Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis
Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis
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DOI：
10.1073/pnas.1001074107
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发表时间：
2010-03-09
影响因子：
11.1
通讯作者：
Mathis, Diane
中科院分区：
文献类型：
--
作者：
Huang, Haochu;Benoist, Christophe;Mathis, Diane
人们越来越认识到B细胞在许多自身免疫性疾病中的重要作用，因此，人们越来越有兴趣通过使用抗CD20的单抗利妥昔单抗来治疗这些疾病。然而，这种药物和相关药物究竟是如何发挥治疗作用的，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体抗体滴度的情况下极大地降低血清自身抗体滴度尚不清楚。我们研究了这种药物在K/BxN小鼠炎性关节炎模型中的作用，该模型首次与人CD20转基因杂交。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)的血清抗体滴度下降，但不降低总抗体滴度。葡萄糖-6-磷酸异构酶特异性浆细胞并不像预期的那样主要驻留在骨髓中，而是驻留在脾和淋巴结中，在那里它们寿命短，表达CD20，并被利妥昔单抗迅速耗尽。这些数据支持这样一种模型，即自体反应性浆细胞(至少其某些特异性)在分化、迁移和生存特性方面与保护性抗微生物浆细胞存在本质上的不同。利妥昔单抗针对前者，而不针对后者。
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.