Adem Jemal, Eray Mine, Eeva Jonna, Nuutinen Ulla, Pelkonen Jukka
Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland.
Department of Pathology (HUSLAB), Helsinki University Hospital, Helsinki, Finland.
Mol Immunol. 2017 Aug;88:135-137. doi: 10.1016/j.molimm.2017.05.023. Epub 2017 Jun 20.
Antibodies produced by B-cells provide protection from infectious agents. However, impaired cell death signaling pathways in B-cells can lead to cancer, immunodeficiency or autoimmune diseases. B-cell signaling molecules such as CD20, CD19, Btk, and BAFF-R are targeted by therapeutic drugs and used to treat B-cell derived lymphomas or autoimmune diseases. Nevertheless, B-cells could develop resistance to these therapeutic drugs or the therapeutic drugs may have off-target effects. For instance, repeated rituximab (anti-CD20 antibody) treatment may lead to the loss of its target cell surface molecule, CD20. In addition, in B-cell malignancies, loss of CD19 expression has been observed. Another target molecule, Btk is expressed not only in B-cells but also in mast cells, macrophages, and dendritic cells. Thus, targeting Btk could negatively regulate the functions of innate immunity. The expression of BAFF-R is thought to be restricted to B-cells but it is also expressed on T-cells. Targeting BAFF-R, therefore, may lead to depletion of T-cells in addition to B-cells. B cell receptor (BCR) expression and signaling, however, are critically important for development, differentiation and survival of B-cells. Moreover, BCR is exclusively expressed on B-cells, which makes it an excellent target to avoid off-target effects.
B细胞产生的抗体可提供针对感染因子的保护。然而，B细胞中细胞死亡信号通路受损会导致癌症、免疫缺陷或自身免疫性疾病。诸如CD20、CD19、Btk和BAFF-R等B细胞信号分子是治疗药物的靶点，用于治疗B细胞源性淋巴瘤或自身免疫性疾病。然而，B细胞可能会对这些治疗药物产生耐药性，或者这些治疗药物可能会产生脱靶效应。例如，重复使用利妥昔单抗（抗CD20抗体）治疗可能会导致其靶细胞表面分子CD20的丢失。此外，在B细胞恶性肿瘤中，已观察到CD19表达缺失。另一个靶分子Btk不仅在B细胞中表达，还在肥大细胞、巨噬细胞和树突状细胞中表达。因此，靶向Btk可能会对先天免疫功能产生负面影响。BAFF-R的表达被认为仅限于B细胞，但它也在T细胞上表达。因此，靶向BAFF-R除了导致B细胞耗竭外，还可能导致T细胞耗竭。然而，B细胞受体（BCR）的表达和信号传导对于B细胞的发育、分化和存活至关重要。此外，BCR仅在B细胞上表达，这使其成为避免脱靶效应的理想靶点。
