Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Nihon University School of Dentistry, Tokyo, Japan.
J Autoimmun. 2024 Jun;146:103245. doi: 10.1016/j.jaut.2024.103245. Epub 2024 May 15.
B cell responses to nucleic acid-containing self-antigens that involve intracellular nucleic acid sensors play a crucial role in autoantibody production in SLE. CD72 is an inhibitory B cell co-receptor that down-regulates BCR signaling, and prevents the development of SLE. We previously showed that CD72 recognizes the RNA-containing self-antigen Sm/RNP, a target of SLE-specific autoantibodies, and induces B cell tolerance to Sm/RNP by specifically inhibiting B cell response to this self-antigen. Here, we address whether CD72 inhibits B cell response to ribosomes because the ribosome is an RNA-containing self-antigen and is a target of SLE-specific autoantibodies as well as Sm/RNP. We demonstrate that CD72 recognizes ribosomes as a ligand, and specifically inhibits BCR signaling induced by ribosomes. Although conventional protein antigens by themselves do not induce proliferation of specific B cells, ribosomes induce proliferation of B cells reactive to ribosomes in a manner dependent on RNA. This proliferative response is down-regulated by CD72. These results suggest that ribosomes activate B cells by inducing dual signaling through BCR and intracellular RNA sensors and that CD72 inhibits B cell response to ribosomes. Moreover, CD72 but not CD72 mice spontaneously produce anti-ribosome autoantibodies. Taken together, CD72 induces B cell self-tolerance to ribosomes by recognizing ribosomes and inhibiting RNA-dependent B cell response to this self-antigen. CD72 appears to prevent development of SLE by inhibiting autoimmune B cell responses to multiple RNA-containing self-antigens. Because these self-antigens but not protein self-antigens induce RNA-dependent B cell activation, self-tolerance to RNA-containing self-antigens may require a distinct tolerance mechanism mediated by CD72.
B 细胞对涉及细胞内核酸传感器的含核酸自身抗原的反应在 SLE 中产生自身抗体的过程中起着至关重要的作用。CD72 是一种抑制性 B 细胞共受体，可下调 BCR 信号转导，从而防止 SLE 的发生。我们之前曾表明，CD72 识别含有 RNA 的自身抗原 Sm/RNP，这是 SLE 特异性自身抗体的靶标，并通过特异性抑制 B 细胞对该自身抗原的反应来诱导 B 细胞对 Sm/RNP 的耐受。在这里，我们研究了 CD72 是否抑制 B 细胞对核糖体的反应，因为核糖体是一种含有 RNA 的自身抗原，也是 SLE 特异性自身抗体以及 Sm/RNP 的靶标。我们证明 CD72 识别核糖体作为配体，并特异性抑制由核糖体诱导的 BCR 信号转导。尽管常规的蛋白质抗原本身不会诱导特异性 B 细胞的增殖，但核糖体以依赖 RNA 的方式诱导对核糖体反应性的 B 细胞增殖。这种增殖反应受 CD72 下调。这些结果表明，核糖体通过诱导 BCR 和细胞内 RNA 传感器的双重信号转导来激活 B 细胞，而 CD72 抑制 B 细胞对核糖体的反应。此外，CD72 而不是 CD72 小鼠自发产生抗核糖体自身抗体。总之，CD72 通过识别核糖体并抑制该自身抗原的 RNA 依赖性 B 细胞反应，诱导 B 细胞对核糖体的自身耐受。CD72 通过抑制对多种含 RNA 的自身抗原的自身反应性 B 细胞反应，似乎可预防 SLE 的发生。由于这些自身抗原而不是蛋白质自身抗原诱导 RNA 依赖性 B 细胞激活，因此对含 RNA 的自身抗原的自身耐受可能需要由 CD72 介导的独特耐受机制。
