HLA-DR Modulates Autoantibody Repertoire, But Not Mortality, in a Humanized Mouse Model of Systemic Lupus Erythematosus

Abstract

To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

Structural availability influences the capacity of autoantigenic epitopes to induce a widespread lupus-like autoimmune response

“…These findings with the A3 peptide support earlier conclusions that the B cells involved in binding this epitope of nRNP A may exhibit more than the capacity to produce antibodies that bind the A3 peptide on the animal's own snRNP. They may also process it and present it on MHC class II molecules, along with other peptide components of the spliceosome, to T cells as has been described (38,39). This process, along with proper immune signaling, would then lead to Ig epitope spreading and autoimmunity as seen in this model.…”

In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response

“…Thus, together, these results and the literature data demonstrate that the association of HLA class II with SS susceptibility is related exclusively to the pattern of autoantibody diversification, rather than to the disease itself. Likewise, in animal models transfected with human HLA class II, natural spreading of immune response from Ro 60 to Ro 52 and La depended only on the nature of the transgenic human HLA class II (22), whereas the clinical course of the disease was not modified (23). In accordance with previous reports (7), this study did not show any association between HLA class II and clinical features of SS, but demonstrated an association between anti-Ro/La antibodies and extraglandular involvement and disease severity.…”

CD4 and CD8 T Cells in Susceptibility/Protection to Collagen-Induced Arthritis in HLA-DQ8-Transgenic Mice: Implications for Rheumatoid Arthritis

“…Stained slides were washed three times in PBS for 15 min and examined by fluorescence microscopy. Autoantibodies to ssDNA, dsDNA, and histone were determined by ELISA as previously described (40).…”