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1.  ANTI-MDA5-ASSOCIATED DERMATOMYOSITIS: EXPANDING THE CLINICAL SPECTRUM 
Arthritis care & research  2013;65(8):1307-1315.
Objective
Autoantibodies against melanoma differentiation-associated protein 5 (MDA5) have been described in several Asian dermatomyositis (DM) cohorts, often associated with amyopathic DM and rapidly progressive interstitial lung disease (ILD). A recent study of a DM cohort seen at a US dermatology clinic reports that MDA5 autoantibodies are associated with a unique cutaneous phenotype. Given the widening spectrum of clinical findings, we evaluated the clinical features of anti-MDA5-positive patients seen at a US myositis referral center.
Methods
160 DM patients were screened for MDA5 autoantibodies by immunoprecipitation and antibody titers were analyzed in longitudinal serum samples. Anti-MDA5 positive patients were evaluated for the presence of additional myositis autoantibodies. Patient clinical characteristics were compared by retrospective chart review.
Results
MDA5 was targeted in 11/160 (6.9%) patients with DM. Of these, nine presented with a symmetric polyarthropathy, six demonstrated overt clinical myopathy and eight had ILD. Eight anti-MDA5-positive patients exhibited the clinical attributes of the antisynthetase syndrome in the absence of Jo-1 or other anti-synthetase autoantibodies. MDA5 autoantibody titers did not correlate with clinical course.
Conclusions
MDA5 autoantibodies are found in DM patients presenting with a symmetric polyarthritis, clinically similar to rheumatoid arthritis. These patients often have features of the antisynthetase syndrome, but in the absence of antisynthetase autoantibodies. Most anti-MDA5 positive patients had overt clinical myopathy and ILD. The latter, while occasionally severe, typically resolved with immunosuppressive therapy. In this cohort, the MDA5 phenotype is frequently a clinical mimic of the antisynthetase syndrome and is not associated with rapidly progressive ILD.
doi:10.1002/acr.21992
PMCID: PMC3689861  PMID: 23436757
2.  Identification of Novel Autoantigens by a Triangulation Approach 
Journal of immunological methods  2012;385(1-2):35-44.
High titer autoantibodies, which are often associated with specific clinical phenotypes, are useful diagnostically and prognostically in systemic autoimmune diseases. In several autoimmune rheumatic diseases (e.g. myositis and Sjogren’s syndrome), 20–40% of patients are autoantibody negative as assessed by conventional assays. The recent discovery of new specificities (e.g., anti-MDA5) in a subset of these autoantibody-negative subjects demonstrates that additional specificities await identification. In this manuscript, we describe a rapid multidimensional method to identify new autoantigens. A central foundation of this rapid approach is the use of an antigen source in which a pathogenic pathway active in the disease is recapitulated. Additionally, the method involves a modified serological proteome analysis strategy which allows confirmation that the correct gel plug has been removed prior to sending for sequencing. Lastly, the approach uses multiple sources of information to enable rapid triangulation and identification of protein candidates. Possible permutations and underlying principles of this triangulation strategy are elaborated to demonstrate the broad utility of this approach for antigen discovery.
doi:10.1016/j.jim.2012.07.024
PMCID: PMC3457001  PMID: 22910000
3.  Isolated elevation of aldolase in the serum of myositis patients: a potential biomarker of damaged early regenerating muscle cells 
Objective
Elevated serum aldolase A levels occur in the absence of elevated creatine kinase M (CK) levels in a subset of myositis patients. This study was undertaken to investigate the cell biology of this unexplained clinical observation.
Methods
Cultured human myoblasts were differentiated in vitro. RNA and protein lysates were prepared and used to determine aldolase and CK gene and protein expression by QPCR and immunoblotting. Cardiotoxin was used to induce muscle injury and repair in an experimental mouse model, and aldolase A and CK were immunoblotted in the muscle lysates. Immunohistochemical staining was performed on myositis patient muscle paraffin sections to assess aldolase A and CK staining in vivo.
Results
Aldolase A mRNA and protein expression is highest in differentiating myoblasts, and remains robust throughout differentiation. In contrast, CK mRNA and protein levels are low in undifferentiated myoblasts and become strikingly upregulated as differentiation progresses. Aldolase A protein expression is high in regenerating muscle in the mouse model of injury/repair, while CK expression was low. Immunohistochemical staining of human myositis biopsies showed that muscle cells with the highest levels of aldolase and no CK staining have features of regeneration.
Conclusion
In undifferentiated muscle cells, and those early in the differentiation process, aldolase A is expressed in the absence of CK. Thereafter, both are expressed. We propose that isolated serum aldolase A elevation in myositis patients (i) reflects preferential immune-mediated damage of early regenerative cells, and (ii) is a biomarker of damaged early regenerating muscle cells.
PMCID: PMC3786178  PMID: 22703875
myositis; aldolase; creatine kinase; muscle regeneration
4.  Type I interferons: crucial participants in disease amplification in autoimmunity 
Nature reviews. Rheumatology  2010;6(1):40-49.
A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. The type I IFN cytokines are pleiotropic in their effects, mediating anti-viral and anti-tumor activities, and possessing numerous immunomodulatory functions for both the innate and adaptive immune responses. A key principle of the type I IFN system is rapid induction and amplification of the signaling pathway, which generates a feed-forward loop of IFN production, ensuring that a vigorous anti-viral immune response is mounted. While such feed-forward pathways are highly adaptive when it comes to rapid and effective virus eradication, this amplification can be maladaptive in immune responses directed against host tissues. Such feed-forward loops, however, create special opportunities for therapy.
doi:10.1038/nrrheum.2009.237
PMCID: PMC3622245  PMID: 20046205
5.  Expression of the dermatomyositis autoantigen Mi-2 in regenerating muscle 
Arthritis and rheumatism  2009;60(12):3784-3793.
Objective
Autoantibodies against the chromatin remodeler Mi-2 are found in a distinct subset of patients with dermatomyositis (DM). Previous quantitative immunoblotting experiments demonstrated that Mi-2 protein is up-regulated in DM muscle. We undertook this study to define the population of cells expressing high levels of Mi-2 in DM muscle and to explore the regulation and functional role of Mi-2 during muscle regeneration.
Methods
We analyzed the expression of Mi-2 in human muscle biopsy specimens using immunofluorescence. Then, we used cardiotoxin (CTX) to induce muscle injury and repair in the mouse; Mi-2 expression during muscle regeneration was studied in this model by immunofluorescence and immunoblotting analysis. Finally, we utilized a cell culture system of muscle differentiation to artificially modulate Mi-2 levels during myoblast proliferation and differentiation.
Results
In DM muscle, increased Mi-2 expression is preferentially found in myofibers within fascicles affected by perifascicular atrophy, particularly in the centralized nuclei of small perifascicular muscle fibers expressing markers of regeneration. In the mouse, Mi-2 is dramatically and persistently up-regulated during muscle regeneration in vivo. Premature silencing of Mi-2 with RNAi in vitro resulted in accelerated myoblast differentiation.
Conclusions
Mi-2 expression is markedly up-regulated during muscle regeneration in the mouse model. It is also up-regulated in DM myofibers expressing markers of regeneration. In vitro studies suggest that this protein may play a role in modulating the kinetics of myoblast differentiation. We propose that high levels of Mi-2 expression in DM muscle biopsies reflect the presence of incompletely differentiated muscle cells.
doi:10.1002/art.24977
PMCID: PMC2828900  PMID: 19950298
7.  Regulatory subunits of PKA define an axis of cellular proliferation/differentiation in ovarian cancer cells 
BMC Medical Genomics  2008;1:43.
Background
The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in two isoforms, RI and RII, which distinguish the PKA isozymes, type I (PKA-I) and type II (PKA-II). Evidence obtained from a variety of different experimental approaches has shown that the relative levels of type I and type II PKA in cells can play a major role in determining the balance between cell growth and differentiation. In order to characterize the effect of PKA type I and type II regulatory subunits on gene transcription at a global level, the PKA regulatory subunit genes for RIα and RIIβ were stably transfected into cells of the ovarian cancer cell line (OVCAR8).
Results
RIα transfected cells exhibit hyper-proliferative growth and RIIβ transfected cells revert to a relatively quiescent state. Profiling by microarray revealed equally profound changes in gene expression between RIα, RIIβ, and parental OVCAR cells. Genes specifically up-regulated in RIα cells were highly enriched for pathways involved in cell growth while genes up-regulated in RIIβ cells were enriched for pathways involved in differentiation. A large group of genes (~3600) was regulated along an axis of proliferation/differentiation between RIα, parental, and RIIβ cells. RIα/wt and RIIβ/wt gene regulation was shown by two separate and distinct gene set analytical methods to be strongly cross-correlated with a generic model of cellular differentiation.
Conclusion
Overexpression of PKA regulatory subunits in an ovarian cancer cell line dramatically influences the cell phenotype. The proliferation phenotype is strongly correlated with recently identified clinical biomarkers predictive of poor prognosis in ovarian cancer suggesting a possible pivotal role for PKA regulation in disease progression.
doi:10.1186/1755-8794-1-43
PMCID: PMC2577111  PMID: 18822129
8.  Sexual dimorphism in immune response genes as a function of puberty 
BMC Immunology  2006;7:2.
Background
Autoimmune diseases are more prevalent in females than in males, whereas males have higher mortality associated with infectious diseases. To increase our understanding of this sexual dimorphism in the immune system, we sought to identify and characterize inherent differences in immune response programs in the spleens of male and female mice before, during and after puberty.
Results
After the onset of puberty, female mice showed a higher expression of adaptive immune response genes, while males had a higher expression of innate immune genes. This result suggested a requirement for sex hormones. Using in vivo and in vitro assays in normal and mutant mouse strains, we found that reverse signaling through FasL was directly influenced by estrogen, with downstream consequences of increased CD8+ T cell-derived B cell help (via cytokines) and enhanced immunoglobulin production.
Conclusion
These results demonstrate that sexual dimorphism in innate and adaptive immune genes is dependent on puberty. This study also revealed that estrogen influences immunoglobulin levels in post-pubertal female mice via the Fas-FasL pathway.
doi:10.1186/1471-2172-7-2
PMCID: PMC1402325  PMID: 16504066

Results 1-8 (8)