Biomarker Of Active Disease Research Articles

Co-expression of CD69, CD49d, CD279 and CD20 in chronic lymphocytic leukemia cells is a new biomarker of active disease before or under therapy.

Not available.

Von Willebrand factor: a possible biomarker for disease activity in vasculitis

Objective Inflammation markers, e.g. C- reactive protein (CRP) and sedimentation rate, can be normal despite active vasculitis. Von Willebrand factor (vWF) is secreted from endothelial cells in response to vascular damage. Some reports suggest increased vWF levels in vasculitis. This study aimed to evaluate vWF serum concentration in vasculitis patients as a possible biomarker of disease activity and to review the current literature. Method Adult patients with systemic vasculitis were prospectively enrolled. Disease activity was recorded using the Birmingham Vasculitis Activity Score (BVAS) version 3. Blood group-adjusted vWF antigen serum level was evaluated at diagnosis and, when available, after treatment. Results Twenty-five vasculitis patients were compared to 15 healthy controls. The mean age of patients was 56 ± 17 years and 56% were women. Forty percent had anti-neutrophil cytoplasmic autoantibody-associated vasculitis, 20% giant cell arteritis, 16% polyarteritis nodosa, 8% Takayasu arteritis, and the rest had other vasculitides. The mean disease duration was 3.4 ± 4.8 years. Mean vWF was higher in patients with active vasculitis than in healthy controls (212 ± 81% vs 106 ± 26%, p < 0.001). vWF levels directly correlated with BVAS. In 13 patients with active vasculitis who reached remission or low disease activity after treatment, vWF level at follow-up decreased significantly. In three out of five patients who were treated with interleukin-6 inhibitors, vWF was elevated despite normal CRP levels, while vasculitis was clinically active. Conclusion vWF antigen serum level is increased in active vasculitis and could potentially serve as a biomarker for active disease.

Tissue and Circulating MicroRNA-31, MicroRNA-200b, and MicroRNA-200c Reflects Disease Activity in Crohn‘s Disease Patients: Results from the BIOMIR Study

MicroRNAs (miR) have altered expression in multiple autoimmune disorders including inflammatory bowel disease. The aim of the study was to assess the tissue and circulating miR-31, miR-200b, and miR-200c expression levels as potential biomarkers for intestinal disease activity in patients with Crohn's disease (CD). The study included 45 patients with histopathological confirmed CD and active disease (defined as fecal calprotectin >50 μg/g and Simple Endoscopic Score (SES) of CD >3), and 21 subjects as controls for the validation cohort. Demographic and clinical data, biomarkers (fecal calprotectin), endoscopy data, the expression levels of miR-31, miR-200b, and miR-200c in tissue and serum were assessed (by RT-PCR). Receiver operating characteristic analysis was performed to assess the miR-31, miR-200b, and miR-200c expression levels as potential biomarkers for active CD. Mean fecal calprotectin was 1540±890 μg/g. Mean SES-CD was 8.9±4.2. Tissue and circulating miR- 31 were significantly correlated with fecal calprotectin (r=0.81, r=0.83, p<0.01) and with SES-CD (r=0.82, r=0.79, p<0.01). The expression level of miR-31 was significantly upregulated in CD tissue cases compared to the control tissue samples (6.24±1.57 vs. 3.70±1.44; p <0.01). Similarly, serum miR-31 expression levels in CD patients were significantly upregulated compared to the control serum samples (0.78±0.42 vs. -2.07±1.00; p<0.01). The expression levels of tissue miR-200b and miR-200c were significantly upregulated in CD tissue cases compared to the control tissue samples (-5.25±0.93 vs. -4.69±0.80, p=0.03 for miR-200b, and -0.86±0.96 vs. 0.39±0.66, p<0.01 for miR-200c). Similarly, serum miR-200b and miR-200c expression levels in CD patients were significantly upregulated compared to the control serum samples (p < 0.05). Receiver operating characteristic analysis revealed that the expression levels of the selected miRNAs could help to discriminate active CD patients from healthy controls with very good specificity and sensitivity. Tissue and circulating miR-31, miR-200b, and miR-200c reflect disease activity in CD patients and can be used as biomarkers for active disease.

Compositional changes in fecal microbiota associated with clinical phenotypes and prognosis in Korean patients with inflammatory bowel disease.

The fecal microbiota of Korean patients with inflammatory bowel disease (IBD) was investigated with respect to disease phenotypes and taxonomic biomarkers for diagnosis and prognosis of IBD. Fecal samples from 70 ulcerative colitis (UC) patients, 39 Crohn's disease (CD) patients, and 100 healthy control individuals (HC) were collected. The fecal samples were amplified via polymerase chain reaction and sequenced using Illumina MiSeq. The relationships between fecal bacteria and clinical phenotypes were analyzed using the EzBioCloud database and 16S microbiome pipeline. The alpha-diversity of fecal bacteria was significantly lower in UC and CD (P<0.05) compared to that in HC. Bacterial community compositions in UC and CD were significantly different from that of HC according to Bray-Curtis dissimilarities, and there was also a difference between community composition in UC and CD (P=0.01). In UC, alpha-diversity was further decreased when the disease was more severe and the extent of disease was greater, and community composition significantly differed depending on the extent of the disease. We identified 9 biomarkers of severity and 6 biomarkers of the extent of UC. We also identified 5 biomarkers of active disease and 3 biomarkers of ileocolonic involvement in CD. Lachnospiraceae and Ruminococcus gnavus were biomarkers for better prognosis in CD. The fecal microbiota profiles of IBD patients were different from those of HC, and several bacterial taxa may be used as biomarkers to determine disease phenotypes and prognosis. These data may also help discover new therapeutic targets for IBD.

CNS endothelial derived extracellular vesicles are biomarkers of active disease in multiple sclerosis

BackgroundMultiple sclerosis (MS) is a complex, heterogenous disease characterized by inflammation, demyelination, and blood–brain barrier (BBB) permeability. Currently, active disease is determined by physician confirmed relapse or detection of contrast enhancing lesions via MRI indicative of BBB permeability. However, clinical confirmation of active disease can be cumbersome. As such, disease monitoring in MS could benefit from identification of an easily accessible biomarker of active disease. We believe extracellular vesicles (EV) isolated from plasma are excellent candidates to fulfill this need. Because of the critical role BBB permeability plays in MS pathogenesis and identification of active disease, we sought to identify EV originating from central nervous system (CNS) endothelial as biomarkers of active MS. Because endothelial cells secrete more EV when stimulated or injured, we hypothesized that circulating concentrations of CNS endothelial derived EV will be increased in MS patients with active disease.MethodsTo test this, we developed a novel method to identify EV originating from CNS endothelial cells isolated from patient plasma using flow cytometry. Endothelial derived EV were identified by the absence of lymphocyte or platelet markers CD3 and CD41, respectively, and positive expression of pan-endothelial markers CD31, CD105, or CD144. To determine if endothelial derived EV originated from CNS endothelial cells, EV expressing CD31, CD105, or CD144 were evaluated for expression of the myelin and lymphocyte protein MAL, a protein specifically expressed by CNS endothelial cells compared to endothelial cells of peripheral organs.ResultsQuality control experiments indicate that EV detected using our flow cytometry method are 0.2 to 1 micron in size. Flow cytometry analysis of EV isolated from 20 healthy controls, 16 relapsing–remitting MS (RRMS) patients with active disease not receiving disease modifying therapy, 14 RRMS patients with stable disease not receiving disease modifying therapy, 17 relapsing-RRMS patients with stable disease receiving natalizumab, and 14 RRMS patients with stable disease receiving ocrelizumab revealed a significant increase in the plasma concentration of CNS endothelial derived EV in patients with active disease compared to all other groups (p = 0.001). Conclusions: For the first time, we have identified a method to identify CNS endothelial derived EV in circulation from human blood samples. Results from our pilot study indicate that increased levels of CNS endothelial derived EV may be a biomarker of BBB permeability and active disease in MS.

Monitoring Eosinophilic Esophagitis Disease Activity With Blood Eosinophil Progenitor Levels

A Henderson, A Magier, JT Schwartz. J Pediatr Gastroenterol Nutr. 2020;70(4):482–488 Since a minimally invasive biomarker for disease is desperately needed in eosinophilic esophagitis (EoE), the purpose of this study was to evaluate if peripheral circulating eosinophil progenitors (EoP) could be used as a biomarker for active disease in pediatric EoE patients. Thirty-four total samples from 31 individuals were included in the final analysis. The study participants included pediatric patients, ages 4 to 17 years, including 18 individuals with inactive EoE and 16 with active EoE at the time of endoscopy. Most patients were white boys (70% boys; 97% white), which is consistent with the known disease demographics. In this prospective observational study, peripheral blood …

Elevated circulating levels of IL-21 and IL-22 define a cytokine signature profile in type 2 autoimmune hepatitis patients

Background and aims. Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver in which the immunological mechanisms involved in tissue destruction and/or repair are still unclear. Different pro-inflammatory cytokines have been shown to play a determinant role in AIH pathogenesis. Here, we aim to compare the circulating levels of pro-and anti-inflammatory cytokines such as IL-6, TNF-α, IL-17A/F, IL-21, IL-22, IL-23, and IL-10 in patients with type 2 AIH compared to patients with type 1 AIH and healthy controls (HC). Fourty-six Mexican patients with AIH were recruited in our study. Patients were classified as type 1 or 2 AIH based on immune serological markers. Fourty-four serum samples from healthy individuals were included as controls. Serum cytokine levels were determined by ELISA technique.Results. Compared to healthy controls, serum levels of IL-17F, IL-21, IL-23, IL-10, IL-6, and TNF-α, but not IL-17A and IL-22, were significantly increased in AIH patients. When patients were grouped by aminotransferase activity, a biomarker of active disease, a positive correlation between serum IL-17F and alanine transaminase (rs: 0.4739; P = 0.0009) and aspartate transaminase (rs: 0.4984; P = 0.0004) levels was found. A cytokine signature profile associated with type 2 AIH was characterized by high serum IL-21 (type 1 AIH: 0.66 pg/mL; type 2 AIH: 331.1 pg/mL; P = 0.0042) and IL-22 (type 1 AIH: 0.1 pg/mL; type 2 AIH: 55.26 pg/mL; P = 0.0028) levels.Conclusions. We show for the first time, differential regulation of certain pro-inflammatory cytokines associated with disease progression and AIH type in Mexican patients.

Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis.

OBJECTIVES:Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and autoimmune pancreatitis (AIP) are characterized by an abundance of circulating and tissue IgG4-positive plasma cells. T-follicular helper (Tfh) cells are necessary for B-cell differentiation into plasma cells. We aimed at elucidating the presence and phenotype of Tfh cells and their relationship with disease activity in IgG4-SC/AIP.METHODS:Circulating Tfh-cell subsets were characterized by multiparametric flow cytometry in IgG4-SC/AIP (n = 18), disease controls with primary sclerosing cholangitis (n = 8), and healthy controls (HCs, n = 9). Tissue Tfh cells were characterized in IgG4-SC/AIP (n = 12) and disease control (n = 10) specimens. Activated PD1+ Tfh cells were cocultured with CD27+ memory B cells to assess their capacity to support B-cell differentiation. Disease activity was assessed using the IgG4–responder index and clinical parameters.RESULTS:Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC/AIP, primary sclerosing cholangitis, and HC (P < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, P = 0.003; Tfh2, P = 0.0006; Th17, P = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (P = 0.01) correlated with the PD-1+ Tfh2 subset (r = 0.69, P = 0.03). Increased IL-4 and IL-21 cytokine production from stimulated cells of IgG4-SC/AIP, important in IgG4 class switch and proliferation, correlated with PD-1+ Tfh2 (r = 0.89, P = 0.02) and PD-1+ Tfh17 (r = 0.83, P = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1− Tfh (P = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (r = 0.70, P = 0.002), sIgE (r = 0.66, P = 0.006), and IgG4–responder index (r = 0.60, P = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC/AIP tissues.CONCLUSIONS:Circulating and tissue-activated Tfh cells are expanded in IgG4-SC/AIP, correlate with disease activity, and can drive class switch and proliferation of IgG4-committed B cells. PD1+ Tfh2 cells may be a biomarker of active disease and a potential target for immunotherapy.

PATH-22. THE DEVELOPMENT OF A NEW ASSAY TO MEASURE 2-HYDROXYGLUTARATE (2-hg) ENANTIOMER LEVELS AND THE UTILITY OF 2-hg AS A BIOMARKER FOR MANAGEMENT OF IDH MUTANT GLIOMAS

The isocitrate dehydrogenase (IDH) gene is mutated in a large percentage of gliomas and produces the oncometabolite, (R)-2-hydroxgylutarate [(R)-2hg]. However, no correlation between total 2hg levels and clinical parameters, like tumor burden, in glioma patients has been identified. This lack is likely due to the presence of significant levels of the enantiomer, (S)-2-hydroxyglutarate [(S)-2hg]. (S)-2hg is normally produced in the body and during hypoxic conditions. Past studies measuring 2hg via mass spectrometry methods either do not differentiate between (R)-and (S)-2hg, both which are normally detectable in serum, or use LC-MS based assays that lack the sensitivities needed to detect changes in (R)-2hg when an IDH mutant glioma is present. In this study, a novel gas chromatography-mass spectrometry method was built to measure 2hg enantiomers and used to determine if serum levels of (R)-2hg:(S)-2hg, or absolute levels of (R)-2hg, could provide clinical utility as a biomarker in patients with IDH mutant gliomas. The derivatization, fragmentation, and quantitation scheme was optimized for sensitive detection of basal 2hg enantiomers using normal human serum. Serum was then collected from patients with IDHmut and IDHwt gliomas and analyzed to measure levels of 2hg enantiomers before and during the course of treatment. The ratio of (R)-2hg:(S)-2hg was increased in a number of patients with actively growing IDHmut tumors, but not in patients with stable IDHmut tumors or IDHwt tumors. These preliminary results demonstrate the utility of the GC-MS assay for measurement of 2hg enantiomers and their ratio as a biomarker for active disease in patients with IDHmut gliomas.

Abstract 4741: Biomarker significance of plasma and tumor miR-21, miR-221, and miR-106a in pediatric osteosarcoma

Abstract Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of surgery and multi-agent chemotherapy, osteosarcoma patients who respond poorly towards chemotherapy or develop relapses have a dismal outcome. Identification of biomarkers for active disease may help to monitor tumor burden, detect early relapses, and predict prognosis in these patients, so that they can be treated as early as possible to improve their survival. In this study, we examined if circulating microRNAs (miRNAs) can be used as biomarkers in osteosarcoma patients. We performed genome-wide miRNA profiling on a discovery cohort of OS plasma samples (n=32) collected from the Texas Children’s Hospital. A total of 56 miRNAs were upregulated and 164 miRNAs were downregulated in osteosarcoma samples when compared to normal plasma samples (n=8). miRNA-21, miR-221 and miRNA-106a were selected for further validation based on their known biological importance. We showed that all three circulating miRNAs were expressed significantly higher in OS samples (n=29) than normal samples (n=17) in an independent cohort obtained from the Children’s Oncology Group. Furthermore, we demonstrated that miR-21 was expressed significantly higher in osteosarcoma tumors (n=89) compared with normal bone controls. More importantly, lower expressions of miR-21 and miR-221, but not miR-106a, significantly correlated with a poor outcome. In conclusion, our results indicate that miR-21, miR-221 and miR-106a are elevated in the circulation of osteosarcoma patients, whereas tumor expressions of miR-21 and miR-221 are prognostically significant. Further investigation of the miRNAs may lead to a better prognostic method and potential miRNA therapeutics for osteosarcoma. Citation Format: Manjula Nakka, Wendy Allen-Rhoades, Yiting Li, Aaron Kelly, Jianhe Shen, Aaron Taylor, Donald A. Barkauskas, Jason Yustein, Irene Andrulis, Jay Wunder, Richard Gorlick, Paul Meltzer, Ching Lau, Tsz-Kwong Man. Biomarker significance of plasma and tumor miR-21, miR-221, and miR-106a in pediatric osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2017-4741

Mycobacterium tuberculosis Induction of Heme Oxygenase-1 Expression Is Dependent on Oxidative Stress and Reflects Treatment Outcomes.

The antioxidant enzyme heme oxygenase-1 (HO-1) is implicated in the pathogenesis of tuberculosis (TB) and has been proposed as a biomarker of active disease. Nevertheless, the mechanisms by which Mycobacterium tuberculosis (Mtb) induces HO-1 as well as how its expression is affected by HIV-1 coinfection and successful antitubercular therapy (ATT) are poorly understood. We found that HO-1 expression is markedly increased in rabbits, mice, and non-human primates during experimental Mtb infection and gradually decreased during ATT. In addition, we examined circulating concentrations of HO-1 in a cohort of 130 HIV-1 coinfected and uninfected pulmonary TB patients undergoing ATT to investigate changes in expression of this biomarker in relation to HIV-1 status, radiological disease severity, and treatment outcome. We found that plasma levels of HO-1 were elevated in untreated HIV-1 coinfected TB patients and correlated positively with HIV-1 viral load and negatively with CD4+ T cell count. In both HIV-1 coinfected and Mtb monoinfected patients, HO-1 levels were substantially reduced during successful TB treatment but not in those who experienced treatment failure or subsequently relapsed. To further delineate the molecular mechanisms involved in induction of HO-1 by Mtb, we performed a series of in vitro experiments using mouse and human macrophages. We found that Mtb-induced HO-1 expression requires NADPH oxidase-dependent reactive oxygen species production induced by the early-secreted antigen ESAT-6, which in turn triggers nuclear translocation of the transcription factor NRF-2. These observations provide further insight into the utility of HO-1 as a biomarker of both disease and successful therapy in TB monoinfected and HIV-TB coinfected patients and reveal a previously undocumented pathway linking expression of the enzyme with oxidative stress.

Neopterin and oxidative stress markers in the diagnosis of extrapulmonary tuberculosis

Background: Extrapulmonary tuberculosis (EPTB) often presents with nonspecific signs and symptoms. Further the paucibacillary nature of extrapulmonary specimens and irregular distribution of bacilli lower the sensitivity of conventional diagnostic methods making EPTB, a diagnostic dilemma.Objective: To study neopterin, protein carbonyl and malondialdehyde (MDA) in EPTB.Methods: Sixty nine clinically confirmed cases with an equal number of age and sex matched healthy controls were enrolled. Ziehl–Neelsen staining for acid fast bacilli and culture on Lowenstein–Jensen medium were performed on all the extrapulmonary specimens. Serum neopterin and protein carbonyl levels were estimated using commercial ELISA kits. Malondialdehyde was determined by measuring thiobarbituric acid reactive substances.Results: Serum neopterin, protein carbonyl and MDA levels were significantly discriminative for cases of EPTB from healthy controls (p < 0.05). Levels of all the three biomarkers under study significantly differed between culture as well as smear positive and negative cases. A positive correlation between neopterin and protein carbonyl was seen among the cases.Conclusions: So far few studies have integrated combination of validated host biomarkers for active disease in EPTB. Our study suggests the potential diagnostic role of neopterin, protein carbonyl and MDA in EPTB.

Pharmacological Inhibition of Host Heme Oxygenase-1 Suppresses Mycobacterium tuberculosis Infection In Vivo by a Mechanism Dependent on T Lymphocytes.

ABSTRACTHeme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function.

MicroRNA expression signatures in lungs of mice infected with Mycobacterium tuberculosis

Tuberculosis (TB) is a major public health concern worldwide; however the factors that account for resistance or susceptibility to disease are not completely understood. Although some studies suggest that the differential expression of miRNAs in peripheral blood of TB patients could be useful as biomarkers of active disease, their involvement during the inflammatory process in lungs of infected individuals is unknown. Here, we evaluated the global expression of miRNAs in the lungs of mice experimentally infected with Mycobacterium tuberculosis on 30 and 60 days post-infection. We observed that several miRNAs were differentially expressed compared to uninfected mice. Furthermore, we verified that the expression of miR-135b, miR-21, miR-155, miR-146a, and miR-146b was significantly altered in distinct leukocyte subsets isolated from lungs of infected mice, while genes potentially targeted by those miRNAs were associated with a diversity of immune related molecular pathways. Importantly, we validated the inhibition of Pellino 1 expression by miR-135b in vitro. Overall, this study contributes to the understanding of the dynamics of miRNA expression in lungs during experimental TB and adds further perspectives into the role of miRNAs on the regulation of immune processes such as leukocyte activation.

Vitamin D-binding protein as a biomarker of active disease in acute intermittent porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant metabolic disorder caused by a deficiency of hepatic porphobilinogen deaminase (PBGD). The disease is characterized by life threatening acute neurovisceral attacks. The aim of this study was to identify metabolites secreted by the hepatocytes that reflect differential metabolic status in the liver and that may predict response to the acute attack treatment. Plasma vitamin D binding protein (VDBP) from a mouse model of AIP displayed an abnormal migration in 2D-electrophoresis that is efficiently recovered upon gene therapy leading to liver specific over-expression of the PBGD protein. The change in VDBP mobility results from a differential isoelectric point suggesting a post-translational modification that takes place preferably in the liver. Liquid chromatography–mass spectrometry (LC–MS) analysis of human samples before and after glycosidase treatment revealed glycosylated plasma VDBP specifically in patients with recurrent attacks of AIP. Glycosylated VDBP recovered normal values in three severely afflicted AIP patients submitted to therapeutic liver transplantation. Our findings suggest that post-translational modification of VDBP might be considered as a promising biomarker to study and monitor the liver metabolic status in patients with AIP. SignificanceWe describe an increased glycosylation of VDBP in porphyric livers. Normal glycosylation was recovered upon liver gene therapy in a mouse model of porphyria or after liver transplantation in severely afflicted patients with AIP. Moreover, quantification of glycosylated VDBP by our ELISA immunoassay or LC–MS protocol in patients undergoing PBGD-gene therapy (www.aipgene.org) may be used as a marker indicating improvement or normalization of the patient's hepatic metabolism.This article is part of a Special Issue entitled: HUPO 2014.

The interferon signature in autoimmune diseases

An increased expression of type I interferon (IFN) regulated genes (an IFN signature) has been reported in blood and tissue cells from patients with SLE and other autoimmune diseases. We review the possible mechanisms behind the IFN signature as well as clinical and therapeutic consequences of this observation. Autoantigens from dying cells trigger plasmacytoid dendritic cells to a continuous synthesis of type I IFN, which is promoted by natural killer (NK) cells and B cells. A growing number of genes connected to type I IFN production and response associates with an increased susceptibility to autoimmunity. Besides type I IFN, type III IFN (IFN-λ) may contribute to the IFN signature. In SLE and primary Sjögren's syndrome, a prominent IFN signature is connected to an active disease, whereas in rheumatoid arthritis the IFN signature defines a disease subset with poor clinical outcome and treatment failure to B-cell depleting therapy. Several therapies aiming to inhibit the IFN signature are in clinical trials and early data suggest clinical benefits without major safety problems. The observed IFN signature in several autoimmune diseases is a biomarker of active disease and is investigated as a tool when selecting treatment for individual patients.

An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis

MPR Berry, CM Graham, FW McNab. Nature. 2010;466(7309):973–977 Most people infected with Mycobacterium tuberculosis (TB) develop a latent form of the disease and remain asymptomatic; however, approximately 10% of these people are at risk of developing active, transmissible disease in their lifetime. An inability to accurately identify these at-risk patients with conventional tests has limited efforts to control TB. The purpose of this study was to identify novel biomarkers of active disease by using genomic techniques. The investigators generated genome-wide transcriptional profiles from the blood of patients with active TB (before treatment), patients with latent TB, and healthy controls. This study was …

Expressions of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients

B-cell activating factor belonging to tumour necrosis factor family (BAFF) is essential for B-cell survival and function through interaction with its receptors BAFF receptor 3 (BR3), B-cell maturation antigen (BCMA) and/or transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), though BCMA and/or TACI can also bind to a proliferation-inducing ligand (APRIL). We evaluate the correlation of the expressions of these ligands/receptors with different clinical manifestations of systemic lupus erythematosus (SLE). Levels of BAFF and APRIL in plasma from 73 SLE patients were determined by enzyme-linked immunosorbent assay. Expressions of BR3, TACI and BCMA on CD19+ B cells were detected by flow cytometry. Clinical data were collected and disease activity was evaluated using SLEDAI-2000. SLE patients had elevated BAFF and APRIL levels in their plasma. BAFF levels correlated positively with SLEDAI while negatively with the BR3 protein expression on CD19+ B cells (p < .05). The detected BR3 protein expression in SLE patients was reduced on CD19+IgD+CD27-, CD19+IgD+CD27+ as well as CD19+IgD-CD27+ B cells compared to the counterparts of healthy controls (p < .001), whereas SLE patients did not differ from healthy controls in BR3 mRNA levels. In untreated new-onset patients, the expression rate of BR3 on CD19+ B cells correlated negatively with SLEDAI (p < .05). Elevation of BAFF and reduction of BR3 on CD19+ B cells were more obvious in those with lupus nephritis (LN, p < .05). TACI expression on CD19+ B cells was up-regulated only in those subjects with LN (p < .05). Elevated plasma BAFF and reduced BR3 protein expression on peripheral B cells could act as biomarkers for active disease in SLE patients. High expression of TACI may indicate the occurrence of LN.