Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

Abstract

Sex-related differences (SrD) are a general characteristic of human autoimmune diseases. There is an increasing body of evidence that suggests a link between sexrelated hormones and autoimmune onsets. Here, through a genetic approach using a lupus mouse model, we attempted to show the involvement of genetic factors in the development of SrD in autoimmune diseases. Using MRL/lpr  (MRL/lpr  C57BL/ 6.Fas lpr )F1 (MBN2) mice, the whole genome was searched to identify linkage loci to autoimmune phenotypes inherited from a lupus MRL/Mp.Fas lpr (MRL/lpr) strain of mice, which exhibits glomerulonephritis, splenomegaly and antinuclear autoantibody. The genome-wide association study confirmed four linkage loci on chromosomes 4, 7, 13, and 17. Furthermore, differential analyses performed using male and female groups of MBN2 mice revealed that two loci located on chromosomes 4 (41-72 cM, MRL/lpr allele) and 7 (4-21 cM, B6/lpr allele) were male specific and suppressed autoimmune phenotypes. Notably, the sum effect of the two loci adequately explained a range of SrD developed in the MBN2 mice. Our present findings suggest the presence of a malepredominant mechanism underlying the development of SrD in autoimmunity, depending on the effects of autosomal loci under an undefined male-specific condition.

Onset of autoimmune glomerulonephritis derived from the telomeric region of MRL-chromosome 1 is associated with the male sex hormone in mice

“…In a previous study, the results of a quantitative trait locus (QTL) analysis performed using F2 generations derived from MRL-lpr and C57BL/6 mice suggested that chromosome 7 in the C57BL/6 genome carries AGN-and splenomegaly-resistant genes regulated by the male sex. 18 These previous findings and our present data indicate that the sex differences on incidence of AGN in B6.MRLc1(82-100) mice might be influenced by the Mag locus and/or by these disease-associated genes in the C57BL/6 genome.…”

Review: Male systemic lupus erythematosus: a review of sex disparities in this disease

“…However, it remains possible that non-sex linked genes also play a role. In a differential analyses performed using MBN2 mice, two loci located on chromosomes 4 (41-72 cM, MRL/lpr allele) and 7 (4-21 cM, B6/lpr allele) were male specific and suppressed autoimmune phenotypes (104). Another comparative gene expression study in BWF1 mice revealed that 77 genes encoded on the autosomal chromosomes were identified as differentially expressed in males versus females (93).…”

“…In a differential analyses performed using MBN2 mice, two loci located on chromosomes 4 (41-72 cM, MRL/lpr allele) and 7 (4-21 cM, B6/lpr allele) were male-specific and suppressed autoimmune phenotypes. 107 Another comparative gene expression study in BWF1 mice revealed that 77 genes encoded on the autosomal chromosomes were identified as differentially expressed in males versus females. 96 In human SLE, Xing et al 108 confirmed the linkage of SLE to 13q32 specific to predisposition of African Americans to a specific form of SLE, with males at high risk.…”

Diagnosis and early detection of CNS-SLE in MRL/lpr mice using peptide microarrays

“…Alterations in these genes can influence disease onset and progression. The involvement of genetics on the development of lupus-like disease in a mouse model, MBN2, revealed two loci on different chromosomes that suppressed the autoimmune phenotype in male mice [23]. Therefore the influence of such genetic elements on the production of autoantibodies that promoted the different banding patterns discovered using our microarrays need additional investigation.…”

“…Females were employed instead of males since in humans there is a sex-related difference where onset is more predominant in females, however for the MRL/lpr mice no overt sex-related differences exist, although there is some suggestion that a propensity does exist at the genetic level [23]. In Study 1, we used 3–6 MRL/lpr, MRL/mp and C3H/HeJ at 4 months and in Study 2 we increased the number to 9–10 MRL/lpr and MRL/mp at 1.5 and 4 months.…”