Alterations in nuclear structure promote lupus autoimmunity in a mouse model

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• Systemic lupus erythematosus (SLE) is an autoimmune disease primarily researched for immune cell dysfunction and genetics.
• Patients with SLE exhibit neutrophil nuclear morphology changes and mRNA mis-splicing in the lamin B receptor (LBR).
• Previous research has not fully explored the role of nuclear structure disruption in lupus autoimmunity.

Purpose of the Study:

• To investigate the hypothesis that nuclear structure disruption contributes to lupus autoimmunity.
• To utilize a novel mouse model to test the impact of LBR gene mutation on lupus development.

Main Methods:

• Crossed lupus-prone New Zealand White (NZW) mice with c57Bl/6 mice carrying a heterozygous mutation in the Lbr gene (B6.Lbr(ic/+)).
• Evaluated (NZW×B6.Lbr(ic))F1 offspring for lupus autoimmunity indicators.
• Analyzed autoantibody profiles, including anti-chromatin and anti-nuclear antibodies, and characterized kidney damage.

Main Results:

• Only female (NZW×B6.Lbr(ic))F1 mice developed lupus autoimmunity, characterized by splenomegaly, kidney damage, and autoantibodies.
• Kidney damage involved immune complex deposition and inflammatory cell infiltration.
• High titers of anti-chromatin IgG2 antibodies were observed, along with complex anti-nuclear antibody staining patterns and anti-calreticulin antibodies.

Conclusions:

• Alterations in nuclear structure contribute to lupus autoimmunity when combined with a lupus-prone genetic background.
• Disruption of nuclear architecture presents a potential mechanism for lupus development in genetically susceptible individuals.
• This study provides new insights into the pathogenesis of SLE, emphasizing the role of nuclear integrity.