Non-Hodgkin B-cell lymphomas are almost invariably derived from B lymphocytes that have undergone productive V (D) J rearrangements of their immunoglobulin genes and may additionally have experienced somatic hypermutation. In the case of follicular lymphomas, malignant clones undergo ongoing somatic hypermutation of the rearranged V (D) J allele as they further expand. The resulting B-cell receptor idiotype contains novel, tumor-specific sequences and thus represents a class of neoantigen unique to B-cell malignancies. Major histocompatibility complex (MHC) presentation and T-cell recognition of the B-cell idiotype have been demonstrated in mice1, 2 and in humans. 3-7

Presentation of B-cell idiotype has typically been inferred through activation of cognate T cells. Immunoglobulin-derived peptides have been eluted from class II MHC (MHC-II) in a murine B-cell hybridoma line. 8 Mass spectrometry has greatly improved direct detection of B-cell MHC ligands9 including germline-encoded immunoglobulin peptides. However, prior studies have found that germline-derived immunoglobulin peptides are not effective targets for T cells due to immune tolerance. 10-12 Thus, immunoglobulin neoantigens may be the most critical antigens for idiotype recognition, but their detection remains a challenge due to their personalized nature.