Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh is linked to severe immunodeficiency syndromes.
• The precise defect caused by Lsh mutation in hematopoiesis remains unclear.

Purpose of the Study:

• To investigate the role of Lsh in hematopoiesis and B cell development.
• To elucidate the molecular mechanisms underlying Lsh-associated immunodeficiency.

Main Methods:

• Conditional Lsh knockout mice (using Mx1 or Vav Cre-recombinase) were generated.
• Bone marrow transplantation studies were performed.
• B lymphocyte function, including proliferation, immunoglobulin production, and class switch recombination (CSR), was assessed in vitro and in vivo.

Main Results:

• Lsh depletion in hematopoietic stem cells led to reduced B cell numbers and impaired B cell development autonomously.
• Lsh-deficient mice showed lower immunoglobulin levels despite normal peripheral B cell counts.
• While CSR initiation was unaffected, Lsh-deficient B cells exhibited impaired canonical end-joining DNA repair pathways.

Conclusions:

• Lsh plays a critical cell-intrinsic role in B cell development and class switch recombination.
• Impaired DNA repair via the end-joining pathway is a key defect in Lsh-deficient B cells.
• Lsh represents a potential therapeutic target for immunodeficiency disorders.