Yongkang Wu

Genetic Polymorphisms of rs3077 and rs9277535 in HLA-DP associated with Systemic lupus erythematosus in a Chinese population.

Although the SLE risk gene loci of HLA-DR and HLA-DQ within the major histocompatibility complex (MHC) region has been gradually revealed by recent Genome-Wide Association studies (GWAS), the association of HLA-DP polymorphisms with SLE was minimally reported. Considering that the variants in rs3077 and rs9277535 in the HLA-DP region could influence the immune response by affecting antigen presentation of HLA class II molecules to CD4+ T cells, the present study aimed to explore the role of HLA-DP polymorphisms in SLE. In total, samples from 335 SLE patients and 635 healthy controls were collected and genotyped by a polymerase chain reaction-high resolution melting (PCR-HRM) assay. A significant positive correlation was observed between the SNP rs3077, rs9277535 of HLA-DP and SLE susceptibility (rs3077, OR = 0.74, 95%CI = 0.60–0.91, P = 0.004; rs9277535, OR = 0.72, 95%CI = 0.59–0.88, P = 0.001). Rs3077 polymorphism was corelated to IL-17, INF-γ and cutaneous vasculitis (P = 0.037, P = 0.020 and P = 0.006, respectively). Additionally, rs3077 AA genotype carriers showed lower concentration of inflammatory cytokines and lower cutaneous vasculitis incidence than did the other two genotype. No significant association was observed between rs9277535 and cytokines or any clinical features. In conclusion, HLA-DP polymorphisms (rs3077 and rs9277535) were associated with SLE susceptibility and the levels of some inflammatory cytokines in SLE patients.

IL-1 β and IL-6 Are Highly Expressed in RF+IgE+ Systemic Lupus Erythematous Subtype

Background. Systemic lupus erythematosus (SLE) is an autoimmune disease with great heterogeneity in pathogenesis and clinical symptoms. Rheumatoid factor (RF) is one key indicator for rheumatoid arthritis (RA) while immunoglobulin E (IgE) is associated with type I hypersensitivity. To better categorize SLE subtypes, we determined the dominant cytokines based on familial SLE patients. Methods. RF, IgE, and multiple cytokines (i.e., IL-1β, IL-6, IL-8, IL-10, IL-17, IFN-γ, IP-10, MCP-1, and MIP-1β) were measured in sera of familial SLE patients (n = 3), noninherited SLE patients (n = 108), and healthy controls (n = 80). Results. Three familial SLE patients and 5 noninherited SLE cases are with features of RF+IgE+. These RF+IgE+ SLE patients expressed significantly higher levels of IL-1β and IL-6 than the other SLE patients (P < 0.05). IL-6 correlated with both IgE and IL-1β levels in RF+IgE+ SLE patients (r2 = 0.583, P = 0.027; r2 = 0.847, P = 0.001), and IgE also correlated with IL-1β (r2 = 0.567, P = 0.031). Conclusion. Both IL-1β and IL-6 are highly expressed cytokines in RF+IgE+ SLE subtype which may be related to the pathogenesis of this special SLE subtype and provide accurate treatment strategy by neutralizing IL-1β and IL-6.

The biological effects of IL-21 signaling on B-cell-mediated responses in organ transplantation

Antibody-mediated rejection has emerged as one of the major issues limiting the success of organ transplantation. It exerts a highly negative impact on graft function and outcome, and effective treatment is lacking. The triggers for antibody development, and the mechanisms leading to graft dysfunction and failure, are incompletely understood. The production of antibodies is dependent on instructions from various immunocytes including CD4 T-helper cells that secrete interleukin (IL)-21 and interact with antigen-specific B-cells via costimulatory molecules. In this article, we discuss the role of IL-21 in the activation and differentiation of B-cells and consider the mechanisms of IL-21 and B-cell interaction. An improved understanding of the biological mechanisms involved in antibody-mediated complications after organ transplantation could lead to the development of novel therapeutic strategies, which control humoral alloreactivity, potentially preventing and treating graft-threatening antibody-mediated rejection.

Adipose Tissue-Derived Mesenchymal Stem Cells Have a Heterogenic Cytokine Secretion Profile

Mesenchymal stem cells derived from adipose tissue (ASC) have immune regulatory function, which makes them interesting candidates for cellular therapy. ASC cultures are however heterogeneous in phenotype. It is unclear whether all ASC contribute equally to immunomodulatory processes. ASC are also responsive to cytokine stimulation, which may affect the ratio between more and less potent ASC populations. In the present study, we determined IL-6 receptor (CD126 and CD130 subunits) and IFN-γ receptor (CD119) expression on ASC by flow cytometry. The production of IL-6 and IFN-γ was measured by ELISA and the frequency of IL-6 and IFN-γ secreting cells by ELISPOT. The results showed that ASC did not express CD126, and only 10–20% of ASC expressed CD130 on their surface, whereas 18–31% of ASC expressed CD119. ASC produced high levels of IL-6 and 100% of ASC were capable of secreting IL-6. Stimulation by IFN-γ or TGF-β had no effect on IL-6 secretion by ASC. IFN-γ was produced by only 1.4% of ASC, and TGF-β significantly increased the frequency to 2.7%. These results demonstrate that ASC cultures are heterogeneous in their cytokine secretion and receptor expression profiles. This knowledge can be employed for selection of potent, cytokine-producing, or responsive ASC subsets for cellular immunotherapy.

Autoimmune disease associated IFIH1 single nucleotide polymorphism related with IL-18 serum levels in Chinese systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) has heterogeneous clinical manifestations. IFIH1 (interferon induced with helicase C domain 1) as one of antiviral helicase genes mediating type I interferon production, plays an essential role in the pathogenesis of SLE. The gene variants in IFIH1 could abnormally activate antiviral defenses and increased type I interferon signaling. The present study aimed to validate associations between single nucleotide polymorphisms (SNP) in IFIH1 and the pathogenesis of SLE. In total, rs1990760, rs3747517 and rs10930046 in IFIH1 are genotyped in 400 SLE patients and 659 health controls in Chinese cohort by an improved multiplex ligation detection reaction (iMLDR) technique. Significant associations were observed between alleles of IFIH1 (rs1990760 C > T, P = 0.005, OR = 1.36, 95%CI = 1.10–1.69; rs3747517 T > C, P = 0.004, OR = 1.31, 95%CI = 1.09–1.58, respectively) and SLE susceptibility. IFIH1 rs1990760 TT genotype carriers had lower serum levels of IL-18 (P < 0.001) and granzyme B (P < 0.001) than CC and CT genotype carriers. IFIH1 rs1990760 CT genotype carriers had higher anti-dsDNA–positive than CC and TT genotype carriers. In conclusion, IFIH1 polymorphisms (rs1990760 and rs3747517) were associated with SLE susceptibility and rs1990760 risk T allele related with IL-18 and granzyme B serum levels in SLE patients.

Evaluating the diagnostic and prognostic value of lone anti-Sm for autoimmune diseases using Euroimmun line immunoassays

To investigate the value of lone anti-Smith antibody (anti-Sm) using Euroimmun line immunoassay (LIA) in a Chinese population. One thousand two hundred eight of 39,766 patients who were analyzed for anti-Sm had positive anti-Sm, and were divided into true group (having both positive Sm and nRNP/Sm bands) and lone group (only having Sm band without nRNP/Sm band). The proportions of clinical diagnosis of autoimmune diseases (AIDs), non-autoimmune diseases (NAIDs), concentration of C3, C4, and rheumatoid factor (RF), positive rate of autoantibodies of antinuclear antibody (ANA) profile, and titer of anti-Sm and ANA in systemic lupus erythematosus (SLE) patients were analyzed. Lone anti-Sm was evident in 271/1208 (22.42%) of all positive cases. One hundred seventy-five of them had definitive diagnoses with AIDs being the most prominent (69.71%, 122/175). Compared to the true group, SLE patients in the lone group showed significantly lower ANA and anti-Sm titers (both P < 0.001). There was no difference in frequency of other autoantibodies or C3, C4, and RF levels of SLE patients between the two groups. In NAIDs patients, lone anti-Sm indicates less incidence of kidney injury than true anti-Sm (P = 0.05). Lone anti-Sm has great diagnostic value in AIDs, especially SLE. Lone anti-Sm has relationship with mild kidney impairment. Positive anti-Sm patients with no clinical findings or SLE diagnosis should be submitted to new testing to identify changes in anti-Sm, because turning of lone anti-Sm to true anti-Sm indicates evolving kidney injury.

Genetic polymorphism of rs9277535 in HLA-DP associated with rheumatoid arthritis and anti-CCP production in a Chinese population

HLA-II molecules are critical in triggering human immune response, especially in activating CD4+ T cells. HLA-DP, belonging to HLA-II molecules, draws increasing attention for its role in presentation of viral antigen and autoantigen to T cells. Researches reported single nucleotide polymorphism (SNP) of HLA-DP associated with HBV infection and autoimmune diseases such as SLE. However, little is known about the relationship between HLA-DP and rheumatoid arthritis (RA). Rs9277535 is located in 3′ UTR region of HLA-DPB1, a subunit of HLA-DP, and was reported to affect HLA-DP mRNA expression. In the present study, we explored the relationship between gene polymorphism of rs9277535 in HLA-DPB1 and RA susceptibility and progression. Samples from 254 patients with RA and 391 age- and sex-matched healthy controls were collected and genotyped by a polymerase chain reaction-high-resolution melting (PCR-HRM) assay. Serological tests (anti-CCP, rheumatoid factor, C-reactive protein, anti-keratin antibody) were detected by laboratory assays. Strong association was observed between SNP rs9277535 in HLA-DP and RA susceptibility (allele frequency distribution: OR = 1.409, 95%CI = 1.121–1.773, P = 0.004). Further validation was provided by disease model analysis (recessive model: OR = 1.889, 95%CI = 1.194–2.990, P = 0.008; dominant model: OR = 1.464, 95%CI = 1.050–2.041, P = 0.025; additive model: OR = 2.208, 95%CI = 1.335–3.652, P = 0.003). Allele A was correlated to increased risk of RA. Serological test results demonstrated patients carrying allele A of rs9277535 had elevated serum anti-CCP antibody level. The present study provided evidence that HLA-DP gene polymorphism associated with RA susceptibility. Allele A of rs9277535 in HLA-DP correlated to increased risk of RA and elevated serum anti-CCP level.

331 Il-1Β and il-6 are highly expressed in rf+ige+ systemic lupus erythematous subtype

Background and aims Systemic lupus erythematous (SLE) is anautoimmune disease with great heterogeneity in pathogenesis and clinical symptoms. To better categorise SLE subtypes we determined the dominant cytokines based on RF+IgE+ (both RF and IgE were positive ) familial SLE. Methods RF, IgE and multiple cytokines (i.e., IL-1β, IL-6, IL-8, IL-10, IL-17, IFN–γ, IP-10, MCP-1 andMIP-1β) were measured in sera of familial SLE (n=3),non-inherited SLE (n=108) and healthy controls (n=80). Results Three SLE patients in family and 5 out of 108 non-inherited patients featured with RF+IgE+. These RF+IgE+SLE patients expressed significantly higher levels of IL-1β and IL-6 than the other SLE patients (p<0.05). IL-6 correlated with both IgE and IL-1β levels in RF+IgE+ SLE patients(r2=0.583,p=0.027; r2=0.847,p=0.001). Conclusions Both IL-1β and IL-6 are highly expressed cytokines in RF+IgE+ SLE subtype which may be related to the pathogenesis of this special SLE subtype.

Anti‐Mitotic Spindle Apparatus Antoantibodies: Prevalence and Disease Association in Chinese Population

Mitotic spindle apparatus (MSA) antibodies are rare findings with undefined clinical significance in clinical research. We aimed at investigating the prevalence and clinical significance of anti‐MSA antibodies in Chinese population.