lgGlgMActivated dendritic cells release a cytokine, BAFF, that augments production of antibody against TI-2 antigens and induces class switching TI-2 antigens alone can signal B cells to produce IgM antibody BBBAFFIgMIgM12 panels). Dendritic cells and macrophages can provide co-stimulatory signals for activation of B cells by TI-2 antigens. One of these co-stimulatory signals is BAFF, which can be secreted by dendritic cells and interacts with the receptor TACI on the B cell (see Fig. 10.25, right panels). The density of TI-2 antigen epitopes is critical; excessive cross-linking of B-cell receptors renders mature B cells unresponsive or anergic, as in immature B cells, while too low a density may be insufficient for activation.
An important class of TI-2 antigens arises during infection by capsulated bacteria. Many common extracellular bacterial pathogens are surrounded by a polysaccharide capsule that enables them to resist ingestion by phagocytes. The bacteria not only escape direct destruction by phagocytes but also avoid stimulating T-cell responses against bacterial peptides presented by macrophages. IgM antibodies rapidly produced against the capsular polysaccharide independent of peptide-specific T-cell help will coat the bacteria, promoting their ingestion and destruction by phagocytes early in the infection.
Not all antibodies against bacterial polysaccharides are produced strictly through this TI-2 mechanism. We mentioned earlier the importance of antibodies against the capsular polysaccharide of Haemophilus influenzae type b in protective immunity to this bacterium. The immunodeficiency disease Wiskott–Aldrich syndrome is caused by defects in T cells that impair their interaction with B cells (see Chapter 13). Patients with Wiskott–Aldrich syndrome respond poorly to protein antigens, but, unexpectedly, also fail to make IgM and IgG antibody against polysaccharide antigens and are highly susceptible to infection with encapsulated bacteria such as H. influenzae. The failure to make IgM seems to be due in part to greatly reduced development of the marginal zone of the spleen, which contains B cells responsible for making much of the ‘natural’ IgM antibody against ubiquitous carbohydrate antigens. Thus, IgM and IgG antibodies induced by TI-2 antigens are likely to be an important part of the humoral immune response in many bacterial infections, and in humans at least, the production of class-switched antibodies to TI-2 antigens might normally rely on some degree of T-cell help.
As well as producing IgM, TI responses can include switching to certain other antibody classes, such as IgG3 in the mouse. This is probably the result of help from dendritic cells (see Fig. 10.25, right panels), which provide secreted cytokines such as BAFF and membrane-bound signals to proliferating plasmablasts as they respond to TI antigens. The distinguishing features of thymus-dependent, TI-1, and TI-2 antibody responses are summarized in Fig. 10.26.
Summary.