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author:("millei, Gabor")
1.  Autoreactive IgE Is Prevalent in Systemic Lupus Erythematosus and Is Associated with Increased Disease Activity and Nephritis 
PLoS ONE  2014;9(2):e90424.
The presence of autoantibodies in systemic lupus erythematosus, particularly those of the IgG subclass, have long been associated with disease onset and activity. Here we explored the prevalence of autoreactive IgE in SLE and its relevance to disease in French (n = 79) and United States (US) (n = 117) cohorts with a mean age of 41.5±12.7 and 43.6±15.3 years and disease duration of 13.5±8.5 and 16.6±11.9 years, respectively. Our findings show that approximately 65% of all SLE subjects studied produced IgE antibodies to the seven autoantigens tested. This positivity was increased to almost 83% when only those subjects with active disease were considered. SLE subjects who were positive for anti-dsDNA, -Sm, and -SSB/La -specific IgE showed a highly significant association in the levels of these antibodies with disease activity similar to that of the corresponding IgG's. A strong association of IgE autoantibodies with active nephritis was also found in the combined cohort analysis. A test of the predictive value of autoreactive IgE’s and IgGs for disease activity (SLE Disease Activity Index (SLEDAI) ≥4) revealed that the best predictors were dsDNA-specific IgE and IgG, and that the age of an SLE subject influenced this predictive model. The finding argue that the overall levels of IgE autoantibodies, independently or in combination with IgG autoantibodies, may serve as indicators of active disease.
doi:10.1371/journal.pone.0090424
PMCID: PMC3938730  PMID: 24587356
2.  Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(12):2071-2074.
Autologous hematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. Since the first consensus statement in 1997, approximately 200 autologous bone marrow or hematopoietic stem cell transplantations have been reported world-wide for SLE. The current state of AHSCT in SLE was reviewed at a recent meeting of the Autoimmune Working Party of the European Group for Blood and Marrow Transplantation. There was general agreement among experts in this field, that in patients with severe SLE refractory to conventional immunosuppressive therapies, AHSCT can achieve sustained clinical remissions (ranging from 50–70% disease free survival at 5 years) associated with qualitative immunological changes not seen with other forms of therapy. However, this clinical benefit is associated with an increase in short-term mortality in most but not all studies. Improving patient selection, long-term follow up of patients after AHSCT, optimization of induction and maintenance therapy along with detailed analysis of the immune system are identified as key areas for future research. Optimally, AHSCT should be compared to conventional therapy in randomized controlled trials. Development of stronger transplant registries, defining a core set of clinical data and standardizing biologic sample collections would make future collaborations and comparison of various studies more feasible.
doi:10.1136/ard.2010.148049
PMCID: PMC3923531  PMID: 21873334
3.  The Percentage of FoxP3+Helios+ Treg Cells Correlates Positively With Disease Activity in Systemic Lupus Erythematosus 
Arthritis and rheumatism  2013;65(11):2898-2906.
Objective
To assess the use of Helios in combination with FoxP3 as a superior method for identifying non–cytokine-producing human Treg cells in patients with systemic lupus erythematosus (SLE) and to determine if FoxP3+Helios+ Treg cells are maintained at normal levels in patients with clinically active disease.
Methods
Peripheral blood mononuclear cells (PBMCs) were purified from the blood of healthy volunteer donors and from 52 consecutive patients with SLE of varying clinical activity (Systemic Lupus Erythematosus Disease Activity Index scores of 0, 2–4, and ≥5). PBMCs (either fresh or after 4 hours of stimulation for cytokine production) were then analyzed by flow cytometry for the expression of cell surface markers (CD4, CD25, CD127, and CD45RA) and transcription factors (FoxP3 and Helios), as well as for the production of cytokines (interleukin-2 and interferon- γ).
Results
FoxP3+Helios+ Treg cells were found to be non–cytokine producing in both SLE patients and healthy controls. Patients with clinically active SLE had higher percentages of FoxP3+Helios+ Treg cells than did patients with inactive SLE or healthy controls. When corrected for the total CD4 cell count, the absolute numbers of FoxP3+Helios+ Treg cells in patients with moderately-to-highly active SLE were normal.
Conclusion
Previous reports of a deficiency in Treg cell number or function in SLE are limited by their use of CD25, either alone or in combination with other markers, to identify human Treg cells. Helios in combination with FoxP3 is a superior method for detecting all non–cytokine-producing Treg cells, irrespective of CD25 or CD45RA expression. Using this method, we showed that FoxP3+Helios+ Treg cell numbers are not reduced in patients with clinically active SLE.
doi:10.1002/art.38119
PMCID: PMC3891045  PMID: 23925905
4.  Interleukin-17 Cytokines Are Critical in Development of Fatal Lupus Glomerulonephritis 
Immunity  2012;37(6):1104-1115.
SUMMARY
Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement.
doi:10.1016/j.immuni.2012.08.014
PMCID: PMC3594848  PMID: 23123062
5.  The expression of APRIL in Sjögren’s syndrome: aberrant expression of APRIL in the salivary gland 
Rheumatology (Oxford, England)  2012;51(9):1557-1562.
Objective. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are B-cell-related mediators and may play a role in the pathogenesis in SS. In this descriptive study we assessed the expression of APRIL and BAFF in the minor salivary gland and serum from SS patients.
Methods. Paraffin-embedded minor salivary gland sections from SS patients, non-SS controls and healthy volunteers were analysed by immunohistochemistry. Digital image quantification was performed to evaluate the expression of BAFF, APRIL and transmembrane activator and CAML interactor. Furthermore, serum was analysed for soluble BAFF and APRIL levels by ELISA. All the data were also analysed for subjects with decreased and normal stimulated salivary flow independent of the classification.
Results. APRIL expression was lower in minor salivary gland biopsies from SS patients compared with healthy volunteers and to a lesser extent non-SS controls, whereas BAFF expression was similar in all groups. Soluble APRIL levels in serum were increased in SS patients and in subjects with decreased salivary flow independent of the classification.
Conclusion. APRIL salivary gland tissue levels are decreased, suggesting that targeting this cytokine locally in the salivary glands would not benefit SS patients. Moreover, the discrepancy between local and systemic levels is striking and future research should assess this in more detail.
doi:10.1093/rheumatology/kes080
PMCID: PMC3418645  PMID: 22562936
Sjögren’s syndrome; minor salivary glands; a proliferation inducing ligand
6.  METHODOLOGIC ISSUES IN THE VALIDATION OF PUTATIVE BIOMARKERS AND SURROGATE ENDPOINTS IN TREATMENT EVALUATION FOR SYSTEMIC LUPUS ERYTHEMATOSUS 
No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the FDA for the last 30 years and one barrier has been the lack of validated of biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and the five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage renal disease from lupus nephritis, we also performed computer simulations for planning a biomarker bio-repository to support the validation process. “Random time window” sampling where a biomarker is obtained in an interval randomly selected from the total follow-up time for that subject yields serious ‘survival bias’. This can be avoided by the “fixed calendar window” design, in which biomarkers are measured within the same, pre-specified period for all cohort members who remain at risk during that period. In lupus nephritis where the incidence rate of end-stage renal disease is relatively low, to accumulate 300 instances of end-stage renal disease, at risk patients would have to be followed for about 5,000 person-years, implying 500 subjects followed, on average, for about 10 years. Increasing the number of biomarker determinations per subject from one to five reduces the required number of subjects by 10-15%, while further increases of the number of observations per subject yielded much smaller gains. The large numbers of subjects required for a bio-repository, makes it essential to maximize the efficiency of study designs and analyses and provides the strongest rationale for collaboration and the use of standardized measures to ensure comparability.
PMCID: PMC3746003  PMID: 19275685
7.  Adrenomedullary Response to Glucagon in Patients with Primary Sjögren’s Syndrome 
Several studies showed signs of autonomic dysfunction in patients with primary Sjögren's syndrome (pSS). Adrenomedullary function might be of importance for pSS pathogenesis by affecting salivary gland functions and modulating immune responses. The aim of the study was to evaluate the adrenomedullary hormonal system in patients with pSS.
The glucagon test (1 mg i.v.) was performed in 18 pSS patients and 13 control subjects. During the testing each patient had electrocardiographic and impedance cardiographic monitoring. Plasma epinephrine and norepinephrine were assayed by liquid chromatography with electrochemical detection after batch alumina extraction.
Baseline concentrations of epinephrine and norepinephrine were comparable between pSS and controls. Glucagon administration induced a significant increase in systolic blood pressure, diastolic blood pressure, heart rate, cardiac output (p < 0.01), stroke volume; however the changes were comparable between pSS and controls. Epinephrine levels increased (p < 0.01) in response to glucagon administration while norepinephrine concentration did not change. There was no significant difference in neurochemical responses to glucagon between pSS and controls. In conclusion, the present results suggest normal adrenomedullary function in pSS.
doi:10.1007/s10571-011-9787-x
PMCID: PMC3378756  PMID: 22350211
Primary Sjögren’s syndrome; epinephrine; adrenal medulla; norepinephrine
8.  MicroRNA Expression Profiles as Biomarkers of Minor Salivary Gland Inflammation and Dysfunction in Sjögren's Syndrome 
Arthritis and rheumatism  2011;63(2):535-544.
Objective
MicroRNA reflect physiologic and pathologic processes and may be used as biomarkers of concurrent pathophysiologic events in complex settings such as autoimmune diseases. We generated microRNA microarray profiles from the minor salivary glands of control subjects without Sjögren's syndrome (SS) and patients with SS who had low-grade or high-grade inflammation and impaired or normal saliva production, to identify microRNA patterns specific to salivary gland inflammation or dysfunction.
Methods
MicroRNA expression profiles were generated by Agilent microRNA arrays. We developed a novel method for data normalization by identifying housekeeping microRNA. MicroRNA profiles were compared by unsupervised mathematical methods to test how well they distinguish between control subjects and various subsets of patients with SS. Several bioinformatics methods were used to predict the messenger RNA targets of the differentially expressed microRNA.
Results
MicroRNA expression patterns accurately distinguished salivary glands from control subjects and patients with SS who had low-degree or high-degree inflammation. Using real-time quantitative polymerase chain reaction, we validated 2 microRNA as markers of inflammation in an independent cohort. Comparing microRNA from patients with preserved or low salivary flow identified a set of differentially expressed microRNA, most of which were up-regulated in the group with decreased salivary gland function, suggesting that the targets of microRNA may have a protective effect on epithelial cells. The predicted biologic targets of microRNA associated with inflammation or salivary gland dysfunction identified both overlapping and distinct biologic pathways and processes.
Conclusion
Distinct microRNA expression patterns are associated with salivary gland inflammation and dysfunction in patients with SS, and microRNA represent a novel group of potential biomarkers.
doi:10.1002/art.30131
PMCID: PMC3653295  PMID: 21280008
9.  Use of a novel virus detection assay to identify coronavirus HKU1 in the lungs of a hematopoietic stem cell transplant recipient with fatal pneumonia 
A 38-year-old patient with systemic lupus erythematosus presented with pulmonary infiltrates and hypoxemia for several months following immunodepleting autologous hematopoietic stem cell transplantation. She was treated for influenza, which was isolated repeatedly from ororpharynx and bronchoalveolar lavage fluids, and later empirically for lupus pneumonitis, but expired 6 months after transplant. Autopsy findings failed to show influenza in the lungs or lupus pneumonitis. A novel generic PCR-based assay using degenerate primers identified human coronavirus HKU1 RNA in bronchoalveolar lavage fluid at autopsy. Coronavirus was confirmed by virus-specific PCRs of lung tissue at autopsy. Electron microscopy showed viral particles consistent with coronavirus HKU1 in lung tissue both at autopsy and from a previous biopsy. While human coronavirus HKU1 infection is not usually severe, in highly immunocompromised patients, it can be associated with fatal pneumonia.
doi:10.1111/j.1399-3062.2011.00657.x
PMCID: PMC3416037  PMID: 21749586
Viral infections; generic virus detection; virus discovery; immunocompromised
10.  Sensitive and robust luminescent profiling of anti-La and other autoantibodies in Sjögren’s syndrome 
Autoimmunity  2009;42(6):515-524.
Sjögren’s syndrome (SjS) patients often have a variety of extraglandular manifestations including neurological and gastrointestinal involvement. In this study we evaluated the diagnostic performance of luciferase immunoprecipitation system (LIPS) that employs mammalian cell-produced recombinant antigens for analyzing SjS autoantibody responses. LIPS testing of mammalian cell-produced La, Ro60 and Ro52 recombinant antigens with defined commercial antibodies demonstrated highly specific immunoprecitation of each antigen without cross-reactivity. Next, sera from 57 SjS and 25 volunteers were evaluated by LIPS against a panel of human autoantigens. LIPS detected robust anti-La antibody levels in 43/57 SjS patients (75% sensitivity) and markedly outperformed an ELISA (46% sensitivity). Profiling of other SjS-associated autoantigens revealed the presence of anti-Ro60, anti-Ro52 in 63% and 61%, of SjS patients, respectively. Interestingly, a C-terminal fragment of Ro52 (Ro52-Δ2), a protein fragment not previously found to be antigenic by ELISA, also showed positive immunoreactivity in 42/57 SjS patients (65% sensitivity). Additional profiling of other autoantigens revealed that certain SjS patients also showed positive immunoreactivity with thyroid peroxidase (14%), AQP-4 (12%) and the H+/K+ gastric ATPase (16%) suggesting potential autoantibody attack of thyroid, neuronal and gastric parietal cells, respectively. These heterogeneous autoantibody responses detected by LIPS in SjS will likely be useful for diagnosis and for evaluating extraglandular manifestations.
doi:10.1080/08916930902911738
PMCID: PMC3417760  PMID: 19657778
Autoantibodies; Autoantigen; Diagnosis Sjögren’s syndrome; SSA; SSB
11.  MicroRNAs in Sjögren’s syndrome as a prototypic autoimmune disease 
Autoimmunity reviews  2010;9(9):618-621.
MicroRNAs are endogenous non-coding RNAs, approximately 22 nucleotides in length. They regulate gene expression and are important in a wide range of physiological and pathological processes. MicroRNA expression is tightly regulated during hematopoiesis and lymphoid cell differentiation and disruption of the entire microRNA network or selected microRNAs may lead to dysregulated immune responses. Abnormalities in microRNA expression related to inflammatory cytokines, Th-17 and regulatory T cells as well as B cells have been described in several autoimmune diseases. Sjögren’s syndrome is characterized by features of systemic autoimmunity and chronic inflammation and dysfunction in exocrine organs. Its clinical characteristics along with the relatively easy access to the target tissue and its product makes Sjögren’s syndrome appealing to study many aspects of microRNAs in a systemic autoimmune disease, such as their potential as diagnostic or prognostic biomarkers and their role in pathogenesis of autoimmunity, inflammation or organ dysfunction. Encouraging preliminary data from pilot studies in Sjögren’s syndrome demonstrate the potential of microRNAs as putative diagnostic and prognostic biomarker candidates which should be tested in larger more definite studies. Combining the comparison of microRNA expression profiles between various clinical subsets of Sjögren’s syndrome with bioinformatic modeling tools may predict formerly unsuspected pathways which may contribute to the disease process and lead to the generation of testable novel hypothesis of pathogenesis.
doi:10.1016/j.autrev.2010.05.009
PMCID: PMC3408312  PMID: 20457282
biomarker; autoimmunity; epigenetics; exocrine dysfunction; pathogenesis
12.  The Majority of MicroRNAs Detectable in Serum and Saliva Is Concentrated in Exosomes 
PLoS ONE  2012;7(3):e30679.
There is an increasing interest in using microRNAs (miRNA) as biomarkers in autoimmune diseases. They are easily accessible in many body fluids but it is controversial if they are circulating freely or are encapsulated in microvesicles, particularly exosomes. We investigated if the majority of miRNas in serum and saliva are free-circulating or concentrated in exosomes. Exosomes were isolated by ultracentrifugation from fresh and frozen human serum and saliva. The amount of selected miRNAs extracted from the exosomal pellet and the exosome-depleted serum and saliva was compared by quantitative RT-PCR. Some miRNAs tested are ubiquitously expressed, others were previously reported as biomarkers. We included miRNAs previously reported to be free circulating and some thought to be exosome specific. The purity of exosome fraction was confirmed by electronmicroscopy and western blot. The concentration of miRNAs was consistently higher in the exosome pellet compared to the exosome-depleted supernatant. We obtained the same results using an equal volume or equal amount of total RNA as input of the RT-qPCR. The concentration of miRNA in whole, unfractionated serum, was between the exosomal pellet and the exosome-depleted supernatant. Selected miRNAs, which were detectable in exosomes, were undetectable in whole serum and the exosome-depleted supernantant. Exosome isolation improves the sensitivity of miRNA amplification from human biologic fluids. Exosomal miRNA should be the starting point for early biomarker studies to reduce the probability of false negative results involving low abundance miRNAs that may be missed by using unfractionated serum or saliva.
doi:10.1371/journal.pone.0030679
PMCID: PMC3302865  PMID: 22427800
14.  The Non-Muscle Myosin Heavy Chain 9 Gene (MYH9) Is Not Associated with Lupus Nephritis in African Americans 
American Journal of Nephrology  2010;32(1):66-72.
Background
African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN.
Methods
Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA.
Results
A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association.
Conclusions
These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA.
doi:10.1159/000314688
PMCID: PMC2914393  PMID: 20523037
African Americans; Genetics; Lupus nephritis; Kidney; MYH9; Systemic lupus erythematosus
15.  Effect of Soluble ICAM-1 on a Sjögren's Syndrome-like Phenotype in NOD Mice Is Disease Stage Dependent 
PLoS ONE  2011;6(5):e19962.
Introduction
Intercellular adhesion molecule-1 (ICAM-1) is involved in migration and co-stimulation of T and B cells. Membrane bound ICAM-1 is over expressed in the salivary glands (SG) of Sjögren's syndrome (SS) patients and has therefore been proposed as a potential therapeutic target. To test the utility of ICAM-1 as a therapeutic target, we used local gene therapy in Non Obese Diabetic (NOD) mice to express soluble (s)ICAM-1 to compete with membrane bound ICAM-1 for binding with its receptor. Therapy was given prior to and just after the influx of immune cells into the SG.
Methods
A recombinant serotype 2 adeno associated virus (rAAV2) encoding ICAM-1/Fc was constructed and its efficacy tested in the female NOD mice after retrograde instillation in SG at eight (early treatment) and ten (late treatment) weeks of age. SG inflammation was evaluated by focus score and immunohistochemical quantification of infiltrating cell types. Serum and SG tissue were analyzed for immunoglobulins (Ig).
Results
Early treatment with ICAM-1/Fc resulted in decreased average number of inflammatory foci without changes in T and B cell composition. In contrast, late treated mice did not show any change in focus scores, but immunohistochemical staining showed an increase in the overall number of CD4+ and CD8+ T cells. Moreover, early treated mice showed decreased IgM within the SGs, whereas late treated mice had increased IgM levels, and on average higher IgG and IgA.
Conclusions
Blocking the ICAM-1/LFA-1 interaction with sICAM-1/Fc may result in worsening of a SS like phenotype when infiltrates have already formed within the SG. As a treatment for human SS, caution should be taken targeting the ICAM-1 axis since most patients are diagnosed when inflammation is clearly present within the SG.
doi:10.1371/journal.pone.0019962
PMCID: PMC3093404  PMID: 21589878
16.  Tocilizumab in Systemic Lupus Erythematosus – Safety, Preliminary Efficacy, and Impact on Circulating Plasma Cells 
Arthritis and rheumatism  2010;62(2):542-552.
Objective
To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).
Methods
In an open label, dose-escalating, Phase I study, 16 patients with mild to moderate disease activity were treated bi-weekly for 12 weeks with one of three doses (2 mg/kg [n=4], 4 mg/kg [n=6], 8 mg/kg [n=6]) of tocilizumab and followed for 8 additional weeks.
Results
The infusions were well tolerated. Tocilizumab led to dose-related decreases in absolute neutrophil count with a median decrease of 38% in the 4 mg/kg and 56% in the 8 mg/kg dose groups. Neutrophil counts returned to normal after cessation of treatment. One subject was withdrawn because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed a significant improvement with 8/15 evaluable patients having a decrease of 4 or more points in the modified SELENA-SLEDAI score. Arthritis improved in all seven patients with arthritis at baseline and resolved in four. Anti-dsDNA antibody levels decreased by a median 47% in the 4 and 8 mg/kg dose groups compared to a 7.8% decrease in IgG levels. These changes together with a significant decrease in circulating plasma cells suggest a specific effect of tocilizumab on autoantibody producing cells.
Conclusion
Although neutropenia may limit the maximum dose of tocilizumab in SLE, the observed clinical and serological response data are promising and warrant further studies to establish the optimal dosing regimen and efficacy.
doi:10.1002/art.27221
PMCID: PMC3057537  PMID: 20112381
17.  Cytokines in Sjögren’s syndrome: potential therapeutic targets 
Annals of the rheumatic diseases  2010;69(6):945-948.
The dysregulated cytokine network in Sjögren’s syndrome (SS) is reflected by local and systemic overexpression of pro-inflammatory cytokines and absent or low levels of anti-inflammatory cytokines. To date, the use of cytokine based therapies in SS has been disappointing. Oral administration of low dose interferon (IFN) α showed inconsistent efficacy in various studies but failed to achieve the primary endpoint in a pivotal randomized controlled trial. Similarly, neither of the two tumor necrosis factor (TNF)- α blockers tested (etanercept and infliximab) showed efficacy in placebo controlled trials. Although the rationale for low dose oral IFN treatment has not been firmly established, TNF blockade was based on solid preclinical data. Therefore, the reason for the lack of efficacy is unclear, but recent data suggest that unexpected biological effects of TNF-antagonists may have contributed to this. Cytokines, given their central role in the pathogenesis of SS, remain attractive targets for future treatments, despite the disappointing early results. Inflammatory cytokines are obvious candidates and agents against several of them are available or under development for other autoimmune diseases similar to SS. New candidate cytokines like IL-17 and IL-12 and/or IL-23 may provide promising targets for SS. Additionally, as an alternative to systemic treatment which has the risk of potentially severe side effects, the use of local cytokine directed therapy should be explored.
doi:10.1136/ard.2009.115378
PMCID: PMC3044243  PMID: 20410069
18.  MicroRNAs as biomarkers in rheumatic diseases 
Nature reviews. Rheumatology  2010;6(7):391-398.
Summary
MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNAs of 19–25 nucleotides in length. They regulate gene expression and are important in a wide range of physiological and pathological processes. MiRNAs are attractive as potential biomarkers because their expression pattern is reflective of the underlying pathophysiologic processes and they are specific to various disease states. Moreover, miRNAs can be detected in a variety of sources, including tissue, blood and body fluids; they are reasonably stable and appear to be resistant to differences in sample handling, which increases their appeal as practical biomarkers. The clinical utility of miRNAs as diagnostic or prognostic biomarkers has been demonstrated in various malignancies and a few nonmalignant diseases. There is accumulating evidence that miRNAs have an important role in systemic rheumatic diseases and that various diseases or different stages of the same disease are associated with distinct miRNA expression profiles. Preliminary data suggest that miRNAs are promising as candidate biomarkers of diagnosis, prognosis, disease activity and severity in autoimmune diseases. MiRNAs identified as potential biomarkers in pilot studies should be validated in larger studies specifically designed for biomarker validation.
doi:10.1038/nrrheum.2010.81
PMCID: PMC3041596  PMID: 20517293
19.  Development of a gene transfer-based treatment for radiation-induced salivary hypofunction 
Oral oncology  2009;46(1):4.
A significant long-term side effect of radiation therapy for head and neck cancers is xerostomia, a dry mouth, due to salivary gland damage. Despite continuing efforts to eliminate this problem, many patients continue to suffer. This brief review describes our efforts to develop a gene transfer approach, employing the aquaporin-1 cDNA, to treat patients with existing radiation-induced salivary hypofunction. A Phase I/II clinical trial, using a recombinant adenoviral vector to mediate gene transfer, is currently underway.
doi:10.1016/j.oraloncology.2009.09.004
PMCID: PMC2818419  PMID: 19892587
xerostomia; radiation; gene therapy; aquaporin-1; adenovirus
20.  Exosomes from Human Saliva as a Source of microRNA Biomarkers 
Oral diseases  2009;16(1):34-38.
Objective
To examine the presence of microRNAs within exosomes isolated from human saliva and to optimize and test methods for successful downstream applications.
Design
Exosomes isolated from fresh and frozen glandular and whole human saliva were used as a source of microRNAs. The presence of microRNAs was validated with TaqMan Real Time PCR and microRNA microarrays.
Results
We successfully isolated exosomes from human saliva from healthy controls and a patient with Sjögren’s syndrome. MicroRNAs extracted from the exosomal fraction were sufficient for quantitative PCR and microarray profiling.
Conclusions
The isolation of microRNAs from easily and non-invasively obtained salivary exosomes with subsequent characterization of the microRNA expression patterns is promising for the development of future biomarkers of the diagnosis and prognosis of various salivary gland pathologies.
doi:10.1111/j.1601-0825.2009.01604.x
PMCID: PMC2844919  PMID: 19627513
salivary exosomes; microRNA; biomarkers
21.  BASOPHILS AND THE T HELPER 2 ENVIRONMENT CAN PROMOTE THE DEVELOPMENT OF LUPUS NEPHRITIS 
Nature medicine  2010;16(6):701-707.
Summary
In systemic lupus erythematosus (SLE) self-reactive antibodies can target the kidney (lupus nephritis) leading to functional failure and possible mortality. We report that activation of basophils by autoreactive IgE, causes their homing to lymph nodes, promoting TH2 cell differentiation, and enhancing the production of self-reactive antibodies that cause lupus-like nephritis in Lyn−/− mice. SLE patients also have elevated serum IgE, self-reactive IgE's, and activated basophils that express CD62L and the MHC Class II molecule, HLA-DR; parameters that were found to be associated with increased disease activity and active lupus nephritis. Basophils were also present in the lymph nodes and spleen of SLE patients. Thus, in Lyn−/− mice, basophils and IgE autoantibodies amplify autoantibody production that leads to lupus nephritis, and in SLE patients, the presence of IgE autoantibodies and activated basophils are factors associated with disease activity and nephritis.
doi:10.1038/nm.2159
PMCID: PMC2909583  PMID: 20512127
22.  Cytokines in Sjögren’s syndrome 
Oral diseases  2009;15(8):519-526.
doi:10.1111/j.1601-0825.2009.01582.x
PMCID: PMC2762015  PMID: 19519622
23.  RAPID VISION LOSS ASSOCIATED WITH FLUDARABINE ADMINISTRATION IN THREE PATIENTS 
Retina (Philadelphia, Pa.)  2010;30(8):1272-1277.
Purpose
The purpose of this study was to report the clinical and pathologic findings of three cases of rapid vision loss associated with fludarabine toxicity.
Methods
A retrospective, single-center case series was conducted. Autopsies of the eyes from three cases were performed.
Results
A 23-year-old man (Case 1) with systemic lupus erythematosus developed rapid and severe vision loss, generalized neurologic decline, and eventual death after administration of fludarabine before stem cell transplantation. A 48-year-old woman (Case 2) and a 60-year-old man (Case 3), both with metastatic melanoma, had similar courses after receiving fludarabine as part of a preparatory regimen before adoptive cell therapy. Fundus examination showed punctuate yellow flecks in the macula after visual decline in two cases. In all three cases, serum antiretinal antibodies were negative before and after treatment; electrophysiological testing showed markedly decreased B-waves; and pathologic analysis showed loss of retinal bipolar and ganglion cells, gliosis within the retina and optic nerve, and optic nerve atrophy.
Conclusion
Fludarabine toxicity can result in severe vision loss attributable to damage to retinal bipolar and ganglion cells. Although effective treatments are not known, care should be taken to consider fludarabine toxicity in patients who present with vision loss ~1 month after treatment.
doi:10.1097/IAE.0b013e3181d20589
PMCID: PMC2943138  PMID: 20224467
fludarabine; purine analog; ocular toxicity; ophthalmic pathology; adoptive cell therapy; stem cell transplantation
24.  Assessment of ovarian function with anti-Müllerian hormone in systemic lupus erythematosus patients undergoing hematopoietic stem cell transplant 
Fertility and sterility  2008;91(4 Suppl):1529-1532.
In this small pilot study, anti-Müllerian hormone (AMH) levels in women undergoing chemotherapy and hematopoietic stem cell transplantation facilitated earlier identification of impaired ovarian reserve compared with FSH and the resumption of menses. Larger studies are needed to accurately assess the clinical significance of AMH levels in the prediction of long-term reproductive outcomes in reproductive-age transplant patients with our current conditioning regimen.
doi:10.1016/j.fertnstert.2008.08.123
PMCID: PMC2843408  PMID: 18930199
Stem cell transplant; ovarian reserve; anti-Müllerian hormone
25.  Pathogenesis of Sjögren's syndrome 
Current opinion in rheumatology  2009;21(5):465-470.
Purpose of review
To summarize recent developments in our understanding of the pathogenesis of Sjögren's syndrome with a focus on the relationship between inflammation and exocrine dysfunction.
Recent findings
Animal models demonstrated the complex interactions between immunologic and nonimmunologic mechanisms in Sjögren's syndrome. Activation of the innate immune system can lead to exocrine dysfunction before or without significant inflammation, whereas in other models, salivary gland function is preserved despite intense inflammatory infiltrates. Primary or inflammation-related abnormalities in water channels contribute to the exocrinopathy. Activation of the innate immunity in patients is demonstrated by the upregulation of type-1 interferon-regulated genes (interferon signature) in peripheral blood and salivary glands and abnormal expression of B cell-activating factor and its receptors. Nonimmune mechanisms that may contribute to exocrine dysfunction include local and systemic androgen deficiency and autonomic nervous system dysfunction. Autoantibodies against the muscarinic acetylcholine receptors would provide a link between autoimmunity and exocrine dysfunction, but the data on the presence, frequency and physiologic affect of these antibodies remain controversial.
Summary
Recent discoveries from studies in patients with Sjögren's syndrome and animal models suggest a complex interplay between genetic factors, environmental and stochastic events that involve innate and adaptive immunity, hormonal mechanisms and the autonomic nervous system. Some of these findings suggest that exocrine gland dysfunction may precede autoimmunity or represent a process independent from inflammation in the pathogenesis of Sjögren's syndrome.
doi:10.1097/BOR.0b013e32832eba21
PMCID: PMC2766246  PMID: 19568172
autonomic nervous system; exocrinopathy; innate immunity; sex steroids

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