Macrophage migration inhibitory factor levels are associated with disease activity and possible complications in membranous nephropathy.

Membranous nephropathy (MN) is an autoimmune disease characterized by the deposition of immunoglobulin G (IgG) and complementary components in the epithelium of the glomerular capillary wall. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator released by macrophages. MIF plays a key regulatory function in the pathogenesis of immune-mediated glomerulonephritis. This study aimed to investigate whether MIF level could be associated with the activity of MN. Plasma and urine samples from 57 MN patients and 20 healthy controls were collected. The MIF levels in plasma and urine were determined by an enzyme-linked immunosorbent assay (ELISA) kit. The expression of MIF in the renal specimens from 5 MN patients was detected by immunohistochemistry (IHC). The associations of the plasma and urinary levels of MIF and glomerular MIF expression with clinical and pathological characteristics were analyzed. It was revealed that with the increase of MIF levels in plasma and urine, the severity of renal pathological injury in MN patients gradually increased. Correlation analysis showed that the MIF levels in plasma were positively correlated with the platelet (PLT) count (r = 0.302, P = 0.022), and inversely correlated with the prothrombin time (PT) (r = - 0.292, P = 0.028) in MN patients. The MIF levels in plasma were positively correlated with the C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) (r = 0.651, P < 0.0001; r = 0.669, P < 0.0001) in MN patients. The urinary levels of MIF were positively correlated with ESR (r = 0.562, P < 0.0001). IHC suggested that MIF was expressed in glomerular basement membrane and tubulointerstitial areas. MIF levels in plasma and urine could reflect the severity of MN, and MIF levels in plasma and urine could be associated with venous thrombosis and infectious complications in MN patients. The glomerular MIF expression could be used to indicate the activity of MN.

Macrophage migration inhibitory factor contributes to anti-neutrophil cytoplasmic antibody-induced neutrophils activation.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is an inflammatory mediator released by macrophages that is central to the innate immune system, with an upstream role in the inflammatory cascade. MIF is one of the most important pathogenic factors in the development of the autoimmune diseases. In the current study, we investigated the role of MIF in anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation. METHODS: Plasma levels of MIF from 31 patients with active ANCA-associated vasculitis (AAV) were analyzed by ELISA. The various effects of MIF in ANCA-induced neutrophil respiratory burst and degranulation were measured. RESULTS: Plasma levels of circulating MIF were significantly higher in AAV patients with active disease compared with those in remission and healthy controls. Compared with MIF-primed neutrophils, the MFI value increased significantly in MIF-primed neutrophils further activated with MPO-ANCA-positive IgG or PR3-ANCA-positive IgG (270.8±9.7 vs. 421.5±9.7, P<0.001; 270.8±9.7 vs. 414.1±15.6, P<0.001, respectively). Compared with MIF-primed neutrophils, the lactoferrin concentration increased significantly in the supernatant of MIF-primed neutrophils further activated by MPO-ANCA-positive IgG (567.8±61.2ng/ml vs. 1677.0±42.5ng/ml, P<0.001) or PR3-ANCA-positive IgG (567.8±61.2ng/ml vs. 1546.0±116.2ng/ml, P<0.001), respectively. Interleukin-8 (IL-8), IL-6 and IL-23 were involved in ANCA-induced activation of MIF-primed neutrophils. CONCLUSIONS: MIF primes neutrophils by increasing ANCA antigen translocation. The primed neutrophils can be further induced by ANCA, resulting in respiratory burst and degranulation.

Genetic polymorphism of CCL2-2518, CXCL10-201, IL8+781 and susceptibility to severity of Enterovirus-71 infection in a Chinese population.

OBJECTIVE: The goal of this study was to examine the relationship between CCL2-2518A/G, CXCL10-201A/G, and IL8+781C/T gene polymorphism and severity of Enterovirus 71 (EV71) infection in a Chinese population. METHODS: A case-control study was conducted to compare the distribution of genotype and genetic frequency of the CCL2-2518A/G, CXCL10-201A/G, and IL8+781C/T gene polymorphisms among EV71-infected patients (n = 186), including mild cases (n = 103), severe cases (n = 83) and healthy control subjects (n = 233) with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and analyzed the relationship between the CCL2-2518A/G, CXCL10-201A/G, and IL8+781C/T gene polymorphism and the susceptibility to EV71 infection. RESULTS: No significant differences were found in the distribution of genotype CCL2-2518A/G, CXCL10-201A/G, and IL8+781C/T between the healthy control group and EV71-infected patients. However, three SNPs were associated with severity of EV71 infection: the G allele (genotypes AG or GG) in the CCL2-2518A/G (OR 2.34, 95 % CI 1.50-3.65, P < 0.001), the A allele (genotypes AA or AG) in the CXCL10-201A/G (OR 3.60, 95 % CI 1.73-7.47, P < 0.001), and the C allele (genotypes CC or CT) in the IL8+781C/T (OR 2.63, 95 % CI 1.67-4.13, P < 0.001) were more frequent in patients with severe EV71 infection. No significant difference was observed between EV71 encephalitis and severe cases. At the same time, there were significant differences in fever days, WBC, CRP and BG concentration, and CCL2, CXCL10 and IL-8 levels according to the three SNPs among 186 EV71-infected patients, but no significant differences were observed in gender, age, ALT, AST, CK-MB, and CSF evaluations. CONCLUSION: The G carrier of the CCL2-2518A/G, the A carrier of the CXCL10-201A/G, and the C carrier of the IL8+781C/T were found to be associated with severity of EV71 infection, and could be susceptibility factors in the development of EV71 infection in the Chinese population.

Impact of endothelial nitric oxide synthase gene polymorphism on severity of enterovirus 71-infection in Chinese children.

OBJECTIVES: Genetic polymorphism G894T on the endothelial nitric oxide synthase (eNOS) gene has been reported as a susceptibility factor in a number of diseases, but evidence of its effect on enterovirus 71 (EV71) infection is lacking. This study investigated the possible association between this polymorphism (rs1799983) and disease severity in Chinese children with EV71 infection. DESIGN AND METHODS: 185 children with EV71 infection (83 with severe and 102 with mild disease) and 234 control healthy children underwent testing with polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP) to detect G894T polymorphism. In addition, plasma levels of nitric oxide (NO), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and serum eNOS activity were measured according to genotype. RESULTS: The presence of GT+TT genotypes and T allele were associated with severe cases compared to genotype GG (OR 2.5, 95% CI 1.2-5.3, P=0.017) and G (OR 2.4, 95% CI 1.2-4.8, P=0.011). Furthermore, in EV71 encephalitis, GT+TT genotype and T allele were also more frequent than GG and G (P<0.05). The NO level and eNOS activity in T carriers (GT+TT) (84.3±2.5µmol/L and 14.4±1.8U/mL) were significantly less compared to in G carriers (GG) (92.0±1.5µmol/L and 19.1±1.7U/mL, P<0.001). But T carriers had higher plasma levels of IL-1ß, IL-6, and TNF-α than people without a T allele (P<0.001), and a significant negative correlation was observed between NO and cytokine levels. CONCLUSION: The results indicate that carrying the T allele of the eNOS G894T gene polymorphism was associated with EV71 infection, and could be a susceptibility factor in the development of EV71 infection in Chinese children.

Association of IP-10 gene polymorphism with susceptibility to Enterovirus 71 infection.

Enterovirus 71 (EV71) often causes large outbreaks of diseases among children worldwide and its pathogenesis remains unclear. The aim of the present study was to investigate the association between interferon-inducible protein 10 (IP-10) polymorphism in children with EV71 infection. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to analyze the gene polymorphisms of IP-10 (-1596C/T) in 58 EV71-infected and 48 control patients. The results showed that in EV71-infected patients the frequency of carrying CT + TT genotype and T allele is 10.3 and 6.0%, respectively, which is significantly lower than that of the controls (29.2 and 15.6%, respectively). Individuals with T allele had a lower risk of EV71 infection [odds ratio (OR) = 0.35, 95% confidence interval (CI), 0.13-0.89]. The results of this study indicated that -1596T allele for the IP-10 gene may be a beneficial factor for EV71 infection.

Association of interleukin 10 and interferon gamma gene polymorphisms with enterovirus 71 encephalitis in patients with hand, foot and mouth disease.

Enterovirus 71 (EV71) is one of the common causative agents of hand, foot and mouth disease (HFMD), and is associated with several outbreaks with neurological complications including encephalitis. This study investigated the polymorphisms of interferon gamma (IFN-γ)+874 T/A and interleukin 10 (IL-10)-1082 G/A in 65 Chinese patients with EV71 encephalitis and 113 Chinese HFMD patients without complications. The polymorphisms of IFN-γ+874 T/A and IL-10-1082 G/A were determined by polymerase chain reaction (PCR)-amplification refractory mutation system (ARMS) and PCR-sequence-specific primer (SSP) analysis, respectively. The IFN-γ + 874 A allele was observed with significantly greater frequency in patients with EV71 encephalitis (76.2%) compared with HFMD patients without complications (61.1%, p < 0.01). Similarly, the IL-10 - 1082 A allele was observed with significantly greater frequency in patients with EV71 encephalitis (86.2%) compared with HFMD patients without complications (77.0%, p < 0.05). IFN-γ + 874 A and IL-10 - 1082 A alleles are associated with susceptibility to EV71 encephalitis in Chinese patients.