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<p>The immunoproteasome (IP) is a specialized form of the 26S proteasome, in which the catalytic subunits β1c, β2c, and β5c of the standard proteasome are replaced by LMP2, MECL-1, and LMP7. The IP is constitutively expressed in hematopoietic cells and its expression in non-hematopoietic cells can be induced by IFN-γ. The IP plays a crucial role in different immune functions, including MHC class-I ligand generation, cytokine production, and T helper cell differentiation. Selective inhibition of the IP has shown therapeutic benefits in treating different autoimmune diseases in pre-clinical animal models. However, the effect of IP inhibition on antibody production in viral infection and vaccination has remained underexplored. In this study, we used ONX 0914, an LMP7/LMP2-selective inhibitor of the IP, to study the effect of IP inhibition on B cells and antibody production. In vitro, continuous exposure to ONX 0914 in a human B cell lymphoma cell line and primary murine B and plasma cells led to poly-ubiquitinated protein accumulation, increased apoptosis, reduced antibody secretion, and impaired immunoglobulin class-switch. However, induction of virus neutralizing antibodies was not affected in IP inhibitor-treated mice. Furthermore, IP inhibition neither impaired vaccine-induced antibody responses, nor affected different B cell populations in two different vaccination models. These findings suggest that IP inhibition does not compromise vaccination efficacy and anti-viral humoral immunity, supporting the potential of IP-targeted therapies for autoimmune diseases.</p>

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Immunoproteasome inhibition triggers protein stress and apoptosis in cells of B cell lineage without impairing vaccination-induced antibody responses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Dennis Mink,
  • Franziska Oliveri,
  • Julia Otto,
  • Nazlim Kutsi,
  • Carolina Gonzalez Siebold,
  • Tony Muchamuel,
  • Jun Li,
  • Michael Basler

摘要

The immunoproteasome (IP) is a specialized form of the 26S proteasome, in which the catalytic subunits β1c, β2c, and β5c of the standard proteasome are replaced by LMP2, MECL-1, and LMP7. The IP is constitutively expressed in hematopoietic cells and its expression in non-hematopoietic cells can be induced by IFN-γ. The IP plays a crucial role in different immune functions, including MHC class-I ligand generation, cytokine production, and T helper cell differentiation. Selective inhibition of the IP has shown therapeutic benefits in treating different autoimmune diseases in pre-clinical animal models. However, the effect of IP inhibition on antibody production in viral infection and vaccination has remained underexplored. In this study, we used ONX 0914, an LMP7/LMP2-selective inhibitor of the IP, to study the effect of IP inhibition on B cells and antibody production. In vitro, continuous exposure to ONX 0914 in a human B cell lymphoma cell line and primary murine B and plasma cells led to poly-ubiquitinated protein accumulation, increased apoptosis, reduced antibody secretion, and impaired immunoglobulin class-switch. However, induction of virus neutralizing antibodies was not affected in IP inhibitor-treated mice. Furthermore, IP inhibition neither impaired vaccine-induced antibody responses, nor affected different B cell populations in two different vaccination models. These findings suggest that IP inhibition does not compromise vaccination efficacy and anti-viral humoral immunity, supporting the potential of IP-targeted therapies for autoimmune diseases.