Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction

Area of Science:

• Immunology
• Autoimmunity
• B cell biology

Background:

• Selective deficiency in secreted IgM (sIgM) is linked to antibody-mediated autoimmunity, but the underlying mechanisms remain unclear.
• B cell development and selection are critical for maintaining self-tolerance and preventing autoimmune responses.

Purpose of the Study:

• To elucidate the role of secreted IgM (sIgM) in B cell development, selection, and its contribution to autoimmune disease.
• To characterize the aberrant B cell populations observed in sIgM-deficient mice.

Main Methods:

• Analysis of B cell populations in sIgM-deficient (sIgM-/-) mice using flow cytometry.
• Assessment of B cell development, selection, and responsiveness to B cell receptor (BCR) signaling in vitro and in vivo.
• Investigating the effect of polyclonal IgM administration on B cell development and autoantibody production.

Main Results:

• sIgM is essential for normal B cell development and selection, including proper repertoire selection.
• Accumulated CD5(+) B cells in sIgM-/- mice were identified as anergic B-2 cells, not B-1a cells.
• sIgM deficiency led to reduced B-1a cells, increased marginal zone B cells, and impaired follicular B cell survival and responsiveness.
• Polyclonal IgM administration rescued B cell development and normalized autoantibody levels.

Conclusions:

• Natural IgM deficiency causes primary autoimmune disease by disrupting B cell development, selection, and central tolerance induction.
• sIgM plays a crucial role in providing positive signals during early B cell development and repertoire selection.
• Restoring natural IgM levels can ameliorate autoimmune manifestations caused by sIgM deficiency.