Background/Purpose: SLE is regarded as a failure of the immune system to maintain tolerance to self-antigens. Despite steady advances defining the importance of inflammatory mediators in the progression and severity of the disease, the underlying mechanisms driving the development of autoimmunity remain unresolved. SLE is characterized by the presence of autoantibodies recognizing components of the cell nucleus. While the contribution of immune system dysfunction to the loss of immunological tolerance is an area of intense investigation, the potential role for alterations in the structure of the nucleus itself has not been considered. The nucleus is stabilized by a network of proteins called lamins, with B-type lamins anchored by associations with Lamin B receptor (Lbr). Lbr spans the inner nuclear membrane and associates with heterochromatin to maintain its distribution at the nuclear membrane margins. Impaired expression of Lbr causes autosomal dominant disruptions in nuclear structure that include the Pelger-Huet Anomaly.  In mice, Lbr is within lupus susceptibility intervals identified on chromosome 1. Given the role of Lbr in stabilizing nuclear structure and its ability to bind chromatin, we hypothesized that an autosomal dominant disruption in Lbr, would contribute to the development of anti-nuclear autoimmunity when expressed in a lupus-prone genetic background. 

Methods: To introduce an autosomal dominant disruption in Lbr into a lupus-prone genetic background, c57Bl/6 mice harboring a spontaneous mutation within a splice junction in Lbr (B6.Lbr^ic/+) were crossed with the lupus-prone mouse strain New Zealand White (NZW). The development of autoantibodies and kidney damage was assessed in the (NZW×B6.Lbr^ic)F₁ offspring.

Results:

Female (NZW×B6.Lbr^ic)F₁ mice developed splenomegaly and glomerulonephritis with immune complex deposition, perivascular cellular infiltrates, and kidney damage. Titers of anti-chromatin antibodies of the IgG2 subclasses exceeded those of aged female MRL-Fas^lpr mice, and autoantibodies recognizing the A-type lamina and histone H3 with covalent modifications associated with gene activation were present.  Anti-neutrophil antibodies developed, but the autoreactivity was not directed against myeloperoxidase or proteinase 3, rather it was attributable to anti-calreticulin of the IgM subclass.

Conclusion:

Alterations in nuclear structure contribute to lupus autoimmunity when expressed in a lupus-prone genetic background.  Thus, environmental factors that disrupt nuclear architecture, such as viral infection or chemical exposure, may also promote lupus autoimmunity in genetically-predisposed individuals, suggesting a fundamental contribution for cell biology in the development of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alterations-in-nuclear-structure-promote-lupus-autoimmunity-in-a-mouse-model/