Abstract
ABSTRACTSystemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the development of autoantibodies that recognize components of the cell nucleus. The vast majority of lupus research has focused on either the contributions of immune cell dysfunction or the genetics of the disease. Because granulocytes isolated from human SLE patients had alterations in neutrophil nuclear morphology that resembled the Pelger–Huet anomaly, and had prominent mis-splicing of mRNA encoding the nuclear membrane protein lamin B receptor (LBR), consistent with their Pelger–Huet-like nuclear morphology, we used a novel mouse model system to test the hypothesis that a disruption in the structure of the nucleus itself also contributes to the development of lupus autoimmunity. The lupus-prone mouse strain New Zealand White (NZW) was crossed with c57Bl/6 mice harboring a heterozygous autosomal dominant mutation in Lbr (B6.Lbric/+), and the (NZW×B6.Lbric)F1 offspring were evaluated for induction of lupus autoimmunity. Only female (NZW×B6.Lbric)F1 mice developed lupus autoimmunity, which included splenomegaly, kidney damage and autoantibodies. Kidney damage was accompanied by immune complex deposition, and perivascular and tubule infiltration of mononuclear cells. The titers of anti-chromatin antibodies exceeded those of aged female MRL-Faslpr mice, and were predominantly of the IgG2 subclasses. The anti-nuclear antibody staining profile of female (NZW×B6.Lbric)F1 sera was complex, and consisted of an anti-nuclear membrane reactivity that colocalized with the A-type lamina, in combination with a homogeneous pattern that was related to the recognition of histones with covalent modifications that are associated with gene activation. An anti-neutrophil IgM recognizing calreticulin, but not myeloperoxidase (MPO) or proteinase 3 (PR3), was also identified. Thus, alterations in nuclear structure contribute to lupus autoimmunity when expressed in the context of a lupus-prone genetic background, suggesting a mechanism for the development of lupus autoimmunity in genetically predisposed individuals that is induced by the disruption of nuclear architecture.
Highlights
Systemic lupus erythematosus (SLE) is regarded as a failure of the immune system to maintain tolerance to self-antigens (Tsokos, 2011; Choi et al, 2012)
Only 7 of 37 lamin B receptor (LBR) subclones obtained from four pairs of Low-density granulocytes (LDGs) and polymorphonuclear cells (PMNs) isolated from SLE patients encoded intact LBR mRNA
The splicing of the nuclear envelope protein LBR is disrupted in PMNs from SLE patients, consistent with their Pelger–Huet-like nuclear morphology; these findings support a model in which alterations in nuclear structure are present in SLE patients
Summary
Systemic lupus erythematosus (SLE) is regarded as a failure of the immune system to maintain tolerance to self-antigens (Tsokos, 2011; Choi et al, 2012). SLE is characterized by the presence of autoantibodies recognizing components of the cell nucleus, and is thought to originate from loss of tolerance to chromatin that spreads to other components, including histones and DNA. Cell aspirates from the bone marrow of individuals with lupus have a variety of abnormalities (Voulgarelis et al, 2006; Oka et al, 2008; Papageorgiou et al, 2013), and alterations in nuclear morphology secondary to SLE is an exclusion in the diagnosis of myelodysplastic disorders. Given the nature of SLE as an autoimmune disorder that targets the cell nucleus, an alternative model for induction of the disease is that alterations in nuclear structure promote the development of an immune response that initially targets aberrant nuclei, which spreads to include additional components of the nucleus
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