IMMUNOLOGY - Roit I. - Mir 2000

Chapter 12. Development of the Immune System in Ontogeny

DIVERSITY OF ANTIBODY CLASSES

B Cells produce Antibodies of five main classes: IgM, IgD, IgG, IgA, and IgE. There are also four subclasses of IgG and two subclasses of IgA (see Chapter 6). Each terminally differentiated plasma Cell originates from a specific B cell and produces antibodies of only a single Class or subclass.

B cells switch to the synthesis of IMMUNOGLOBULINS of another class via heavy chain Gene recombination

The first B cells to appear during development bear IgM as their antigen receptor (see above). The expression of other immunoglobulin classes begins subsequently. The fact that cells carrying surface immunoglobulins other than IgM are descendants of IgM-bearing cells has been proven in experiments on chickens and mice: following the administration of anti-μ antibodies, the animals lost The ability to produce antibodies belonging to any immunoglobulin class. Constant region genes encoding various heavy chains (CH) are responsible for The formation of antibody classes and subclasses. These genes are clustered at the 3' end of the immunoglobulin heavy chain (IgH) locus and, in humans, are arranged in a specific sequence on chromosome 14. The switching of B cells from IgM production to the synthesis of immunoglobulins of other classes or subclasses occurs As a result of recombination between repetitive 3' switch regions (such a region is located upstream of each CH gene) and the deletion of intervening CH genes. This process, known as class (isotype) switching, is described in detail in Chapter 8. Some B cells express both IgM and IgD isotypes on their surface; this is ensured by differential splicing of long nuclear RNA transcripts of CH genes.

Isotype switching occurs during B cell maturation and proliferation

Isotype switching occurs mainly during B cell proliferation, although it can also take place during early clonal expansion and B cell maturation, even before their encounter with an exogenous antigen (Fig. 12.18). This is evidenced by the fact that some progeny of immature B cells synthesize antibodies belonging to other immunoglobulin classes, including IgG and IgA. Further differentiation of B cells leads to the synthesis of surface IgD, an antibody class present almost exclusively on the B cell membrane. Different sIg classes on the same B cell share the same antigenic Specificity—i.e., they represent the same V gene region, although later, following the switch, somatic Mutations may generate additional sIg diversity within the same clone. Evidence that immunoglobulin class switching can occur independently of antigen exposure was obtained from experiments on vertebrates raised in a gnotobiotic (virtually germ-free) environment—that is, under conditions that severely restrict exposure to exogenous Antigens.

Antigen type can influence isotype expression. Certain antigens preferentially induce The production of antibodies of a specific isotype. For example, Introduction/37.html">Bacterial Cell wall CARBOHYDRATES elicit a T cell-independent Immune Response in mice, resulting in the production of antibodies predominantly of the IgG3 isotype, whereas viral infections more commonly trigger the formation of IgG2a isotype antibodies. In humans, anti-polysaccharide antibodies are predominantly of the IgG2 isotype. Two mechanisms may underlie this selective isotype production:

✵ spontaneous immunoglobulin class switching prior to B-cell clone Selection (Fig. 12.18), and

✵ de novo-induced switching resulting from interactions with cytokines—products of accessory cells—and with T cells.

Fig. 12.18. Immature B cells produce only IgM, whereas mature cells are capable of expressing multiple surface antibodies, since mRNA and surface immunoglobulins persist even after class switching. IgD is also expressed during clonal maturation. Maturation can occur in the absence of antigen, but differentiation into plasma cells (which express minimal amounts of immunoglobulin on their surface yet contain large amounts in their Cytoplasm) requires the presence of antigen and (typically) T-cell help. Photomicrographs show B cells stained for surface IgM using fluorescently labeled anti-μ antibodies (green, 1), and plasma cells stained for cytoplasmic IgM (using fluorescently labeled anti-μ antibodies) and IgG (using anti-γ antibodies conjugated with rhodamine) (green and red, respectively, 2).

Today, the involvement of T cells and their cytokines in de novo isotype switching is well established. In mice, T cells stimulate mucosal IgA production. The cytokine IL-4 switches polyclonally activated (by lipopolysaccharide, LPS) B cells to preferentially synthesize the IgG1 isotype while simultaneously suppressing the expression of other isotypes (Fig. 12.19). In a similar system, IL-5 induces a 5-to-10-fold increase in IgA production without affecting the Synthesis of Other isotypes, whereas IFNγ enhances IgG2a production while suppressing the output of all other Ig isotypes. Notably, the cytokines IL-4 and IFNγ, which reciprocally regulate antibody isotype expression, are produced by distinct T-helper subpopulations. In mice, Th1 cells secrete IFNγ, while Th2 cells secrete IL-4, IL-5, and IL-10 (see Chapter 10). Recently, similar subpopulations have been discovered in humans; furthermore, it has been established that in atopic individuals, T-cell-derived IL-4 stimulates the overproduction of IgE (see Chapter 23).

Fig. 12.19. Effects of the cytokines IFNγ (produced by Th1 cells) and IL-4/IL-5 (produced by Th2 cells), leading to an increase (↑), decrease (↓), or no effect (=) on the proportion of B cells producing specific isotypes following in vitro stimulation with the polyclonal activator of antibodygenesis, lipopolysaccharide. The cytokine IFNγ induces IgG2a production, IL-4 induces IgG1 and IgE production, and IL-5 increases the number of IgA-secreting B cells.

The chronological appearance of different immunoglobulin classes during human B-cell maturation can be traced through the antibody profile in fetal and neonatal serum. IgM is synthesized before birth, whereas IgG and IgA appear during the perinatal period (Fig. 12.20). Serum IgG concentration reaches adult levels only by 1–2 years of age, and IgA concentration even later.

Fig. 12.20. In the fetus and newborn, IgG is exclusively of maternal origin. By 9 months of age, maternal IgG disappears, and the infant begins to synthesize its own IgG. Newborns also produce their own IgM and IgA; immunoglobulins of these classes do not cross the Placenta. In a one-year-old child, the production of IgG is 80%, IgM is 75%, and IgA is 20% of their respective adult levels.