifteenth as much IgM as IgG is produced. Because of its size, it generally stays within the systemic circulation and, unlike IgG, will not cross the blood–brain barrier or the placenta. This antibody is expressed early on the surface of B cells. Therefore, initial antibody responses to exogenous pathogens, such as Toxoplasma gondii, are of this class. The observation of an IgM-specific antibody response helps to confirm a newly acquired infection. IgM has a complementbinding site and can mediate phagocytosis by fixing C3b, a component of the complement system.

One major role of both IgG and IgM is to interact with both effector cells and the complement system to limit the

invasion of exogenous organisms. These immunoglobulins aid effector cells through opsonization, which occurs by the antibody coating an invading organism and assisting the phagocytic process. The Fc portion of the antibody molecule then can readily interact with effector cells, such as macrophages, thereby helping effectively resolve the infection. Persons with deficiencies in IgG and IgM are particularly prone to infection by pyogenic organisms such as Streptococcus and Neisseria species. In addition, both of these antibodies will activate the complement pathway, inducing cell lysis by that mechanism as well.

IgA is the major extravascular immunoglobulin, although it comprises only about 10–15% of the intravascular total. Two isotypes of IgA are noted: IgA1 is more commonly seen intravascularly, whereas IgA2 is somewhat more prevalent in the extravascular space. The IgA-secreting plasma cells are found in the subepithelial spaces of the gut, respiratory tract, tonsils, and salivary and lacrimal glands. IgA is an important component to the defense mechanism of the ocular surface, being found in a dimer linked by a J chain, a polypeptide needed for polymerization. In addition, a secretory component, a unique protein with parts of its molecule having no homology to other proteins, is needed for the IgA to appear in the gut and outside vessels. The secretory component is produced locally by epithelial cells that then form a complex with the IgA dimer/J chain (Fig. 1-8). This new complex is internalized by mucosal cells and then released on the apical surface of the cell through a proteolytic process. The amount of IgA within the eye is quite small. IgA can fix complement through the alternate pathway, and can serve as an opsonin for phagocytosis. IgA appears to exert its major role by preventing entry of pathogens into the internal environment of the organism by binding with the infectious agent. It may also impede the absorption of potential toxins and allergens into the body. Further, it can induce eosinophil degranulation.

IgE is slightly heavier than IgG because its heavy chain has an additional constant domain. Mast cells and basophils

J chain

Figure 1-7.  IgM pentamer with J chain.

Figure 1-8.  IgA dimer with J chain and secretory piece.