The gene, CRTH2, encoding a receptor for prostaglandin D(2) (PGD(2)), is located within the peak linkage region for asthma on chromosome (Chr.) 11q reported in African American families. Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3'-untranslated region of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P = 0.003) of SNP rs545659. Haplotype analysis yielded additional evidence of linkage disequilibrium for the 1544G-1651G haplotype (P < 0.001). Population-based case-control analyses were conducted in two independent populations, and demonstrated significant association of the 1544G-1651G haplotype with asthma in an African American population (P = 0.004), and in a population of Chinese children (P < 0.001). Moreover, in the Chinese children the frequency of the 1651G allele in near-fatal asthmatics was significantly higher than mild-to-moderate asthmatics (P = 0.001) and normal controls (P < 0.001). The 1651G allele of SNP re545659 was also associated with a higher degree of bronchial hyperresponsiveness (P < 0.027). Transcriptional pulsing experiments showed that the 1544G-1651G haplotype confers a significantly higher level of reporter mRNA stability, when compared with a non-transmitted haplotype (1544C-1651A), suggesting that the CRTH2 gene on Chr. 11q is a strong candidate gene for asthma.

Recent evidence indicates that bone marrow-derived mesenchymal stem cells (BM-MSCs) possess immunosuppressive properties both in vitro and in vivo. We have previously demonstrated that transplantation of human MSCs can significantly improve the autoimmune conditions in MRL/lpr mice. The current study aimed to determine the mechanisms by which murine BM-MSC transplantation (MSCT) ameliorates nephritis in MRL/lpr mice. In this study, we found that MSCT can significantly prolong the survival of MRL/lpr mice. Eight weeks after transplantation, MSCT-treated mice showed significantly smaller spleens than control animals, with fewer marginal zones (MZs), T1, T2, activated B-cells, and plasma cells. Moreover, serum levels of B-cell activating factor (BAFF) and IL-10 in MSCT-treated mice decreased significantly compared to those in the control group, while levels of serum TGF-β were increased. Notably, decreased BAFF expression in both spleen and kidney was accompanied by decreased production of anti-dsDNA autoantibodies and proteinuria in MSCT-treated mice. Since BAFF is mainly expressed by T-cells and dendritic cells, we incubated BM-MSCs and DCs together and found that the production of BAFF by DCs was suppressed by MSCs. Thus, our findings suggest that MSCT may suppress the excessive activation of B-cells via inhibition of BAFF production in MRL/lpr mice.

Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guérin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-γ integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-γ pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-γR1, IFN-γR2, IL-12p40, IL-12R-β1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN-γ (autoAbs-IFN-γ), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent MSMD phenotype lacking BCG-induced diseases.

The identification of biomarkers helps to perform early diagnosis, thus benefits the outcome of patients with systemic lupus erythematosus (SLE), in which delayed treatment has been proposed as an independent adverse prognostic factor. In this study, we assessed the values of expression levels of five type I interferon (IFN)-inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) and total IFN score for the diagnosis of SLE. Quantitative real-time PCR was applied to determine gene expressions at transcription level in peripheral blood from 69 SLE patients, 42 patients with other connective tissue diseases, and 26 normal controls. Expressions of five genes and IFN score, calculated according to the expressions of IFN-inducible genes, were all significantly increased in SLE patients compared to those in normal subjects and disease controls. IFN score was not related to age, gender, and the dose of steroids, but weakly correlated with SLE disease activity index. None of the gene expression was associated with concomitant infection status or elevated antibodies against Epstein-Barr (EB) virus in SLE. Both modified IFN score (calculated by the expression of three major IFN-inducible genes) and LY6E level showed good diagnostic accuracy in discriminating between SLE patients and disease controls as well as normal subjects (area under the receiver operating characteristic curve was 0.812 and 0.815, respectively), with 70-80 % specificity and 70-80 % sensitivity at the cutoff of 2.37 and 3.23. In conclusion, high IFN-inducible gene expression is constitutional for SLE patients. The modified IFN score or the LY6E level alone may serve as good biomarkers for SLE diagnosis.

Objective Macrophage migration inhibitory factor (MIF) is a key regulator of both atherosclerosis and systemic lupus erythematosus (SLE), yet factors leading to its overproduction remain unclear. To explore regulation of MIF in SLE, we studied effects and potential mechanisms of type I interferon (IFN) and artesunate (ART), an anti-malarial agent extracted from Chinese herbs, on levels of MIF. Methods Serum and peripheral blood cells from SLE patients and healthy controls were measured for MIF levels by ELISA and type I IFN inducible gene expressions by real-time PCR respectively, and assessed for associations by Spearman correlation. ART was added to human umbilical vein endothelial cells (HUVECs) cultures with or without prior IFNα-1b stimulation and to SLE peripheral blood mononuclear cells (PBMC) cultures. Protein levels of STATs and phosphorylated (p-) STATs in HUVECs were determined by Western blotting. Results Serum MIF levels were elevated in SLE patients and positively associated with disease activity (r = 0.86, p < 0.0001), accumulated damage (r = 0.34, p < 0.05), and IFN scores in SLE PBMCs (r = 0.74, p = 0.0002). The addition of IFNα-1b promoted MIF production in a time and dose-dependent manner in HUVEC cultures. ART could inhibit expressions of IFN inducible genes (LY6E and ISG15) in both HUVEC and SLE PBMC cultures, and suppress MIF production and over-expression of p-STAT1, but not p-STAT3 or STAT5, induced by IFNα-1b stimulation. IFNγ-induced expression of p-STAT1 in HUVECs was not inhibited by ART. Conclusion MIF could be regulated by type I IFN in SLE patients. ART counteracts the effect of IFNα to inhibit MIF production by blocking STAT1 phosphorylation and thus may 3 have therapeutic potential for SLE-associated atherosclerosis.

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Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune disease of unknown mechanism. We established a PBC animal model by injecting C57BL/6 mice with polyinosinic-polycytidylic acid sodium (polyI:C) to investigate the therapeutic effect of bone marrow-derived mesenchymal stem cells (BM-MSC) on this model. After 6 weeks of MSC infusion, serum aminotransferase and autoimmune antibodies declined, and histological examination by hematoxylin and eosin staining showed significant amelioration of monocytes infiltration around bile ducts of mice treated with BM-MSC. Interestingly, allogeneic BM-MSC transplantation markedly increased CD4(+)Foxp3(+) regulatory T cells in peripheral blood as well as in lymph nodes when analyzed by flow cytometry. Further examination showed serum TGF-β1 increased but IFN-γ decreased significantly in PBC mice treated with MSC, while with no obvious change in IL-10 expression. Our results for the first time suggested that BM-MSC transplantation could regulate systemic immune response and enhance recovery in liver inflammation of PBC mice, raising the possibility for clinical application of allogeneic MSC in treatment of early-stage PBC patients.