A role for sex chromosome complement in the female bias in autoimmune disease

Most autoimmune diseases are more common in women than in men. This may be caused by differences in sex hormones, sex chromosomes, or both. In this study, we determined if there was a contribution of sex chromosomes to sex differences in susceptibility to two immunologically distinct disease models, experimental autoimmune encephalomyelitis (EAE) and pristane-induced lupus. Transgenic SJL mice were created to permit a comparison between XX and XY within a common gonadal type. Mice of the XX sex chromosome complement, as compared with XY, demonstrated greater susceptibility to both EAE and lupus. This is the first evidence that the XX sex chromosome complement, as compared with XY, confers greater susceptibility to autoimmune disease

Dicer insufficiency and microRNA-155 overexpression in lupus regulatory T cells: an apparent paradox in the setting of an inflammatory milieu.

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance to self-Ags and activation of autoreactive T cells. Regulatory T (Treg) cells play a critical role in controlling the activation of autoreactive T cells. In this study, we investigated mechanisms of potential Treg cell defects in systemic lupus erythematosus using MRL-Fas(lpr/lpr) (MRL/lpr) and MRL-Fas(+/+) mouse models. We found a significant increase in CD4(+)CD25(+)Foxp3(+) Treg cells, albeit with an altered phenotype (CD62L(-)CD69(+)) and with a reduced suppressive capacity, in the lymphoid organs of MRL strains compared with non-autoimmune C3H/HeOuj mice. A search for mechanisms underlying the altered Treg cell phenotype in MRL/lpr mice led us to find a profound reduction in Dicer expression and an altered microRNA (miRNA, miR) profile in MRL/lpr Treg cells. Despite having a reduced level of Dicer, MRL/lpr Treg cells exhibited a significant overexpression of several miRNAs, including let-7a, let-7f, miR-16, miR-23a, miR-23b, miR-27a, and miR-155. Using computational approaches, we identified one of the upregulated miRNAs, miR-155, that can target CD62L and may thus confer the altered Treg cell phenotype in MRL/lpr mice. In fact, the induced overexpression of miR-155 in otherwise normal (C3H/HeOuj) Treg cells reduced their CD62L expression, which mimics the altered Treg cell phenotype in MRL/lpr mice. These data suggest a role of Dicer and miR-155 in regulating Treg cell phenotype. Furthermore, simultaneous appearance of Dicer insufficiency and miR-155 overexpression in diseased mice suggests a Dicer-independent alternative mechanism of miRNA regulation under inflammatory conditions

Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4(+) T cells in the broncho-alveolar lavage of patients with systemic sclerosis.

T cells, particularly those producing IL-4, are implicated in inflammation-mediated fibrosis. In our phase I/IIa open-label pilot study in 15 patients with scleroderma-interstitial lung disease (SSc-ILD), high-dose imatinib treatment showed modest improvement in lung function and skin score, but with several adverse events. Here, we investigated T cell phenotype and cytokine production in bronchoalveolar lavage (BAL) from patients enrolled in this trial. We found that IL-4(+) T cells showed a stronger correlation with ground glass opacity (GGO) than fibrosis scores on lung high-resolution computer tomography scans. Frequencies of IL-4(+) T cells also discriminated patients with high (≥20) versus low (<20) GGO scores. Functional annotation clustering of proteins that correlated with T cells identified two major clusters that belonged to immune/inflammatory and wounding response. Repeat analyses after 1 year of treatment in 10 BAL samples, one each from the right middle and lower lobes of lung from 5 patients, showed that post-imatinib, IL-4(+) T cells were profoundly reduced but CD4(+) T cells increased, except in one patient who showed worsening of SSc-ILD. Post-imatinib increase in CD4(+) T cells correlated with soluble ICAM-3 and PECAM-1 levels in BAL, which associated with the lack of worsening in SSc-ILD. Thus, imatinib might confer its therapeutic effect in fibrosis via re-directing T cell responses from type 2 to other, non-type 2 cytokine producing CD4(+) T cells

A role for sex chromosome complement in the female bias in autoimmune disease.

Most autoimmune diseases are more common in women than in men. This may be caused by differences in sex hormones, sex chromosomes, or both. In this study, we determined if there was a contribution of sex chromosomes to sex differences in susceptibility to two immunologically distinct disease models, experimental autoimmune encephalomyelitis (EAE) and pristane-induced lupus. Transgenic SJL mice were created to permit a comparison between XX and XY within a common gonadal type. Mice of the XX sex chromosome complement, as compared with XY, demonstrated greater susceptibility to both EAE and lupus. This is the first evidence that the XX sex chromosome complement, as compared with XY, confers greater susceptibility to autoimmune disease

(A) Castrated male XX and XY SJL mice were injected with pristane and monitored daily for signs of disease

By 26 wk, XX mice had increased mortality as compared with XY mice. P = 0.027. XX, •, = 12; XY, ▴, = 13. (B) Ovariectomized female XX and XY SJL mice were injected with pristane and monitored daily for signs of disease. At 26 wk, XX mice had increased mortality as compared with XY mice. P = 0.036. XX, •, = 13; XY, ▴, = 15. Data are representative of two independent experiments. (C) Kidneys from ovariectomized female XX and XY female SJL mice injected with pristane were harvested upon death for renal pathology. Representative renal histology from pristane-induced lupus SJL mice showing that ovariectomized female XX mice (left) have more severe nephritis than ovariectomized female XY mice (right). GI, glomerular infiltration; GS, segmental glomerulosclerosis; Cr, cellular crescent; TC, tubular casts; TA, tubular atrophy; FSP, focal segmental proliferative; MM, mild mesangial matrix. Bars, 50 μm. (D) Lesions from pristane-injected ovariectomized female XX and XY mice were scored, ranked, and expressed as the percent frequency of mice in each group. A greater percentage of XX mice showed severe tubular disease scores (≥10; P = 0.006), chronic lesion scores (≥3; P = 0.046), and vascular lesion scores (P = 0.013) than their XY littermates. In addition, a greater percentage of XX mice showed severe glomerular disease scores (≥10; NS). XX, = 13; XY, = 14. XX, white columns; XY, shaded columns. (E) Effect of sex chromosome complement on autoantibody levels in pristane-induced lupus. Ovariectomized female XX and XY SJL mice were bled to detect anti-dsDNA antibodies in serum. 16 wk after pristane injection, XX mice had significantly higher levels of anti-dsDNA IgG antibody in sera than XY mice. P < 0.01. XX, = 9, white columns; XY, = 9, shaded columns; (NZBxNZW)F1 (+control), diagonal-lined columns; BALB/c (−control), vertical-lined columns. Histograms show the means and the SEM for mice in each group from one of three independent experiments. Female symbol with x overlay indicates ovariectomized female; male symbol with x overlay indicates castrated male.<p><b>Copyright information:</b></p><p>Taken from "A role for sex chromosome complement in the female bias in autoimmune disease"</p><p></p><p>The Journal of Experimental Medicine 2008;205(5):1099-1108.</p><p>Published online 12 May 2008</p><p>PMCID:PMC2373842.</p><p></p