Sjogrens Syndrome (SS) is an autoimmune disease, characterized by widespread inflammation in the exocrine glands and other organs resulting in dryness of the lining surfaces of the body, most notably, dry mouth and dry eyes. In addition, it can involve numerous other organs such as the joints, skin and nervous system. The MPTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in MPTB, other NIH laboratories and Institutions outside the NIH in order to understand the mechanisms underlying this disease. The ultimate goal of our research is to find treatments for SS that are safe, effective and target specific steps in the pathogenesis of SS. We focus our research in two broad categories. Natural history studies include observational and retrospective studies with the goal to expand our knowledge about the pathogenesis of SS, to improve our diagnostic and prognostic tools and to identify targets for new therapies. The other major area involves the evaluation of novel treatments in patients with SS. Treatment study using efalizumab (Raptiva) an anti-LFA1 monoclonal antibody In this study we tested Raptiva (efalizumab, Genentech), an anti-LFA1 monoclonal antibody targeting the LFA1-ICAM pathway involved in several functions in Sjogrens Syndrome, in a pilot Phase 2 study. The protocol was prematurely terminated due to serious complications reported with Raptiva in patients with psoriasis. Up to then we had enrolled ten patients and treated nine. Six patients received Raptiva and three placebo during the first placebo controlled phase of the study. Primary response criteria were only met by one of the placebo recipients. Raptiva has increased inflammation in the salivary gland, worsened salivary gland function in most patients and led to significant increase in immunoglobulin production and the emergence of new autoantibodies in two patients. The mechanism of these unexpected effects are currently under investigation by a variety of methods including gene expression analysis in the peripheral blood and salivary gland biopsies, microRNA arrays of biopsies, immunohistochemistry and metabolomics. Autonomic nervous system (ANS) dysfunction in SS The range of symptoms in SS suggests that there may be perturbations in the nervous and immune systems and in pathways through which these systems communicate and mediate each other. Compared to normal healthy individuals, SS patients have significantly more prevalent nervous system involvement including impaired ANS function (which regulates the homeostasis via effects on the smooth muscle, glands and cardiovascular system) unique to these patients. We hypothesize that ANS dysfunction is central to the pathogenesis of SS and, in collaboration with Dr. David Goldsteins group (NINDS), we are conducting a protocol to investigate ANS function in patients with SS and the association between ANS dysfunction and autoimmunity. This protocol consists of a comprehensive evaluation of autonomic function, using physiological, neuropharmacologic, neurochemical, and imaging approaches, to identify consistent distinctive patterns of ANS involvement in SS and thereby improve the diagnosis and understanding of pathophysiologic mechanisms of SS. We completed testing in 14 patients and 5 controls We also completed non-invasive testing of the ANS in over 200 subjects in the natural history protocol. We are currently analyzing the data and plan to prepare a manuscript by the end of the year. Natural history of Sjogrens Syndrome protocol Current classification criteria of SS use whole unstimulated salivary flow as the measurement of SG function. This has been adopted by most investigators primarily because its simplicity. Some other academic SS centers, including us, have used glandular collection of saliva for classification purposes. To test if this was reasonable we compared these two measurement and their impact of EACG classification using 340 concomitant observations and have shown a reasonable good correlation between the two methods. In another study we evaluated the association between salivary gland inflammation and hypofunction. In a cohort of 339 pSS patients we found that inflammation accounted only for 10 percent of the variation if flow. These data suggest that salivary inflammation and dysfunction may be two different processes in the pathogenesis of SS. This may have significant implications on evaluating disease models, selecting appropriate outcome measures and designing clinical trials of pSS. Biomarker studies Salivary gland microRNA expression A major focus of this study was to evaluate the potential of microRNAs (miRNAs) as biomarkers. In a pilot study we used 24 Agilent microRNA microarrays to profile miRNAs isolated from healthy volunteers and Sjogrens patients minor salivary glands (MSGs) with high or low grade inflammation. In each group half of the patients had normal and half had decreased salivary flow. Using a novel method for data normalization we identified microRNA profiles that can serve as biomarkers for diagnosis (SS vs controls), function (salivary flow) or degree of inflammation in SS. We identified two miRNAs that changed in opposite direction between the low and high focus score samples. The ratio of expression levels of those 2 microRNAs correlated very well with the inflammatory status of the MSGs in an independent set of samples. We also found significant difference between patient with preserved and decreased salivary flow in the high focus score group. Salivary exosomal microRNAs We have published a paper of our methodology for the identification of microRNAs from exosomes in whole and glandular saliva. Genetic studies We have continued to expand our DNA bank for patients with SS. We have provided DNAs to Dr. John Harleys group in Oklahoma for genome wide association studies SS. The first results of these studies identified a BLK (a B lymphocyte tyrosine kinase) polymorphism for pSS and were presented at the 2008 ACR meeting. MPTB translational research project on Sjogrens Syndrome To narrow the gap between basic science and clinical practice we continued our collaboration several groups in NIDCR. Several gene therapy projects are underway in Dr. Chiorinis laboratory targeting various molecules in murine models of SS. As part of the salivary gland initiative we have successfully completed mRNA gene expression studies of 11 normal volunteer and 46 pSS samples in collaboration with the Chiorini group. We are analyzing the differences between healthy male and female salivary glands as well as differences between various patient subsets and controls. With the Ambudkar group we confirmed that miR150, one of the most differentially expressed microRNAs in SS salivary gland, decreases the expression of STIM-1 in vitro and showed patients with SS have a defect in STIM1 expression with significantly lower STIM1 levels in peripheral blood mononuclear cells compared to controls. These data suggest that STIM1 may play an important role in the pathogenesis of SS and that it may be downregulated by miR150. Future plans We plan to develop several early stage clinical studies to establish the safety and toxicity of an intervention, and at the same time, collect data about its possible efficacy. We establish collaborations to combine these clinical trials with thorough basic science evaluations. We will continue to collaborate on preclinical studies to learn about the pathogenesis of SS and to enable gene therapy and cellular therapy in the future. In addition to these treatment studies we will do non-interventional clinical studies to address clinical manifestations of Sjogrens Syndrome that are poorly understood and/or not explained by systemic autoimmunity, such as ANS dysfunction and metabolic abnormalities.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2009
Total Cost
$1,480,118
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
City
State
Country
Zip Code
Billings, M; Amin Hadavand, M; Alevizos, I (2018) Comparative analysis of the 2016 ACR-EULAR and the 2002 AECG classification criteria for Sjögren's syndrome: Findings from the NIH cohort. Oral Dis 24:184-190
Billings, M; Dye, B A; Iafolla, T et al. (2017) Elucidating the role of hyposalivation and autoimmunity in oral candidiasis. Oral Dis 23:387-394
Corden, A; Handelman, B; Yin, H et al. (2017) Neutralizing antibodies against adeno-associated viruses in Sjögren's patients: implications for gene therapy. Gene Ther 24:241-244
Alevizos, I; Zheng, C; Cotrim, A P et al. (2017) Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Gene Ther 24:176-186
Teos, Leyla Y; Alevizos, Ilias (2017) Genetics of Sjögren's syndrome. Clin Immunol 182:41-47
Alevizos, I; Zheng, C; Cotrim, A P et al. (2017) Immune reactivity after adenoviral-mediated aquaporin-1 cDNA transfer to human parotid glands. Oral Dis 23:337-346
Tandon, Mayank; Perez, Paola; Burbelo, Peter D et al. (2017) Laser microdissection coupled with RNA-seq reveal cell-type and disease-specific markers in the salivary gland of Sjögren's syndrome patients. Clin Exp Rheumatol :
Burbelo, Peter D; Gunti, Sreenivasulu; Keller, Jason M et al. (2017) Ultrarapid Measurement of Diagnostic Antibodies by Magnetic Capture of Immune Complexes. Sci Rep 7:3818
Gallo, Alessia; Jang, Shyh-Ing; Ong, Hwei Ling et al. (2016) Targeting the Ca(2+) Sensor STIM1 by Exosomal Transfer of Ebv-miR-BART13-3p is Associated with Sjögren's Syndrome. EBioMedicine 10:216-26
Jang, Shyh-Ing; Ong, Hwei Ling; Liu, Xibao et al. (2016) Up-regulation of Store-operated Ca2+ Entry and Nuclear Factor of Activated T Cells Promote the Acinar Phenotype of the Primary Human Salivary Gland Cells. J Biol Chem 291:8709-20

Showing the most recent 10 out of 59 publications