Disease relevance of Sle1

• The systemic lupus erythematosus 1 (Sle1) locus mediates the loss of tolerance to nuclear Ags in the NZM2410 mouse model of lupus through intrinsic defects in both B and T cells [1].
• (B6.NZMc1[Sle1] x NZW)F1 hybrids develop severe humoral autoimmunity and fatal lupus nephritis, indicating that suppression of Sle1 from NZW is recessive [2].
• The combination of Sle1 with Sle2, Sle3, or the BXSB-derived autoimmune accelerating gene yaa results in the development of systemic autoimmunity with variably penetrant severe glomerulonephritis culminating in kidney failure [3].
• Sle1 coexpressed with either one of these single susceptibility alleles resulted in a highly penetrant nephritis, splenomegaly, production of nephrophilic antibodies, and increased expression of B- and T-cell activation markers [4].
• Unlike Atl, Sle1 is not directly involved in autolysis of S. aureus [5].

High impact information on Sle1

• The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to three loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse [6].
• Sle1 and Sle3 are NZW-derived loci that mediate lupus nephritis on a C57BL/6 background [2].
• Moreover, Sles1 was sufficient to completely suppress autoimmunity initiated by Sle1 in B6.NZMc1 x NZW hybrids [2].
• These studies indicate that Sle1 and FAS(lpr) must be impacting alternate pathways leading to lymphoproliferative autoimmunity [7].
• Whereas FAS(lpr) functions as a recessive gene, Sle1 exhibits a gene dosage effect [7].

Biological context of Sle1

• Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes [8].
• These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes [9].
• OBJECTIVE: To assess the effects of altered class II major histocompatibility complex (MHCII) expression on circulating autoantibody levels in C57BL/6 (B6) mice congenic for the Sle1 (B6.Sle1 mice) or Nba2 (B6.Nba2 mice) regions [10].
• B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations [11].
• These experiments showed that Sle1 expression results in both B and T cells intrinsic defects and demonstrate that the documented involvement of each cell compartment in the production of anti-chromatin Abs corresponds to genetic defects rather than bystander effects [12].

Anatomical context of Sle1

• We hypothesize that Sle1 may lead to the presentation of chromatin in an immunogenic fashion, or directly impact tolerance of chromatin-specific B cells [8].
• Interactions between the three Sle1 loci and lpr resulted in lymphocyte activation and lupus nephritis, but a significant mortality was observed only for the Sle1a.lpr combination [4].
• We have shown by mixed bone marrow chimeras with allotypic markers that Sle1 is expressed in B cells [12].
• Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells [13].

Regulatory relationships of Sle1

• We show here that Sle1-expressing CD4(+) T cells present an activated phenotype associated with increased proliferation and cytokine production [14].

Other interactions of Sle1

• This suggests a major role for the FAS pathway in keeping in check the loss of tolerance mediated by the Sle1 loci, especially for Sle1a [4].
• One of them (Cgnz1) is on the telomeric end of chromosome 1 and close to Sle1 [15].
• We have used congenic strains to analyze the interactions between the Sle1 subloci and other lupus susceptibility loci using Y autoimmunity accelerator (Yaa) and Faslpr as sensitizing mutations [4].
• Despite this suppression of the Sle1-mediated cell surface activation phenotypes, B6.Sle1 Sles1 splenic B cells still exhibit intrinsic ERK phosphorylation [16].
• RESULTS: Two recessive susceptibility loci of the MRL allele were identified on chromosomes 4 and 1, which had previously been defined as the autoimmune related loci termed Arvm1 and Sle-1/Nba2, respectively [17].

Analytical, diagnostic and therapeutic context of Sle1

• In this communication, we show by adoptive transfer experiments that the autoimmune phenotypes of Sle1 are completely reconstituted in B6 radiation chimeras receiving B6.NZMc1 bone marrow but not by the reciprocal reconstitution, demonstrating that Sle1 is functionally expressed in B cells [18].
• Identification and molecular characterization of an N-acetylmuramyl-L-alanine amidase Sle1 involved in cell separation of Staphylococcus aureus [5].

References