B-cell tolerance checkpoints and loss of self-tolerance in different forms of secondary ITP. Tolerance pathways are denoted by green dashed lines. Solid blue lines represent normal B-cell developmental stages. Where failures in central and peripheral B-cell tolerance might occur in secondary forms of ITP are shown by the solid pink lines. Central B-lymphocyte tolerance checkpoints operate during primary cell maturation in the bone marrow and include clonal deletion and receptor editing. Cross-linking of membrane-bound antibodies on immature B cells leads to apoptosis.¹²²  Antigen receptor specificity is also revised by receptor editing, that is, the continuation or reinitiation of antibody gene rearrangement, usually at light chain loci, in lymphocytes that already have functional antibody.¹²³  Receptor editing can change a self-reactive light chain (shown in pink) to a non–self-reactive light chain (shown in purple). Peripheral tolerance checkpoints monitor and alter the repertoire in lymphocytes that have exited from primary lymphoid organs. Even if central tolerance is perfect, there is a need to regulate peripheral tolerance because somatic mutation can randomly generate autoreactive specificities. Somatic mutations are shown as pink circles on the heavy and light chain V-regions. Heavy chain isotype switching (which usually accompanies somatic mutation during an immune response) is shown by the change in color of the heavy chain constant region from green to blue. Anergy and death of lymphocytes after an immune response also contribute to peripheral tolerance.¹²⁴  Immune stimulation with a pathogen that mimics self-antigen (molecular mimicry) can also lead to a loss of peripheral tolerance and feed into the antiself ITP pathway. Peripheral AS cells in ITP can arise either primarily, through a defect in central or early tolerance checkpoints, or secondarily as a result of immune stimulation. Autoreactive peripheral B lymphocytes in ITP can include memory cells and plasma cells. Because of space constraints, only the activated cell arising from an immune response for the ITP pathway (not the plasmablast, memory cell or plasma cell) is shown. AS indicates antiself (autoreactive); NS, nonself-reactive; Ag, antigen. Professional illustration by Paulette Dennis.