Certain bacterial-associated antigens can elicit a T-cell-independent B-cell response (Mond et al., 1995). These thymus-independent (TI) antigens tend to have highly repetitive epitopes, which enable extensive cross-linking of surface immunoglobulin molecules, resulting in B-cell activation. Typical bacterial TI antigens are capsular polysaccharides, lipopolysaccharides and polymeric proteins. T-cell-independent B-cell responses provide a rapid specific response directed against bacteria possessing anti-phagocytic polysaccharide capsules, e.g. Streptococcus pneumoniae.
In general, B-cell activation requires signals from two sources; the first arises from the binding of B-cell surface-bound IgM/D to the complementary microorganism surface epitope and the second is Th-cell-derived (Fig. 1.7). This Th-cell facilitation of B-cell activation is essential for full expression of the humoral immune response, particularly isotype switching, affinity maturation and the efficient development of memory B-cells. To enable Th-cell facilitation of B-cell activation, B-cells are able to internalize antigen-immunoglobulin complexes and then express the resulting pathogen peptide sequences in an MHC class II-restricted fashion on the B-cell surface. It is these peptide-MHC class II complexes that are recognized by the Th-cell. It is essential that the pep-tide sequences recognized by the Th-cell originate from the antigen recognized by the B-cell. This process of linked recognition means that the B-cell and the Th-cell respond to different epitopes; however, the epitopes originate from the same antigen. Typically, the B-cell recognizes a surface epitope and the Th-cell possibly an internal peptide sequence.
The second signal provided by the Th-cell to enable B-cell activation takes the form of secreted and cell-bound signals. Effector Th-cells express surface CD40 ligand and this binds to B-cell surface CD40. Th-cell cytokine secretion is also critical in B-cell activation and maturation. Once activated, B-cells undergo clonal expansion and differentiation into immunoglobulin-secreting plasma cells, each secreting immunoglobulin isotypes with the same antigen specificity
Antigen binds to B-cell surface immunoglobulin receptor
Internalized antigen presented in an MHC class Il-restricted manner on B-cell surface
CD4 Th-cell binds to antigen peptide-MHC complex
CD4 Th-cell provides second signal to activate B-cell
_ B-cell proliferates and
<—^ resulting plasma cells secrete _ immunoglobulins
Fig. 1.7. Schematic representation of Th-cell-dependent B-cell activation through linked recognition of a pathogen antigen.
as the parent B-cell. Although plasma cells tend to localize to lymph nodes and bone marrow, their anti-microbial actions are widespread because of the extensive distribution of their secreted immunoglobulins.
Although macrophages and B-cells are critically dependent on Th-cells, clinical and experimental observations suggest that there is selective utilization of these cells during immune responses. Some CD4 Th-cell-mediated responses are predominantly antibody-based, while others are macrophage-dependent. For example, healing tuberculoid leprosy is associated with strong macrophage-mediated immunity with low antibody levels, whereas non-healing lepromatous leprosy is associated with high (but ineffective) antibody levels, weak macrophage-based effector responses and uncontrolled proliferation of microorganisms. The discovery that Th-cells are functionally diverse has helped in the understanding of these observations.
Th-cell functional diversity (Abbas et a/., 1996; Mosmann and Sad, 1996)
The ability of CD4 Th-cells to initiate immune responses with differing effector mechanisms was clarified by a demonstration by Mosmann and Coffman (1989) that murine CD4 T-cell clones could be categorized into two broad functional groups, Th1 and Th2, depending on their secreted cytokines. Th1 cells secrete IFN-7, IL-2 and tumour necrosis factor (3 (TNF-p), while Th2 cells secrete IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13. Human Th1 and Th2 secretory cytokine patterns are similar to the murine model, although the synthesis of IL-2, IL-6, IL-10 and IL-13 is not so tightly restricted to a single subset. Additionally, however, individual human Th-cells can secrete both Th1 and Th2 cytokines and these are commonly known as Th0 cells. Human Th-cells appear to form a continuum, with some extremely polarized cells secreting either typically Th1 or Th2 cytokines but the majority are Th0 cells, secreting a mixture of Th1 and Th2 cytokines. The subdivision of Th-cells is complicated further by the recognition that some Th2 cells secrete the suppressive regulatory cytokine TGF-p, with some authorities terming these cells Th3. In recent years, it has become apparent that the Th1/Th2 subdivision is overly simple, but the concept of the functional dichotomy of Th1/Th2 is extremely useful in aiding the understanding of immune responses.
Th1 and Th2 cytokines have important effector and Th-cell regulatory functions (Fig. 1.8). Th1 and Th2 cytokines augment Th-cell differentiation in favour of the secreting subset, i.e. Th1 cytokines promote differentiation towards the Th1 phenotype and Th2 cytokines towards the Th2 phenotype. In addition, Th cytokines inhibit Th-cell differentiation towards the reciprocal phe-notype, i.e. Th1 cytokines inhibit differentiation towards the Th2 phenotype and Th2 cytokines antagonize development of Th1 cells. The consequence of this self-amplification and mutual antagonism of the reciprocal phenotype is that, once a Th-cell-mediated immune response deviates towards either the Th1 or Th2 phenotype, the Th-cell response becomes increasingly polarized towards that phenotype.
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