Autoimmune Biomarkers Research Articles

Thyroglobulin antibodies and risk of readmission at one year in subjects with bipolar disorder

Thyroid autoimmunity has been proposed as an endophenotype for Bipolar Disorder (BD), although its relationship with clinical outcomes remains unclear. We aimed to determine whether thyroid autoimmune status (thyroperoxidase antibodies [TPO-Abs] and thyroglobulin antibodies [TG-Abs]) in BD is associated with a greater risk for readmission at one year. We studied 77 inpatients with BD admitted for an index manic or mixed episode. Serum thyroid antibodies (TPO-Abs and TG-Abs) were determined at admission. We compared the readmission risk at 1 year, based on patients׳ thyroid autoimmunity profile using survival analyses. Cox regression was used to control covariates. TG-Abs+ but not TPO-Abs+ was associated with a lower risk of relapse. The Kaplan–Meier mean estimated survival times were 341.6 days (CI95% 316.4–366.8) for the TG-Abs+ group and 261.9 days (CI95%: 221.8 to 302.0) for the TG-Abs− group. Cox proportional hazards regression indicated that subjects with TG-Abs+ were 3.7 (1/OR=1/0.27) times less likely to get admitted during the follow-up period than those with TG-Abs−. Our study suggests that an autoimmune biomarker in patients with BD (i.e., the presence of TG-Abs) is associated with a lower risk of psychiatric readmission after an index hospitalization for a manic or mixed episode.

Islet Antigen-Specific Th17 Cells Can Induce TNF-α–Dependent Autoimmune Diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β-cells. Although Th1 cells are key orchestrators of T1D, the function(s) of the more recently identified Th17 subset are unclear due to inherent plasticity. In this study, we analyzed Th17 cells for stability and diabetogenicity in NOD mice. We found that like Th1 cells, Th17 are a distinct population throughout the prediabetic phase. At diabetes onset, there were marked increases in IL-17-producing Th17 cells and IFN-γ-producing Th1 cells in the pancreas as well as in the serum levels of these cytokines, indicating that these proinflammatory mediators serve as biomarkers of advanced autoimmunity. Although naturally occurring Th17 cells in diabetic mice did not contribute to diabetes development in transfer models, islet-specific Th17 cells were diabetogenic independently of IL-17 and displayed inflammation-induced Th17-to-Th1 reprogramming that could be elicited by Th1 cells. However, an inability to generate Th1 cells because of Stat4, Ifngr, and Ifng deficiencies did not prevent diabetes. Instead, TNF-α could mediate diabetes in response to either Th17 cells or Th1 cells. The results identify a previously unknown mechanism by which Th17 cells can contribute to T1D. Our studies also suggest that when developing interventions for T1D, it will be potentially advantageous to focus on mechanisms common to effector T cells rather than on the signature cytokines of various subsets.

Autoantibodies to apolipoprotein A-1 as a biomarker of cardiovascular autoimmunity.

Immune-driven inflammation plays an important part in atherogenesis and is therefore believed to be key to the development of cardiovascular disease (CVD), which is currently the leading cause of death in the Western world. By fulfilling some of the Koch postulates, atherogenesis has even been proposed to be considered as an autoimmune disease, raising the hope that CVD could be prevented by immunomodulation. Nevertheless, the role of the immune system and autoimmune reactions in atherosclerosis appear to be a double edged-sword, with both pro-atherogenic and anti-atherogenic attributes. Hence, if immunomodulation is to become a therapeutic option for atherosclerosis and CVD, it will be crucial to correctly identify patients who might benefit from targeted suppression of deleterious autoimmune responses. This could be achieved, for example, by the detection of disease-associated autoantibodies. In this work, we will review the currently available clinical, in vitro, and animal studies dedicated to autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG), the major proteic fraction of high density lipoprotein. Current clinical studies indicate that high levels of anti-apoA-1 IgG are associated with a worse cardiovascular prognosis. In addition, in vitro and animal studies indicate a pro-inflammatory and pro-atherogenic role, supporting the hypothesis that these autoantibodies may play a direct causal role in CVD, and furthermore that they could potentially represent a therapeutic target for CVD in the future.

Clinical update on genetic and autoimmune biomarkers in pediatric diabetes.

The purpose of this clinical update is to review the etiology of diabetes types affecting youth under 20 and describe diabetes-related genetic and autoimmune biomarkers based on the most recent literature. This information will support diabetes care providers' efforts to better explain the complex topic to patients and families. A PubMed search identified 396 reviews published from 2008 to 2011 that included the topics of etiology, epidemiology, genetics/epigenetics, pathogenesis, or immunology related to diabetes in youth. The current clinical update includes 19 of these. The majority of youth under 20 years with diabetes have Type 1 diabetes. Other forms of the disease affecting this population include Type 2, monogenic, and secondary diabetes. Genetic and autoimmune biomarkers can help determine the risk and diagnosis of both Type 1 and monogenic diabetes. An accurate diagnosis of diabetes type allows for determination of optimal treatment options. The complexity of determining etiology, risk, diagnosis, and treatment for diabetes in youth is increasing with the rate of related genetic and immunologic advances. Diabetes care providers must be able to explain the complex genetic and autoimmune biomarkers used in determining the risk of diabetes, diagnosis of the disease, and identification of treatment options to patients and families.

Autoimmune Phenotype in Refractory Chronic Urticaria Does Not Affect Response to Omalizumab

FEBRUARY 2013 AB30 Abstracts S A T U R D A Y 108 Autoimmune Phenotype in Refractory Chronic Urticaria Does Not Affect Response to Omalizumab Ravi K. Viswanathan,MD, Sameer K. Mathur, MD, PhD, FAAAAI; University ofWisconsin School of Medicine and Public Health, Madison, WI, William S. Middleton Veterans Hospital, Madison, WI. RATIONALE: Omalizumab has been shown to be efficacious in refractory (2-4x H1/H2 +/LTRA +/immunomodulator) chronic idiopathic urticaria (CIU) patients in numerous reports. However, it remains unknown whether there are specific phenotypes of CIU that are more responsive to omalizumab therapy.We sought to address this by characterizing a series of CIU patients who have undergone omalizumab therapy and their response patterns. METHODS: A retrospective chart-review analysis of CIU patients treated with omalizumab at the University of Wisconsin Allergy Clinic was performed with particular focus on their autoimmune characteristics, response to therapy, and dosing/duration parameters. RESULTS: We analyzed 13 refractory CIU patients (12/13 previously used >5 1 immunomodulator) treated with omalizumab and observed an overall response rate of 92% (11/12, 1 unknown) to its usage. Of these 11 responders, 5 patients (45%) had a complete response and 6 patients (55%) had a partial response. Seven patients were categorized as ‘‘autoimmune’’ (presence of 1 positive autoimmune biomarker) with 3 patients (43%) demonstrating complete response and 4 patients (57%) showing partial response to omalizumab therapy. Among the five patients categorized as ‘‘non-autoimmune, two (40%) reported a complete response, two (40%) had a partial response, and one (20%) had no response. The mean duration of therapy for all patients was 4.83 months with cumulative doses ranging from 300mg every 4 weeks to 600mg every 4 weeks. CONCLUSIONS: Our retrospective analysis suggests that omalizumab appears to demonstrate robust efficacy in refractory CIU patients regardless of their autoimmune status with similar dosing and duration parameters.

Increased serum interleukin-33 levels in patients with Graves’ disease

Interleukin-33 (IL-33), a 30 kDa cytokine, is a member of IL-1 family. It is considered to be an autoimmune biomarker associated with T helper 2 (Th 2) response. γ-interferon is also produced by T helper 1 (Th 1) cells to induce cellular responses. γ-interferon is a 143-amino acid residue glycoprotein with several biological functions including potent anti-viral activity, stimulation of macrophage activity, modulation of Major Histocompatibilty Complex class I/class II expression, and regulation of a diversity of specific immune responses. The aim of this study was to investigate the serum levels of IL-33 and γ-interferon in different thyroid disorders. Twenty patients with Graves' disease, 21 patients with Hashimoto hypothyroidism, 21 euthyroid Hashimoto patients, and 27 control subjects were recruited to this study. Blood samples were drawn and IL-33 and γ-interferon tests were analyzed from 89 participants. Serum IL-33 and γ-interferon analyses were performed by enzyme-linked immunosorbent assay. There was no statistically significant difference between groups for serum γ-interferon levels. Serum IL-33 concentrations were significantly higher in Graves' disease group compared to the other groups (p<0.000) There was a positive correlation between serum IL-33 and free triiodothyronine (fT3) and thyroxine (fT4). Also, negative correlation between serum IL-33 and thyroid-stimulating hormone (TSH) was statistically significant (p<0.000). The correlation of serum IL-33 with thyroid hormone levels may be a useful indicator for Graves' disease. These findings may help to make evident the pathophysiologic processes of the autoimmune thyroid diseases and improve therapeutic methods. .

Enhanced oxidative stress in Hashimoto's thyroiditis: Inter-relationships to biomarkers of thyroid function

ObjectivesOxidative stress has been implicated in the pathogenesis of several inflammatory and immune-mediated disorders including Hashimoto's thyroiditis (HT). The objectives of the present cross-sectional investigation were to estimate serum glutathione (GSH) status and the activities of its recycling enzymes in HT and to explore their interrelationships with biomarkers of autoimmunity and thyroid function. Design and methodsNewly diagnosed females with HT (n=44) and 58 matched control subjects were recruited. Thyroid hormone profile, anti-thyroperoxidase anti-body (TPO-AB), anti-thyroglublin antibody (Tg-AB), thyroid volume (Tvol), urinary iodine excretion (UIE), GSH and the activities of glutathione peroxidase (GPx), glutathione reductase and gamma-glutamyltransferase were assessed. ResultsMedian UIE in HT was slightly but not significantly higher than that of controls. HT group exhibited higher levels of TSH, TPO-AB, Tg-AB and larger Tvol when compared with controls (P<0.001). The means of GSH and GPx in HT patients were significantly different from those of controls (P<0.001). In HT subjects, significant associations were seen between Tvol on TSH, GSH on TPO-AB, GSH on TSH and TPO-AB titers on TSH, respectively. ConclusionsThis is the first study to demonstrate a substantial reduction in GSH status in HT subjects. Secondly, the interrelationship between the GSH contents and TPO-AB titers in HT provides a preliminary data to support the notion that GSH diminution is a hallmark of in the events leading to oxidative stress activation and the development of immunological intolerance in HT. Further studies are required to elucidate the role of GSH in the etiology of down-regulation of thyroid function.

Immune-Mediated Mechanisms in the Pathogenesis of Hopkins Syndrome

Hopkins syndrome occurs after an acute asthma attack. An immune-mediated mechanism has been suggested. Immunoglobulin or methylprednisone pulse therapies comprise the most useful treatment. We describe a 3-year-old girl who developed severe weakness in her left arm, 7 days after an acute asthma attack. A complete blood count with autoimmune biomarkers, immunoglobulin profile, and virology study and magnetic resonance of the brain, spine, and brachial plexus produced normal results. In the cerebrospinal fluid, T lymphocytes comprised the predominant leukocyte population, and oligoclonal bands were positive. An electromyogram revealed a partial axonal lesion (normal motor nerve conduction velocity with low amplitude) of the axillary, musculocutaneus, and interosseous nerves of the left arm, with normal sensory nerve conduction and partial denervation. We began therapy with intravenous immunoglobulin for 5 consecutive days, repeated every 4 weeks for 2 months. Afterward, our patient recovered. This report contributes to understanding the role of immune-mediated mechanisms in the pathogenesis of this disease, and the importance of immunotherapy in its treatment.

NIEHS's New Strategic Plan

I am pleased to present “our” new strategic plan for the National Institute of Environmental Health Sciences (NIEHS 2012). I say that it’s “our” plan because the entire document reflects tremendous thought, discussion, and sharing of ideas by hundreds of scientists and community stakeholders, and it speaks to the entire field of environmental health research. This plan is about what we will strive to accomplish together as we devote ourselves to research that, in my opinion, has the greatest chance for preventing disease and for improving health throughout the world. As reflected in the new strategic plan (NIEHS 2012), the NIEHS has a fresh vision, not because our values have changed but because our research has been so successful—and many of you have made a huge contribution to that progress. New technologies and increasing knowledge bring exciting new opportunities each and every year. The NIEHS’s new strategic plan builds upon the accomplishments and vision that came before. The NIEHS has come a long way in making environmental health research responsive to the needs and concerns of the American people— to make environmental health part of the public health debate. This continues to be a source of motivation and purpose for NIEHS staff and our research partners. Environmental justice is an everlasting core value for NIEHS research. In the past few years, we at the NIEHS have made some important progress in exposure science, supporting new technologies for sensor devices and bioinformatics. We have been embracing new science such as epigenetics and exposure phenotyping, focusing on interdisciplinary research and translational research. In addition, our clinical research unit is now up and running. As the NIEHS moves forward, our overall goal is to make the institute, including the National Toxicology Program (NTP), the foremost trusted source of environmental health knowledge, leading the field in innovation and the application of research to solve health problems. Our new vision statement (NIEHS 2012) captures our collective dreams and aspirations, and reflects our strong commitment to making a real difference: The vision of the National Institute of Environmental Health Sciences is to provide global leadership for innovative research that improves public health by preventing disease and disability from our environment. What this means in practical terms is that we are pursuing some of the “big influences” that have been understudied, all of which interact with traditional environmental exposures: the microbiome, for example, and inflammation pathways, immunological pathways, nutrition, and epigenetic processes. We also want to lead the process of defining the “exposome,” which is the totality of exposure encountered by humans. We have elevated the NTP to the divisional level within the NIEHS. And we will continue to integrate our toxicology research with our excellent basic and translational science programs, not because I am a toxicologist but because the NTP is a problem-solving program—a truly translational component of the NIEHS. For example, the NTP is part of our consortium on bisphenol A, contributing to the scientific deliberations, right along with our intramural scientists and our grantees. The NTP is leading the Tox21 initiative along with the National Institute of Health’s National Center for Comparative Genomics, the U.S. Environmental Protection Agency, and the Food and Drug Administration. This high throughput testing program shows great promise not only as a new and faster method but also for moving toxicology into a predictive science. The NTP is moving beyond the traditional approaches of testing one chemical at a time and are taking on the significant challenge of evaluating mixtures. We are also looking at the effects of exposures throughout the life span, expanding our research and testing to include prenatal exposures and how they may link to adult disease. It is clear that there are multiple windows of susceptibility and that exposures early in life may have long-lasting consequences to both health and disease. Finally, the antiquated idea that the dose makes the poison is overly simplistic. The newest research clearly shows that biology is affected by low doses of chemicals, often within the range of general population exposure, and that these biological changes can be harmful, especially during periods of development. Therefore, low-dose research must go hand in hand with our life-span approach. The NIEHS’s job doesn’t stop with the publication of scientific results. We also have an obligation to help translate the nation’s research investment into public health intervention, new policy, and preventive clinical practice. To be successful, we at the NIEHS need to conduct and support the best science, whether it is led by an individual researcher or a multidisiplinary team, and this means working together with all of our partners. We thank everyone who joined us in our strategic planning process. We appreciate your commitment and support.

Reversible Paraneoplastic Tonic Pupil with PCA-Tr IgG and Hodgkin Lymphoma

Purkinje cell cytoplasmic autoantibody-Tr (PCA-Tr [in recognition of the original reporting investigator, Dr. John L. Trotter]) is an immunoglobulin G (IgG) biomarker of paraneoplastic neurologic autoimmunity associated with Hodgkin lymphoma. Neurologic presentations reported to date include

AUTOIMMUNE AND INFLAMMATORY DISEASES BIOMARKERS

One of the major challenges facing the healthcare industry is how to personalize, or tailor healthcare products and services to individuals' unique genetic and biomarker make-ups. Biomarkers are characteristics that can be objectively measured and evaluated. They provide information about normal or patho-physiological processes to detect or define disease progression or to predict or quantify therapeutic responses. Once these footprints have been identified and measured, they can then be used to personalize or tailor treatment plans, products and services to each individual's unique makeup and background. Biomarkers enable early diagnosis, guide molecularly targeted therapy and monitor the activity and therapeutic responses across these diseases. Development of new, predictive safety and efficacy biomarkers is expected to reduce the time and cost of drug development. This review summarizes the integration and use of biomarkers in drug development, regulation and clinical practice with special emphasis on autoimmune and inflammatory diseases biomarkers.

The role of autoimmune testing in chronic idiopathic urticaria

BackgroundThe clinical implications of autoimmune testing in chronic idiopathic urticaria (CIU) are not well established. ObjectiveTo identify the association of autoimmune biomarkers in CIU with disease severity. MethodsWe retrospectively evaluated 195 patients with a diagnosis of CIU for the presence of antinuclear antibody (ANA), anti-thyroglobulin antibody (ATG), anti-thyroperoxidase antibody (ATPO), and Chronic Urticaria (CU) Index. The patients were categorized into controlled and refractory subgroups based on their response to antihistamines with or without a leukotriene receptor antagonist. ResultsThe percentage of patients with a positive test for ANA (titer>1:160), ATG, ATPO, and CU Index were 29%, 6%, 26%, and 38%, respectively. Among those tested, the percentage of patients categorized as refractory was significantly higher in those with a positive CU index (80% vs 46%; P = .01) or a positive ANA titer (50% vs 30%; P = .04) than those with negative test results; however, a similar relationship was not observed for ATPO or ATG antibodies. Odds ratios of individual or combinations of autoimmune biomarkers in CIU were examined for associations with refractoriness to antihistamines with or without a leukotriene receptor antagonist. The CU Index alone has an odds ratio of 4.5 (P = .005), whereas the combination of ANA, ATG, and ATPO has an odds ratio of 3.1 (P = .01) and ANA alone has an odds ratio of 2.3 (P = .04) for correlating with a refractory outcome. ConclusionOur data indicate the CU Index independently has the strongest correlation with disease severity followed by the combination of ANA, ATG, and ATPO and the ANA alone.

Proteomic identification of aldolase A as an autoantibody target in patients with atypical movement disorders

We tried to identify the target/s of autoantibodies to basal ganglia neurons found in a patient with hyperkinetic movement disorders (HMD) characterized by rapid, rhythmic involuntary movements or spasms in both face and neck. Patient and control sera were used in Western blot to probe mouse brain homogenates. Two-dimensional gel electrophoresis (2-DE) SDS-PAGE protein spots recognized by the patient's antibodies were excised and sequenced by mass spectrometry analysis, and the glycolytic enzyme aldolase A was identified as the antigen recognized by the patient's autoantibodies. To assess relevance and specificity of these antibodies to the identified targets as biomarkers of autoimmunity in movement disorders, autoantibody responses to the identified target were then measured by ELISA in various diseases of the central nervous system. Anti-aldolase A autoantibodies were associated mainly with HMD (7/17, 41%) and Parkinson's disease (4/30, 13%) patients, and undetectable in subjects with other inflammatory and non-inflammatory central nervous system diseases. We, thus, identified aldolase A as an autoantigen in a sub-group of patients with HMD, a clinically ill-defined syndrome. Anti-aldolase A antibodies may represent a useful biomarker of autoimmunity in HMD patients.

Hypogalactosylation of serum N-glycans fails to predict clinical response to methotrexate and TNF inhibition in rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is associated with hypogalactosylation of immunoglobulin G (IgG). We examined whether a proxy measure for galactosylation of IgG N-glycans could predict response to therapy or was differentially affected by methotrexate (MTX) or TNF blockade.MethodsUsing a previously defined normal phase high-performance liquid chromatography approach, we ascertained the galactosylation status of whole serum N-glycans in two well-defined RA clinical cohorts: the Autoimmune Biomarkers Collaborative Network (n = 98) and Nested I (n = 64). The ratio of agalactosylated to monogalactosylated N-glycans in serum (sG0/G1) was determined before and during therapy with MTX or TNF inhibition and correlated with anticitrullinated peptide antibody (ACPA) status and clinical response as assessed by 28-joint Disease Activity Score utilizing C-reactive peptide and European League Against Rheumatism response criteria.ResultsRA patients from both cohorts exhibited elevation of sG0/G1 at baseline. Improvement in clinical scores correlated with a reduction in sG0/G1 (Spearman's ρ = 0.31 to 0.37; P < 0.05 for each cohort). However, pretreatment sG0/G1 was not predictive of clinical response. Changes in sG0/G1 were similar in the MTX and TNF inhibitor groups. Corrected for disease activity, ACPA positivity correlated with higher sG0/G1.ConclusionsBaseline serum N-glycan hypogalactosylation, an index previously correlated with hypogalactosylation of IgG N-glycans, did not distinguish patients with rheumatoid arthritis who were likely to experience a favorable clinical response to MTX or TNF blockade. Clinical improvement was associated with partial glycan normalization. ACPA-positive patients demonstrated enhanced N-glycan aberrancy compared with ACPA-negative patients.

Gene Expression Profiling of Early-Phase Sjögren's Syndrome in C57BL/6.NOD-Aec1Aec2Mice Identifies Focal Adhesion Maturation Associated with Infiltrating Leukocytes

Despite considerable efforts, the molecular and cellular events in lacrimal gland tissues initiating inflammatory responses leading to keratoconjunctivitis sicca (KCS), autoimmunity, and Sjögren's syndrome (SjS) have yet to be defined. To determine whether altered glandular homeostasis occurs before the onset of autoimmunity, a temporal transcriptome study was carried out in an animal model of primary SjS. Using oligonucleotide microarrays, gene expression profiles were generated for lacrimal glands of C57BL/6.NOD-Aec1Aec2 mice 4 to 20 weeks of age. Pairwise analyses identified genes differentially expressed, relative to their 4-week expression, during the development of SjS-like disease. Statistical analyses defined differentially and coordinately expressed gene sets. The PANTHER (Protein ANalysis THrough Evolutionary Relationships) classification system was used to define annotated biological processes or functions. Temporal transcript expression profiles of C57BL/6.NOD-Aec1Aec2 lacrimal glands before, or concomitant with, the first appearance of inflammatory cells revealed a highly restricted subset of differentially expressed genes encoding interactive extracellular matrix proteins, fibronectin, integrins, and syndecans. In contrast, genes encoding interepithelial junctional complex proteins defined alterations in tight junctions (TJ), adherens, desmosomes, and gap junctions, suggesting perturbations in the permeability of the paracellular spaces between epithelial barriers. Correlating with this were gene sets defining focal adhesion (FA) maturation and Ras/Raf-Mek/Erk signal transduction. Immunohistochemically, FAs were associated with infiltrating leukocytes and not with lacrimal epithelial cells. For the first time, FA maturations are implicated as initial biomarkers of impending autoimmunity in lacrimal glands of SjS-prone mice. Changes in TJ complex genes support an increased movement of cells through paracellular spaces.

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease–associated dysgammaglobulinemia

AbstractManifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19+ B cells (165 vs 454 vs 417 × 106/L) with elevated CD19+CD21low immature (16.5%, 7.7%, and 9.1%) and CD19+CD21int-highCD38highIgMhigh transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19+CD10−CD27−CD21high naive B cells were highly elevated in all patients with cGVHD. CD19+CD27+IgD+ non–class-switched (4 vs 12 vs 11 × 106/L) and class-switched (7 vs 35 vs 42 × 106/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8% and cryoglobulinemia was demonstrated in 36.9% patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8% and cryoglobulinemia was demonstrated in 36.9% patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.

The identification of auto-antibodies in pancreatic cancer patient sera using a naturally fractionated Panc-1 cell line

The immunogenic nature of cancer can be explored to distinguish pancreatic cancer from related non-cancer conditions. We describe a liquid-based microarray approach followed by statistical analysis and confirmation for discovery of auto-immune biomarkers for pancreatic cancer. Proteins from the Panc-1 pancreatic cancer cell line were fractionated using a 2-D liquid separation method into over 1052 fractions and spotted onto nitrocellulose coated glass slides. The slides were hybridized with 37 pancreatic cancer sera, 24 chronic pancreatitis sera and 23 normal sera to detect elevated levels of reactivity against the proteins in spotted fractions. The response data obtained from protein microarrays was first analyzed by Wilcoxon Rank-Sum Tests to generate two lists of fractions that positively responded to the cancer sera and showed p-values less than 0.02 in the pairwise comparison between cancer specimens and normal and chronic pancreatitis specimens. The top 3 fractions with the lowest correlations were combined in receiver operating characteristic analyses. The area-under-the-curve (AUC) values are 0.813 and 0.792 for cancer vs. normal and cancer vs. pancreatitis respectively. Outlier-Sum statistics were then applied to the microarray data to determine the existence of outliers exclusive in cancer sera. The selected fractions were identified by LC-MS/MS. We further confirmed the occurrence of outliers with three proteins among cancer samples in a confirmation experiment using a separate dataset of 165 serum samples containing 48 cancer sera and 117 non-cancer controls. Phosphoglycerate kinase 1 (PGK1) elicited greater reactivity in 20.9% (10 in 48) of the samples in the cancer group, while no outlier was present in the non-cancer groups.

Longitudinal expression of type I interferon responsive genes in systemic lupus erythematosus

Cross-sectional studies of patients with systemic lupus erythematosus (SLE) have demonstrated an association between activation of type I interferon (IFN) pathway and disease activity. This study examined longitudinal changes in IFN-regulated gene expression in peripheral blood using microarrays. A cross-section of 66 patients from the Autoimmune Biomarkers Collaborative Network SLE archive was evaluated. We also examined paired samples from a 15 patient subset collected during a period of low disease activity (Baseline) and at a subsequent flare event, and baseline scores of 29 patients who maintained low disease activity. IFN response (IFNr) scores were calculated from three IFN-regulated genes. Overall, higher IFNr scores were associated with increased disease activity. However, IFNr scores were not significantly different between the paired Baseline and Flare samples. An extended longitudinal analysis in 11 patients indicated little change in IFNr scores over time, even during dynamic disease activity. In patients with low disease activity, IFNr scores were not different between patients who experienced a subsequent flare and those who maintained low disease activity. In summary, although higher IFNr scores were associated with greater disease activity, IFNr scores of individual patients did not correlate with changes in disease severity or flare risk.