Hspa13 Deficiency Impaired Marginal Zone B Cells Regulatory Function and Contributed to Lupus Pathogenesis

Area of Science:

• Immunology
• Molecular Biology
• Autoimmune Diseases

Background:

• Dysregulated IL-10 producing regulatory B cells (Bregs) are linked to systemic lupus erythematosus (SLE) progression.
• Heat shock proteins (HSPs) have immunomodulatory roles in autoimmune diseases, but Hspa13's specific function in Bregs and lupus is unknown.

Purpose of the Study:

• To elucidate the molecular mechanism of Hspa13 in regulating Breg function and its impact on lupus pathogenesis.

Main Methods:

• Compared Hspa13 expression in Bregs and IL-10-negative B cells.
• Assessed IL-10 production in B cells with Hspa13 knockdown/knockout.
• Investigated Hspa13 binding to the IL-10 promoter.
• Analyzed Breg and regulatory T cell (Treg) differentiation in CD19creHspa13fl/fl mice.
• Evaluated the therapeutic potential of Hspa13-expressing Bregs in lupus models.

Main Results:

• Bregs exhibit higher Hspa13 expression than IL-10-negative B cells.
• Hspa13 knockdown/knockout impairs IL-10 induction in B cells.
• Hspa13 directly binds to the IL-10 promoter, activating transcription.
• Hspa13 is enriched in marginal zone (MZ) B cells for IL-10 regulation.
• CD19creHspa13fl/fl mice show impaired Treg differentiation and worsened lupus pathology.
• Adoptive transfer of Hspa13-deficient Bregs fails to ameliorate lupus symptoms.

Conclusions:

• Hspa13 plays a critical role in regulating IL-10 production by Bregs, particularly within MZ B cells.
• Hspa13 deficiency impairs Breg-mediated Treg induction, exacerbating lupus pathogenesis.
• Hspa13 represents a potential therapeutic target for managing lupus and related autoimmune diseases.