Neuromyelitis optica (NMO) is a kind of demyelinating disorder that preferentially affects the optic nerves and spinal cord and results in permanent vision loss. NMO pathogenesis is thought to involve binding of anti-aquaporin-4 (AQP4) auto-antibodies to astrocytes, which causes complement-dependent cytotoxicity (CDC) and downstream inflammation leading to oligodendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. In recent years, a number of groups have found complements play an important role in the pathogenesis of NMO, and basic researches in NMO therapy due to its specificity and uniformity. Its inhibition would protect against proteins in the classical complement pathway so that cure the disease. This review will expound the the role of complement signaling pathway in the pathogenesis of NMO, and provide reference for a more in-depth understanding and clinical treatments of NMO.
ObjectiveTo observe the effect of complement receptor 1 (CR1) on barrier of cultured human retinal epithelial cells (hRPE) under complement-activated oxidative stress. MethodsThe third to fifth passage of hRPE cultured on Transwell insert were used to establish a stable hRPE monolayer barrier. The hRPE monolayer barrier was exposed to 500 μmol/L ten-butyl hydroperoxide and 10% normal human serum to establish the hRPE monolayer barrier model of complement-activated oxidative stress in vitro. hRPE monolayer barriers under complement-activated oxidative stress were divided into two groups including model group and CR1 treatment (1 μg/ml) group. Model group and CR1 treatment group were treated with 1 μl phosphate buffer solution (PBS) or CR1 for 4 hours. Normal hRPE monolayer barrier were used as control in transepithelial resistance (TER) measurement experiment. TER was measured to evaluate the barrier function of hRPE. The hRPE-secreted vascular endothelial growth factor (VEGF) and chemokine (C-C Motif) Ligand 2 (CCL2), together with complement bioactive fragments (C3a, C5a) and membrane-attack complex (MAC) in the supernatant were detected by enzyme-linked immune sorbent assay. ResultsStable hRPE monolayer barrier was established 3 weeks after hRPE seeded on Transwell insert. Complement-activated oxidative stress resulted in a sharp decrease of TER to 54.51% compared with normal hRPE barrier. CR1 treatment could significantly improve TER of barrier under complement-activated oxidative stress to 63.48% compared with normal hRPE barrier(t=21.60, P < 0.05). Compared with model group, CR1 treatment could significantly decrease the concentration of VEGF and CCL2 by 11.48% and 23.47% secreted by hRPE under complement-activated oxidative stress (t=3.26, 2.43; P < 0.05). Compared with model group, CR1 treatment could also decreased the concentration of C3a, C5a and MAC by 24.00%, 27.87%, 22.44%.The difference were statistically significant (t=9.86, 2.63, 6.94; P < 0.05). ConclusionsCR1 could protect the barrier function of hRPE cells against complement-activated oxidative stress. The underlying mechanism may involve inhibiting complement activation and down-regulating the expression of VEGF and CCL2.
Objective To explore the relationship between immune state and disease progression or severity of patients with hepatitis B virus (HBV). Methods A total of 332 patients infected with HBV diagnosed and treated from January 2012 to December 2013 were divided into acute hepatitis B (AHB) group (n=25), chronic hepatitis B (CHB) group (n=237) and cirrhosis group (n=70) according to disease progression. Moreover, CHB group was divided into mild (n=24), moderate (n=103), serious (n=72) and severe group (liver failure group,n=38) according to disease severity, while cirrhosis group was divided into hepatocellular carcinoma (HCC) group (n=13) and non-HCC group (n=57). The immune indexes including immunoglobulin (Ig), complement (C) and T-lymphocyte subsets were tested and compared. Results The immune indexes were not significantly different between AHB group and CHB group (P>0.05). Compared with AHB group and CHB group, cirrhosis group had higher levels of IgG and IgA, and lower levels of CD3+, CD4+ and CD8+ T cells count (P<0.05). Compared with non-HCC group, HCC group had more male patients without antiviral therapy, who had higher levels of C3 and C4 (P<0.05). As disease progressed, the levels of alanine fcell couaminotransferase, aspartate aminotransferase, total cholesterol, Fibroscan index, IgG, and IgA of CHB patients all gradually increased, while the levels of C3 and C4 and the counts of CD3+ and CD4+ T cells gradually declined. Conclusions The immune state of patients infected with HBV has a certain relationship with disease progression or severity, and immunoglobulin, complement and T cells count can partly reflect the severity of the disease. Cirrhosis patients accompanied with high levels of C3 and C4 should pay high attention to antiviral therapy and be vigilant on HCC.
摘要:目的:动态观察大鼠脑出血后血肿周围组织补体激活与细胞凋亡的规律。方法:用胶原酶注入到大鼠尾状核的方法制作脑出血模型。将大鼠分为脑出血、假手术组、正常组3组。采用苏木素伊红(HE) 染色、免疫组织化学染色及原位末端脱氧核苷酸转移酶介导的dUTP 缺口末端标记法(TUNEL)分别观察各组在脑出血后第6 h、12 h、24 h、48 h、72 h、5 d、7 d时血肿周围补体C3、促凋亡基因(Bax)、抑凋亡基因(Bclxl)及TUNEL的表达。结果补体C3的表达峰值在24~48 h;TUNEL、Bax蛋白表达术后12h增加,48~72 h达高峰,而Bclxl蛋白表达高峰在48h。结论:大鼠脑出血后血肿周围组织补体C3的表达增加与细胞凋亡的演变趋势一致,C3与凋亡有相关。Abstract: Objective: To study the complement activation and apoptosis regular genes changes in the tissues of the perihematoma of intracerebral hemorrhage (ICH) in rats. Methods: Intracerebral hemorrhage was induced in rats by injection of bacterial collagenase into the caudate nucleus. Histopathological changes were studied in 6 h,12 h, 24 h, 2 d, 3 d, 5 d, 7 d after the injection. The immunohistochemistry and TUNEL analysis were performed. The expression of complement factor C3, the TUNELpositive cells, the proapoptotic gene expression (Bax) and the antiapoptotic gene (Bclxl) were examined. Results: The expression of C3 increased to its maximum between 2448 h. The TUNELpositive cells and Bax protein expression increased gradually and reached the peak level between 4872 h. The Bclxl protein reached the peak level at 48 h. The correlation analysis showed that the quantity of C3 was positively related to that of the TUNELpositive cells, but the bax protein was not related to Bclxl protein. Conclusion: The expression of complement factor C3 may contributes to the nerve injury after cerebral hemorrhage and relate to the apotosis in the tissues surrounding the hametoma in rats.
Objective To observe preserving effect on myocytes in porcine aortic valve replacement with minimal extracorporeal circulation (MECC). Methods 7 pigs were collected as experimental animals and undertook aortic valve replacement with MECC. Morphological and immunofluorescence intensity changes of right atrial and left ventricular tissues were observed. Results HE staining showed that there were not significant changes and edema or injury of myocytes of right atriums and left ventricles between preoperation and postoperation. Immunofluorescence staining showed complement C3b/c in right atrial myocardial tissues after the operation were a little ber, and innate antibody IgG were a little ber in left ventricular myocardial tissues but similarly weak in right atrial myocardial tissues pre- and post-operation. There was not significant changes in HSPG staining in pre-and post-operative right atrial myocardial tissues, but HSPG were obviously weaker in left ventricular myocardial tissues after the operation. Conclusion MECC is effective on support of porcine aorta valve replacement.
ObjectiveTo understand the role of complement system in the immune mechanism of hepatocellular carcinoma (HCC) and its potential therapy value. MethodThe national and international literature relavant researches of complement system in the HCC was reviewed. ResultsBased on HCC as an immunogenic cancer and the complement system as a part of the innate immune system, it had potential application value in immunotherapy. Eight complement components (complement intrinsic components C1q, C3, and mannose binding lectin, soluble regulatory proteins complement factor H and C4b, and membrane regulatory proteins CD46 and CD59, as well as complement receptor C5aR1) were closely associated with HCC. The activation of the complement system could participate in the occurrence and development of HCC through various mechanisms. The complement inhibitor, it could regulate the activity of complement related activation pathways, enhance anti-tumor ability, and provide a potential new strategy for immunotherapy of HCC. ConclusionsAt present, only a few complement components have been found in HCC research. Although it has been found that multiple complement components play a role in regulating the immune mechanism of HCC, there is still no definite or recognized theoretical basis. In the future, further exploration of the protective or pathogenic mechanisms of complement components in HCC immunity is needed to objectively evaluate the risks and benefits of complement related inhibitor therapy and in combination with other anti-tumor immune therapies.
Objective To observe the genetic predisposition of complement C5 gene polymorphisms in proliferative diabetic retinopathy (PDR) in Chongqing Han population. Methods 400 type 2 diabetes (T2D) patients (case group) and 600 age- and sex-matched healthy controls (control group) were enrolled in this study. There were 8 PDR patients in case group. All the subjects were Han ethnic people. The immune-related representative SNP locus of C5 gene including rs2269067, rs7040033, rs7027797 were screened by linkage disequilibrium analysis. Locus rs1017119 was selected by TagSNP and was around the above three loci. Subjects′ peripheral venous blood was collected and DNA was extracted. Genotyping was examined by PCR-restriction fragment length polymorphism method. The level of C5 plasma protein was measured by enzyme-linked immunoabsorbent assay. Results The frequency of GG genotype of rs2269067 was significantly increased in PDR patients in cases group compared with controls (Pc=3.4×10-5, OR=1.87, 95%CI=1.43 - 2.44；P=3.1×10-6). There was no differences in frequency of G, CC and CG genotype of rs2269067 between two groups (P=1.4×10-4, 1.000, 1.0×10-6). There were no differences in frequency of G, CC, CG, GG genotype of rs7040033, rs1017119, and rs7027797 between two groups (P > 0.05). The production of C5 plasma protein was significantly increased in case group as compare with control group (P=0.0004). An increased production of C5 plasma protein was observed in rs2269067 GG genotype cases compared to CG or CC cases (P=0.003, 0.001). Conclusion C5 rs2269067 GG genotype may be associated with the PDR of T2D in Chongqing Han population.