Fig. 15.17 Epitope spreading occurs when B cells specific for various components of a complex antigen are stimulated by an autoreactive helper T cell of a single specificity. In patients with SLE, an ever‑broadening immune response is made against nucleoprotein antigens such as nucleosomes, which consist of histones and DNA and are released from dying and disintegrating cells. The upper panel shows how the emergence of a single clone of autoreactive CD4 T cells can lead to a diverse B‑cell response to nucleosome components. The T cell in the center is specific for a particular peptide (red) from the linker histone H1, which is present on the surface of the nucleosome. The B cells at the top are specific for epitopes on the surface of a nucleosome, on H1 and DNA, respectively, and thus bind and endocytose intact nucleosomes, process the constituents, and present the H1 peptide to the helper T cell. Such B cells will be activated to make antibodies, which in the case of the DNA‑specific B cell will be anti‑DNA antibodies. The B cell at the bottom right is specific for an epitope on histone H2, which is hidden inside the intact nucleosome and is thus inaccessible to the B‑cell receptor. This B cell does not bind the nucleosome and does not become activated by the H1‑specific helper T cell. A B cell specific for another type of nucleoprotein particle, the ribosome (which is composed of RNA and specific ribosomal proteins), will not bind nucleosomes (bottom left) and will not be activated by the T cell. In reality a T cell interacts with one B cell at a time, but different members of the same T‑cell clone will interact with B cells of different specificity. The lower panel shows the broadening of the T‑cell response to the nucleosome. The H1‑specific B cell in the center has processed an intact nucleosome and is presenting a variety of nucleosome‑derived peptide antigens on its MHC class II molecules. This B cell can activate a T cell specific for any of these peptide antigens, which will include those from the internal histones H2, H3, and H4 as well as those from H1. This H1‑specific B cell will not activate T cells specific for peptide antigens of ribosomes because ribosomes do not contain histones.
autoantibodies to the extracellular domains of these adhesion molecules causes dissociation of the junctions and dissolution of the affected tissue. Pemphigus vulgaris usually starts with lesions in the oral and genital mucosa; only later does the skin become involved. In the mucosal stage, only autoantibodies against certain epitopes on desmoglein Dsg-3 are found, and these antibodies seem unable to cause skin blistering. Progression to the skin disease is associated both with intramolecular epitope spreading within Dsg-3, which gives rise to autoantibodies that can cause deep skin blistering, and with intermolecular epitope spreading to another desmoglein, Dsg-1, which is more abundant in the epidermis. Dsg-1 is also the autoantigen in a less severe variant of the disease, pemphigus foliaceus. In that disease, the autoantibodies first produced against Dsg-1 cause no damage, and disease appears only after autoantibodies are made against epitopes on parts of the protein involved in the adhesion of epidermal cells.
15-12 Both antibody and effector T cells can cause tissue damage in autoimmune disease.
The manifestations of autoimmune disease are caused by effector mechanisms of the immune system being directed at the body’s own tissues. As discussed previously, the response can be amplified and maintained by the constant supply of new autoantigen. An exception to this rule is type 1 diabetes, in which the autoimmune response destroys most or all of the target cells. This leads to a failure to produce sufficient insulin to maintain glucose homeostasis, resulting in the symptoms of diabetes.