B cells with specifcity for DNA bind soluble fragments of DNA, sending a signal through the B-cell receptor The cross-linked B-cell receptor is internalized with the bound DNA molecule GC-rich fragments from the internalized DNA bind to TLR-9 in an endosomal compartment, sending a co-stimulatory signal TLR-9 naive B cells through binding by TLR-7 or TLR-8. Autoantibodies against DNA, chromatin, and ribonucleoproteins are produced in the autoimmune disease systemic lupus erythematosus (SLE), and this appears to be one mechanism by which self-reactive B cells are stimulated to produce them.
Another mechanism by which ignorant lymphocytes can be drawn into action is by the changing of the availability or form of self antigens. Some antigens are normally intracellular and not encountered by lymphocytes, but they may be released as a result of massive tissue injury or inflammation. These antigens can then activate ignorant T and B cells, leading to autoimmunity. This can occur after myocardial infarction, when an autoimmune response is detectable some days after the release of cardiac antigens. Such reactions are typically transient and cease when the autoantigens have been removed; however, when clearance mechanisms are inadequate, they can continue, causing clinical autoimmune disease.
Additionally, some autoantigens are present in great quantity but are usually in a nonimmunogenic form. IgG is a good example, as there are large quantities of it in blood and extracellular fluids. B cells specific for the IgG constant region are not usually activated, because IgG is monomeric and cannot cross-link the B-cell receptor. However, when immune complexes form following infection or immunization, enough IgG is in multivalent form to evoke a response from otherwise ignorant B cells. The anti-IgG autoantibody they produce is called rheumatoid factor because it is often present in rheumatoid arthritis. Again, this response is normally short-lived, as long as the immune complexes are cleared rapidly.
A unique situation can occur when activated B cells undergo somatic hypermutation in germinal centers (see Section 10-7), resulting in some activated B cells increasing their affinity for a self antigen or becoming newly self-reactive (Fig. 15.6). There seems, however, to be a mechanism to control germinal center B cells that have acquired affinity for self. In this case, if a hypermutated self-reactive B cell encounters strong cross-linking of its B-cell receptor in the germinal center, it undergoes apoptosis rather than further proliferation.
15-5 Antigens in immunologically privileged sites do not induce immune attack but can serve as targets.
Foreign tissue grafts placed in some body sites do not elicit immune responses. For instance, grafts placed in the brain and anterior chamber of the eye do not induce rejection. Such locations are termed immunologically privileged sites (Fig. 15.7). It was originally believed that immunological privilege arose from the failure of antigens to leave privileged sites and induce immune responses.
Subsequent studies have shown that antigens do leave these sites and interact with T cells. However, instead of eliciting an effector immune response, they induce a tolerogenic response that does not injure the tissue.