Mice with an inactivated joining chain locus have perturbed IgM secretion

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The joining chain (J chain) is crucial for the polymerization of immunoglobulins, particularly IgM and IgA.
• Understanding the J chain's role is essential for comprehending humoral immunity and immunoglobulin function.

Purpose of the Study:

• To investigate the in vivo function of the J chain by creating and analyzing mice with an inactivated J chain locus.
• To determine the effects of J chain deficiency on immunoglobulin levels, B cell compartments, and immune responses.

Main Methods:

• Gene targeting in embryonic stem cells to delete the first exon of the J chain locus.
• Analysis of serum immunoglobulin levels (total and isotype distribution).
• Flow cytometry to assess peripheral B cell populations.
• Complement activation assays.
• In vitro B cell stimulation assays (lipopolysaccharide).
• In vivo immunization studies with T-dependent and T-independent antigens.

Main Results:

• Mice with inactivated J chain locus (J-/-) exhibited normal total immunoglobulin levels but altered isotype distribution (elevated IgA, reduced IgM).
• High molecular weight IgM was reduced, replaced by oligomeric forms, with diminished complement activation.
• Reduced IgM plaque-forming cells in spleen and bone marrow, even after in vitro stimulation.
• Intracellular IgM was detected, suggesting a defect in late-stage B cell differentiation or secretion.
• Humoral immune response showed reduced IgM but only marginally affected IgG production.

Conclusions:

• The J chain is essential for normal IgM structure, secretion, and function, including complement activation.
• J chain deficiency impacts B cell differentiation at a late stage, affecting IgM production.
• While IgM responses are significantly impaired, IgG responses show less sensitivity to J chain inactivation.