Progression of the autoimmune response is often accompanied by recruitment of new clones of lymphocytes reactive to new epitopes on the initiating autoantigen, as well as new autoantigens. This phenomenon is known as epitope spreading, and is important in perpetuating and amplifying disease. As seen in Chapter 10, activated B cells can internalize cognate antigens by receptor-mediated endocytosis via their antigen receptor, process them, and present the derived peptides to T cells. Epitope spreading can occur in several ways. Because antibody-bound antigens can be more efficiently presented, self antigens that are normally present in concentrations too low to activate naive cell processing of the internalized autoantigen can reveal novel, previously hidden, peptide epitopes called cryptic epitopes that the B cell can then present to T cells. Autoreactive T cells responding to these ‘new’ epitopes will provide help to any B cells presenting these peptides, recruiting additional B-cell clones to the autoimmune reaction, with the consequent production of a greater variety of autoantibodies. In addition, on binding and internalizing specific antigen via their B-cell receptor, B cells will also internalize any other molecules closely associated with that antigen. By these routes, B cells can act as antigen-presenting cells for peptides derived from antigens completely different from the original autoantigen that initiated the autoimmune reaction.
The autoantibody response in SLE initiates these mechanisms of epitope spreading. In this disease, autoantibodies against both the protein and DNA components of chromatin are found. Figure 15.17 shows how autoreactive B cells specific for DNA can recruit autoreactive T cells specific for histone proteins, another component of chromatin, into the autoimmune response. In turn, these T cells provide help not only to the original DNA-specific B cells but also to histone-specific B cells, resulting in the production of both anti-DNA and anti-histone antibodies.
Another autoimmune disease in which epitope spreading is linked to the progression of disease is pemphigus vulgaris, which is characterized by severe blistering of the skin and mucosal membranes. It is caused by autoantibodies against desmogleins, a type of cadherin present in cell junctions (desmosomes) that hold cells of the epidermis together (Fig. 15.18). Binding of