BackgroundMore than 1.2 million new cases of colorectal cancer are reported each year worldwide. Despite actual screening programs, about 50% of the patients are diagnosed at advanced tumor stages presenting poor prognosis. Innovative screening tools could aid the detection at early stages and allow curative treatment interventions.MethodsA nine target multiplex serum protein biochip was generated and evaluated using a training- and validation-set of 317 highly standardized, liquid nitrogen preserved serum samples comprising controls, adenomas, and colon cancers.ResultsSerum levels of CEA, IL-8, VEGF, S100A11, MCSF, C3adesArg, CD26, and CRP showed significant differences between cases and controls. The largest areas under the receiver operating characteristics curve were observed for CEA, IL-8, and CRP. At threshold levels yielding 90% specificity, sensitivities for CEA, IL-8 and CRP were 26%, 22%, and 17%, respectively. The most promising marker combinations were CEA + IL-8 reaching 37% sensitivity at 83% specificity and CEA + CRP with 35% sensitivity at 81% specificity. In an independent validation set CEA + IL-8 reached 47% sensitivity at 86% specificity while CEA + CRP obtained 39% sensitivity at 86% specificity. Early carcinomas were detected with 33% sensitivity for CEA + IL-8 and 28% for CEA + CRP.ConclusionsApart from CEA, IL-8, and CRP, the screening value of additional blood markers and the potential advantage of combining serum biochip testing with fecal occult blood testing needs to be studied. Multiplex biochip array technology utilizing serum samples offers an innovative approach to colorectal cancer screening.
Development and progression of colon cancer may be related to cytokines. Cytokines with diagnostic value have been identified individually but have not been implemented into clinical praxis. Using a multiplex protein array, the authors explore a panel of cytokines simultaneously and compared its performance to carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Serum concentrations of 12 cytokines were simultaneously determined by multiplex biochip technology in 50 colon cancer patients and 50 healthy controls. Serum levels of interleukin-8 (IL-8) and CEA were significantly higher in cancer patients than in healthy controls. Areas under the receiver operating characteristic curves (AUCs) were largest for IL-8, followed by CEA, vascular endothelial growth factor (VEGF), and CA 19-9. Analyses regarding marker combinations showed an advantage over single marker performance for CEA, VEGF, and CA 19-9 but not for IL-8. Multiplex biochip array technology represents a practical tool in cytokine and cancer research when simultaneous determination of different biomarkers is of interest. The results suggest that the assessment of IL-8, CEA, VEGF, and possibly CA 19-9 serum levels could be useful for colon cancer screening with the potential of also detecting early stage tumors. Further validation studies using these and additional markers on a multiplex array format are encouraged.
We conclude that three freeze-thaw cycles modulated serum marker levels significantly, but do not compromise biochip diagnostic performance. For our marker panel, serum preservation at -80°C seems comparable to -170°C; however, storage at -80°C could lead to misdiagnosis. Our findings emphasize the need for standardized sample collection, processing, storage, and reporting.
Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...
SummaryDeficiencies in early complement components are associated with the development of systemic lupus erythematosus (SLE) and therefore early complement components have been proposed to influence B lymphocyte activation and tolerance induction. A defect in apoptosis is a potential mechanism for breaking of peripheral B cell tolerance, and we hypothesized that the lack of the early complement component C4 could initiate autoimmunity through a defect in peripheral B lymphocyte apoptosis. Previous studies have shown that injection of a high dose of soluble antigen, during an established primary immune response, induces massive apoptotic death in germinal centre B cells. Here, we tested if the antigen-induced apoptosis within germinal centres is influenced by early complement components by comparing complement C4-deficient mice with C57BL/6 wild-type mice. We demonstrate that after the application of a high dose of soluble antigen in wild-type mice, antibody levels declined temporarily but were restored almost completely after a week. However, after antigen-induced apoptosis, B cell memory was severely limited. Interestingly, no difference was observed between wild-type and complement C4-deficient animals in the number of apoptotic cells, restoration of antibody levels and memory response.
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