Autoantigens recognized by CD4 T cells can be identified by adding cells or tissues containing autoantigens to cultures of blood mononuclear cells, and testing for recognition by CD4 cells derived from an autoimmune patient. If the autoantigen is present, it should be effectively recognized by autoreactive CD4 T cells. The identification of autoantigenic peptides is particularly difficult in autoimmune diseases in which CD8 T cells have a role, because autoantigens recognized by CD8 T cells are not effectively presented in such cultures. Peptides presented by MHC class I molecules must usually be made by the target cells themselves (see Chapter 6); intact cells of target tissue from the patient must therefore be used to study autoreactive CD8 T cells that cause tissue damage. Conversely, the pathogenesis of the disease can itself give clues to the identity of the antigen in some CD8 T-cell-mediated diseases. For example, in type 1 diabetes, the insulin-producing β cells seem to be specifically targeted and destroyed by CD8 T cells (Fig. 15.27). This suggests that a protein unique to β cells is the source of the peptide recognized by the pathogenic CD8 T cells. Studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes have shown that peptides from insulin itself are recognized by pathogenic CD8 T cells, confirming insulin as one of the principal autoantigens in this model of diabetes.
Multiple sclerosis (MS) is a T-cell-mediated neurologic disease caused by a destructive immune response against central nervous system myelin antigens,
Fig. 15.26 Deposition of immune complexes in the renal glomeruli causes renal failure in systemic lupus erythematosus (SLE). Panel a: a section through a renal glomerulus from a patient with SLE, showing that the deposition of immune complexes has caused thickening of the glomerular basement membrane, seen as the clear ‘canals’ running through the glomerulus. Panel b: a similar section stained with fluorescent antiimmunoglobulin, revealing immunoglobulin deposits in the basement membrane. In panel c, the immune complexes are seen under the electron microscope as dense protein deposits between the glomerular basement membrane and the renal epithelial cells. Polymorphonuclear neutrophilic leukocytes are also present, attracted by the deposited immune complexes. Photographs courtesy of H.T. Cook and M. Kashgarian.
Fig. 15.27 Selective destruction of pancreatic β cells in type 1 diabetes indicates that the autoantigen is produced in β cells and recognized on their surface. In type 1 diabetes there is highly specific destruction of insulin‑producing β cells in the pancreatic islets of Langerhans, sparing other islet cell types (α and δ). This is shown schematically in the upper panels. In the lower panels, islets from normal (left) and diabetic (right) mice are stained for insulin (brown), which shows the β cells, and for glucagon (black), which shows the α cells. Note the lymphocytes infiltrating the islet in the diabetic mouse (right) and the selective loss of the β cells (brown), whereas the α cells (black) are spared. The characteristic morphology of the islet is also disrupted with the loss of the β cells. Photographs courtesy of I. Visintin.