SMS2 deficiency impairs PKCδ-regulated B cell tolerance in the germinal center

Cell Rep. 2021 Aug 31;36(9):109624. doi: 10.1016/j.celrep.2021.109624.

Abstract

B cell tolerance prevents autoimmunity by deleting or deactivating autoreactive B cells that otherwise may cause autoantibody-driven disorders, including systemic lupus erythematosus (lupus). Lupus is characterized by immunoglobulin Gs carrying a double-stranded (ds)-DNA autospecificity derived mainly from somatic hypermutation in the germinal center (GC), pointing to a checkpoint breach of GC B cell tolerance that leads to lupus. However, tolerance mechanisms in the GC remain poorly understood. Here, we show that upregulated sphingomyelin synthase 2 (SMS2) in anti-dsDNA GC B cells induces apoptosis by directly activating protein kinase C δ (PKCδ)'s pro-apoptotic activity. This tolerance mechanism prevents lupus autoimmunity in C57/BL6 mice and can be stimulated pharmacologically to inhibit lupus pathogenesis in lupus-prone NZBWF1 mice. Patients with lupus consistently have substantially reduced SMS2 expression in B cells and to an even greater extent in autoimmune-prone, age-associated B cells, suggesting that patients with lupus have insufficient SMS2-regulated B cell tolerance.

Keywords: 2OHOA; B cell tolerance; PKCδ; SMS2; age-associated B cells; germinal center; lupus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Autoimmunity* / drug effects
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Activation
  • Enzyme Activators / pharmacology
  • Female
  • Genetic Predisposition to Disease
  • Germinal Center / drug effects
  • Germinal Center / enzymology*
  • Germinal Center / immunology
  • Germinal Center / pathology
  • Immune Tolerance* / drug effects
  • Lupus Erythematosus, Systemic / enzymology*
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Erythematosus, Systemic / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NZB
  • Mice, Knockout
  • Protein Kinase C-delta / genetics
  • Protein Kinase C-delta / metabolism*
  • Signal Transduction
  • Transferases (Other Substituted Phosphate Groups) / deficiency*
  • Transferases (Other Substituted Phosphate Groups) / genetics
  • Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

  • Enzyme Activators
  • Prkcd protein, mouse
  • Protein Kinase C-delta
  • SGMS2 protein, human
  • Transferases (Other Substituted Phosphate Groups)
  • Sgms2 protein, mouse