Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA.
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4658-63. doi: 10.1073/pnas.1001074107. Epub 2010 Feb 22.
There is increasing appreciation of the important role of B cells in many autoimmune diseases and consequently, increasing interest in treating these disorders through B cell-depletion therapy with rituximab, an anti-CD20 monoclonal antibody. Yet, precisely how this and related drugs exert their therapeutic effects remains controversial. In particular, it is unclear how, in a number of contexts, rituximab can greatly reduce the titer of serum autoantibodies without substantially altering the overall antibody titer. We have studied the action of this drug in the K/BxN mouse model of inflammatory arthritis after first crossing in a human CD20 transgene. Rituximab treatment of these mice led to a decrease in the titer of serum antibodies targeting glucose-6-phosphate isomerase, the relevant autoantigen, but not in the total antibody titer. Glucose-6-phosphate isomerase-specific plasma cells did not reside primarily in the bone marrow as expected but rather in the spleen and lymph nodes, where they had short lives, expressed CD20, and were rapidly depleted by rituximab. These data support a model whereby autoreactive plasma cells (at least certain specificities thereof) are intrinsically different from protective antimicrobial plasma cells in their differentiation, migration, and survival properties. Rituximab targets the former and spares the latter.
人们越来越意识到 B 细胞在许多自身免疫性疾病中的重要作用，因此，人们越来越感兴趣地通过用抗 CD20 单克隆抗体利妥昔单抗进行 B 细胞耗竭疗法来治疗这些疾病。然而，确切地说，这些药物和相关药物如何发挥其治疗作用仍然存在争议。特别是，在许多情况下，利妥昔单抗如何在不显著改变总抗体滴度的情况下大大降低血清自身抗体的滴度尚不清楚。我们在首次导入人 CD20 转基因后，在 K/BxN 小鼠炎症性关节炎模型中研究了这种药物的作用。利妥昔单抗治疗这些小鼠导致针对葡萄糖-6-磷酸异构酶（相关自身抗原）的血清抗体滴度降低，但总抗体滴度没有降低。葡萄糖-6-磷酸异构酶特异性浆细胞并未如预期的那样主要存在于骨髓中，而是存在于脾脏和淋巴结中，它们寿命短，表达 CD20 ，并且很快被利妥昔单抗耗竭。这些数据支持这样一种模型，即自身反应性浆细胞（至少是其某些特异性）在分化、迁移和存活特性上与保护性抗微生物浆细胞固有不同。利妥昔单抗针对前者，而后者则不受影响。
