Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells

Abstract

The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4+ T cells and reduces the number and function of Foxp3+ regulatory T cells. In this study, we first showed that Sle1a contributes to autoimmunity by increasing anti-nuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft vs. host disease response indicating an expansion of the autoreactive B cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4+ T cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. Since the Sle1a.1 and Sle1a.2 intervals contain only one and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also demonstrate that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the co-expression of multiple genetic variants with individual weak effects.

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

“…Thus, the NZB chromosome 1 interval joins a growing number of congenic intervals that based upon mapping studies were thought to contain a single susceptibility locus, but upon further dissection were found to contain multiple susceptibility loci. [15][16][17] These findings are consistent with the concept that the original mapping studies were underpowered to detect individual genetic loci, that in general have relatively small effects, and therefore only detected regions where multiple loci interacted additively or multiplicatively to produce a stronger signal.…”

Interleukin‐21 Receptor Blockade Inhibits Secondary Humoral Responses and Halts the Progression of Preestablished Disease in the (NZB × NZW)F1 Systemic Lupus Erythematosus Model

“…Other loci contain candidate genes that are potentially responsible for unregulated B cell proliferation (36), enhanced CD41 T cell activity due to mitochondrial defects (37), and elevated antichromatin antibodies due to reduced IL-10 receptor expression (38). Additional loci where causal genes have not yet been defined are associated with the clearance of apoptotic debris (39), DNA-specific B cell activation (40), and induction of inflammatory T cells that are resistant to Treg cell-mediated suppression (41). In this latter study, Treg cells from mice congenic for the Sle1a locus were found to be reduced in frequency and function; however, in aged NZB/NZW mice, Treg cells are highly enriched and possess normal in vitro suppressor activity (16,42).…”

The Murine Pbx1-d Lupus Susceptibility Allele Accelerates Mesenchymal Stem Cell Differentiation and Impairs Their Immunosuppressive Function

“…Our in vitro and in vivo studies were conducted on MSCs derived from young Sle1a1 mice, whereby this strain does not develop clinical disease (7). This excludes the possible contribution of a lupus-related inflammatory milieu to the phenotype and altered function of Sle1a1 MSCs.…”

“…Sle1a1 is a contributor to the Sle1 global locus, which controls the loss of tolerance to chromatin (5-7), and is necessary for disease initiation (8,9). NZM2410-derived B6.Sle1a1 (Sle1a1) congenic mice as well as TC mice, which carry Sle1a1, present an elevated number of activated autoreactive CD4 + T cell that provide help to B cells producing anti-chromatin IgG (6,7). Pbx1, the only gene located in the Sle1a1 interval, is a wellcharacterized member of the TALE family of homeodomain proteins that functions as a transcriptional regulator through the modulation of the DNA-binding function of Hox proteins (10).…”