Identification Of The Atypically Modified Autoantigen Ars2 As The Target Of B-Cell Receptors From Activated B-Cell-Type Diffuse Large B-Cell Lymphoma

It has been suggested that stimulation of B-cell receptors (BCR) by specific antigens plays a pathogenic role in diffuse large B-cell lym-phoma (DLBCL). Here, it was the aim to screen for specific reactivi-ties of DLBCL-BCR in the spectrum of autoantigens and antigens of infectious origin. Arsenite resistance protein 2 (Ars2) was identified as the BCR target of three of five activated B-cell type DLBCL cell lines and two of 11 primary DLBCL cases. Compared to controls, Ars2 was hypophosphorylated exclusively in cases and cell lines with Ars2-specif-ic BCR. In a validation cohort, hypophosphorylated Ars2 was found in eight of 31 activated B-cell type DLBCL, but in only one of 20 germinal center B-cell like type DLBCL. Incubation with Ars2 induced BCR-path-way activation and increased proliferation, while an Ars2/ETA' toxin conjugate induced killing of cell lines with Ars2-reactive BCR. Ars2 appears to play a role in a subgroup of activated B-cell-type DLBCL. Moreover, transformed DLBCL lines with Ars2-reactive BCR still showed growth advantage after incubation with Ars2. These results provide knowledge about the pathogenic role of a specific antigen stim-ulating the BCR pathway in DLCBL.