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Papers by Deborah McCurdy

Research paper thumbnail of Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Proceedings of the National Academy of Sciences of the United States of America, Jan 10, 2012

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating... more Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 wi...

Research paper thumbnail of Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

Proceedings of the National Academy of Sciences, 2009

Research paper thumbnail of Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Proceedings of the National Academy of Sciences, 2007

Research paper thumbnail of THE PRESENCE OF IgA-RHEUMATOID FACTOR IN ACTIVE JUVENILE RHEUMATOID ARTHRITIS

Research paper thumbnail of MAGE Xp-2: A Member of the MAGE Gene Family Isolated from an Expression Library Using Systemic Lupus Erythematosus Sera

Molecular Genetics and Metabolism, 1998

Two regions of the genome contain members of cell line. Subsequently, MAGE-1 was found to be the ... more Two regions of the genome contain members of cell line. Subsequently, MAGE-1 was found to be the MAGE gene family; Xq27-qter and Xp21.3. We expressed in tumors of various histological types isolated a transcript, MAGE Xp-2, by screening a such as melanomas and lung and breast carcinomas cDNA library from the human epithelial carcinoma (2,3). cell line, HEp-2, using autoantibodies from patients In melanoma cell lines, the MAGE-1 gene product with systemic lupus erythematosus (SLE). The open reading frame (ORF) of MAGE Xp-2 is entirely con-is recognized by CTLs in combination with HLA tained in exon 4, a signature feature of the MAGE Class I surface antigens (4). The target for the CTL gene family. While MAGE Xp-2 shares genomic horecognition is a nonapeptide presented by HLA-A1 mology with MAGE Xp-1, the predicted proteins are combining to form the antigen, MZ2-E. By probing quite divergent. Specific primers were designed to cosmid libraries with MAGE-1 sequence, 11 closely reliably distinguish between MAGE Xp-1 and MAGE related genes were subsequently identified, reveal-Xp-2 expression. MAGE Xp-2 is expressed in testis, ing that MAGE-1 belongs to a multigene family. Anbut not in other normal tissues. It is also expressed alyzing DNA from hamster-human somatic cell hystrongly in two of seven melanoma cell lines and brids localized the 12 MAGE genes to the terminal one of four breast carcinomas. MAGE gene expresregion of the long arm of chromosome X (Xq27-qter) sion may be important not only for tumor recogni-(5). The other MAGE gene products (MAGE 2-12), tion and cancer therapy, but, because it is the apparent target of autoantibodies in SLE sera, it may also although structurally similar to MAGE-1, do not play a role in autoimmune diseases. ᭧ 1998 Academic contain the nonapeptide and are not recognized by Press CTLs with specificity for MZ2-E.

Research paper thumbnail of MAGE-B2 Autoantibody: A New Biomarker for Pediatric Systemic Lupus Erythematosus

The Journal of Rheumatology, 2008

ObjectiveMelanoma-associated antigen gene B2 (MAGE-B2) encodes an embryonic antigen normally sile... more ObjectiveMelanoma-associated antigen gene B2 (MAGE-B2) encodes an embryonic antigen normally silenced after birth except in testis and placenta. We identified the MAGE-B2 gene and autoantibodies in pediatric patients with systemic lupus erythematosus (SLE) glomerulonephritis. We investigated the prevalence of MAGE-B2 autoantibodies in association with active SLE, to determine a pathogenetic role of MAGE-B2 protein through its distribution in cells and tissues.MethodsAcross-sectional study analyzed the frequency of MAGE-B2 autoantibodies in 40 patients with pediatric SLE, 23 adult controls, and 16 patients with pediatric juvenile rheumatoid arthritis (JRA) using Western blots containing recombinant MAGE-B2. SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG) index measured SLE disease activity. Tissue distribution of MAGE-B2 protein was assessed by immunohistochemistry, immunofluorescence, and Western blots.ResultsSeventeen (43%) of 40 pediatr...

Research paper thumbnail of Identification of new SLE-associated genes with a two-step Bayesian study design

Genes and Immunity, 2009

In our previous study, we utilized a Bayesian design to probe the association of ~1,000 genes (~1... more In our previous study, we utilized a Bayesian design to probe the association of ~1,000 genes (~10,000 SNPs) with SLE on a moderate number of trios of parents and children with SLE. Two genes associated with SLE with a multitest corrected False Discovery Rate (FDR) of <0.05. were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In the present report, using a large population of controls and adultor-childhood onset SLE cases, we have extended the previous investigation to explore the SLE association of ten of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit significant (FDR < 0.05) association with SLE, both confirming some genes that have previously been found to be associated with SLE (PTPN22 and IRF5) and novel findings of genes (KLRG1, IL-16, PTPRT, TLR8 and CASP10) which have not been previously reported. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Research paper thumbnail of Osteopontin Polymorphisms in Juvenile Idiopathic Arthritis and Pediatric Systemic Lupus Erythematosus

Clinical Immunology, 2010

Background: The concept of polarization describes macrophage heterogeneity under specific microen... more Background: The concept of polarization describes macrophage heterogeneity under specific microenvironmental

Research paper thumbnail of F.80. Polymorphism in IL-1 Alpha (-889 C to T Substitution) in Patients with JRA and SLE Fails to Show An Association with Clinical Presentation

Clinical Immunology, 2006

Research paper thumbnail of Etanercept associated optic neuropathy

Clinical & Experimental Ophthalmology, 2007

We report the case of a 14-year-old boy who developed optic neuropathy subsequent to the use of e... more We report the case of a 14-year-old boy who developed optic neuropathy subsequent to the use of etanercept. There have been 15 reported cases of anti-TNF-alpha-associated optic neuropathy to date and their characteristics are reviewed in this report, as well as possible pathophysiologic mechanisms behind such phenomenon. Such cases demonstrate the importance of prompt ophthalmologic evaluation of visual changes in patients being treated with anti-TNF-alpha antagonists.

Research paper thumbnail of Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus

Arthritis Care & Research, 2012

Objective-To formulate consensus treatment plans (CTPs) for induction therapy of newlydiagnosed p... more Objective-To formulate consensus treatment plans (CTPs) for induction therapy of newlydiagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).

Research paper thumbnail of Defective DNA double-strand break repair in pediatric systemic lupus erythematosus

Arthritis & Rheumatism, 2012

Objective. Previous reports of cells from patients with systemic lupus erythematosus (SLE) note t... more Objective. Previous reports of cells from patients with systemic lupus erythematosus (SLE) note that repair of single-strand breaks is delayed, and these lesions may be converted to double-strand breaks (DSBs) at DNA replication forks. We undertook this study to assess the integrity of DSB recognition, signaling, and repair mechanisms in B lymphoblastoid cell lines derived from patients with pediatric SLE. Methods. Nine assays were used to interrogate DSB repair and recognition in lymphoblastoid cell lines from patients with pediatric SLE, including the neutral comet assay (NCA), colony survival assay (CSA), irradiation-induced foci formation for ␥-H2AX and 53BP1 proteins, kinetics of phosphorylation of structural maintenance of chromosomes protein 1 (SMC1), postirradiation bromodeoxyuridine incorporation to evaluate S phase checkpoint integrity, monoubiquitination of Fanconi protein D2, ATM protein expression, and non-homologous DNA end joining protein expression and function. Results. Three of the 9 assays revealed abnormal patterns of response to irradiation-induced DNA damage. The NCA and CSA yielded aberrant results in the majority of SLE lymphoblastoid cell lines. Abnormal prolongation of SMC1 phosphorylation was also noted in 2 of 16 SLE lymphoblastoid cell lines. Conclusion. Our data suggest that DSB repair is defective in some lymphoblastoid cell lines from pediatric patients with SLE, especially when assessed by both NCA and CSA. Since these studies are nonspecific, further studies of DNA repair and kinetics are indicated to further delineate the underlying pathogenesis of SLE and possibly identify therapeutic targets.

Research paper thumbnail of Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform

Arthritis & Rheumatism, 2007

Objective. Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patie... more Objective. Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. Methods. Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. Results. Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P ‫؍‬ 5.74 ؋ 10 ؊6) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P ‫؍‬ 9.58 ؋ 10 ؊6). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. Conclusion. SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.

Research paper thumbnail of High prevalence of iga rheumatoid factor in severe polyarticular-onset juvenile rheumatoid arthritis, but not in systemic-onset or pauciarticular-onset disease

Arthritis & Rheumatism, 1990

The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in a... more The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in adult rheumatoid arthritis (RA), but IgA-RF has not been reported in juvenile rheumatoid arthritis (JRA). In the present study, IgA-RF was assayed by an enzyme-linked immunosorbent assay and was found in the sera of 14 of 24 children (58%) with active polyarticular JRA. The presence of IgA-RF correlated with the degree of functional disability. In contrast, IgA-RF was not found in the sera of systemic-onset disease patients, regardless of the degree of dysfunction. IgA-RF was detected in only 1 patient with pauciarticular disease, despite the fact that several patients in this group had severe disease. The presence of IgA-RF in polyarticular JRA did not correlate with serum IgA levels, but did correlate with the presence and the level of serum IgM-RF. Thus, the presence of IgA-RF appears to be specific for polyarticular JRA, and shows a correlation with severe disease in this group.

Research paper thumbnail of Premature atherosclerosis in pediatric systemic lupus erythematosus: Risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort

Arthritis & Rheumatism, 2009

Objective-To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population.... more Objective-To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population. Methods-A prospective multicenter cohort of 221 patients underwent baseline measurements of carotid intima medial thickening (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess thickness of the bilateral common carotids and mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT that were examined in multivariable linear regression modeling. Results-Based on mean-mean common or mean-max CIMT as the dependent variable, univariable analysis showed significant associations with increased CIMT: increasing age, longer SLE duration, minority status, higher BMI, male sex, increased creatinine clearance, higher Lp(a), proteinuria, azathioprine use, and prednisone dose. Azathioprine use (P=0.005 for mean-mean common; P=0.102 for mean-max model) and male sex (P< 0.001) were both associated with increases in mean-max CIMT. Moderate dose prednisone (0.15-0.4 mg/kg/day) was associated with decreases in mean-max CIMT (P=0.024) while high or low dose prednisone was associated with mean-mean common CIMT (P=0.021) or mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031), remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing Lp(a) (P=0.005) were associated with increased mean-max CIMT. Conclusion-Traditional as well as non-traditional risk factors are associated with increased CIMT in pediatric SLE patients in this cohort. Azathioprine treatment was associated with increased CIMT. The relationship of CIMT with prednisone dose may not be linear. Over the last 3 decades, lupus-related mortality has decreased in all categories except cardiovascular disease (1). The lack of improvement in cardiovascular morbidity and

Research paper thumbnail of A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis

Arthritis & Rheumatism, 2007

Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind stu... more Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo ClinicalTrials.gov identifier: NCT00036374.

Research paper thumbnail of Coronary arthritis in mice following the systemic injection of group bLactobacillus casei cell walls in aqueous suspension

Arthritis & Rheumatism, 1985

We describe the induction of an asymmetric, focal, inflammatory coronary arteritis by a single in... more We describe the induction of an asymmetric, focal, inflammatory coronary arteritis by a single intraperitoneal injection of group B Lactobacillus casei cell wall fragments in various inbred mouse strains. This coronary arteritis resembles the arteritis which is responsible for the 1-2% fatality rate among children with mucocutaneous lymph node syndrome. Coronary arteritis developed in 18 of 26 C57BL/6, 14 of 26 AIJ, 7 of 15 Balbk, and 8 of 15 C3HeblFeJ mice injected. It also developed in 2 of 4 "nude" AIJ background mice and 3 of 4 "nude" C57BL/6 mice, but in 0 of 15 C3WHeJ mice. Lesions were evident as early as 3 days following injection. The development of arteritis was accompanied by disruption of the arterial intima and media with true aneurysm formation. Measurement of serial IgG and

Research paper thumbnail of Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice

Arthritis & Rheumatism, 2009

Objective-To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an impor... more Objective-To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an important autoantigen that drives the production of certain IgG-anticardiolipin (aCL) antibodies in patients with the antiphospholipid syndrome. Methods-BALB/cJ and MRL/MpJ mice were immunized with Freund's complete adjuvant in the presence or absence of human plasmin. The mouse sera were analyzed for production of IgGantiplasmin, IgG-aCL, and IgG-anti-β 2-glycoprotein I (anti-β 2 GPI) antibodies. IgG monoclonal antibodies (mAb) were generated from the plasmin-immunized MRL/MpJ mice with high titers of aCL, and these 10 mAb were studied for their binding properties and functional activity in vitro. Results-Plasmin-immunized BALB/cJ mice produced high titers of IgG-antiplasmin only, while plasmin-immunized MRL/MpJ mice produced high titers of IgG-antiplasmin, IgG-aCL, and IgGanti-β 2 GPI. Both strains of mice immunized with the adjuvant alone did not develop IgG-antiplasmin or IgG-aCL. All 10 of the IgG mAb bound to human plasmin and cardiolipin, while 4 of 10 bound to β 2 GPI, 3 of 10 bound to thrombin, and 4 of 10 bound to the activated coagulation factor X (FXa). Functionally, 4 of the 10 IgG mAb inhibited plasmin activity, 1 of 10 hindered inactivation of thrombin by antithrombin III (AT), and 2 of 10 inhibited inactivation of FXa by AT. Conclusion-Plasmin immunization leads to production of the IgG mAb antiplasmin, aCL, and anti-β 2 GPI in MRL/MpJ mice, but leads to production of only IgG-antiplasmin in BALB/cJ mice. IgG mAb generated from the plasmin-immunized MRL/MpJ mice bind to various antigens and exhibit procoagulant activity in vitro. These results suggest that plasmin may drive the potentially prothrombotic activities of aCL in genetically susceptible individuals. The antiphospholipid syndrome (APS) is characterized by clinical manifestations of vascular thrombosis and pregnancy loss associated with the presence of persistently and significantly increased titers of antiphospholipid antibodies (aPL) (1-6). The antigenic specificities of aPL have been the subject of a number of studies, and these studies have shown that aPL represent a heterogeneous group of immunologically and functionally distinct antibodies that recognize

Research paper thumbnail of High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups

Arthritis & Rheumatism, 2009

Objective-Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with ... more Objective-Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.

Research paper thumbnail of Classification, presentation, and initial treatment of Wegener's granulomatosis in childhood

Arthritis & Rheumatism, 2009

Methods. Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis")... more Methods. Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.

Research paper thumbnail of Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Proceedings of the National Academy of Sciences of the United States of America, Jan 10, 2012

Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating... more Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 wi...

Research paper thumbnail of Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

Proceedings of the National Academy of Sciences, 2009

Research paper thumbnail of Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Proceedings of the National Academy of Sciences, 2007

Research paper thumbnail of THE PRESENCE OF IgA-RHEUMATOID FACTOR IN ACTIVE JUVENILE RHEUMATOID ARTHRITIS

Research paper thumbnail of MAGE Xp-2: A Member of the MAGE Gene Family Isolated from an Expression Library Using Systemic Lupus Erythematosus Sera

Molecular Genetics and Metabolism, 1998

Two regions of the genome contain members of cell line. Subsequently, MAGE-1 was found to be the ... more Two regions of the genome contain members of cell line. Subsequently, MAGE-1 was found to be the MAGE gene family; Xq27-qter and Xp21.3. We expressed in tumors of various histological types isolated a transcript, MAGE Xp-2, by screening a such as melanomas and lung and breast carcinomas cDNA library from the human epithelial carcinoma (2,3). cell line, HEp-2, using autoantibodies from patients In melanoma cell lines, the MAGE-1 gene product with systemic lupus erythematosus (SLE). The open reading frame (ORF) of MAGE Xp-2 is entirely con-is recognized by CTLs in combination with HLA tained in exon 4, a signature feature of the MAGE Class I surface antigens (4). The target for the CTL gene family. While MAGE Xp-2 shares genomic horecognition is a nonapeptide presented by HLA-A1 mology with MAGE Xp-1, the predicted proteins are combining to form the antigen, MZ2-E. By probing quite divergent. Specific primers were designed to cosmid libraries with MAGE-1 sequence, 11 closely reliably distinguish between MAGE Xp-1 and MAGE related genes were subsequently identified, reveal-Xp-2 expression. MAGE Xp-2 is expressed in testis, ing that MAGE-1 belongs to a multigene family. Anbut not in other normal tissues. It is also expressed alyzing DNA from hamster-human somatic cell hystrongly in two of seven melanoma cell lines and brids localized the 12 MAGE genes to the terminal one of four breast carcinomas. MAGE gene expresregion of the long arm of chromosome X (Xq27-qter) sion may be important not only for tumor recogni-(5). The other MAGE gene products (MAGE 2-12), tion and cancer therapy, but, because it is the apparent target of autoantibodies in SLE sera, it may also although structurally similar to MAGE-1, do not play a role in autoimmune diseases. ᭧ 1998 Academic contain the nonapeptide and are not recognized by Press CTLs with specificity for MZ2-E.

Research paper thumbnail of MAGE-B2 Autoantibody: A New Biomarker for Pediatric Systemic Lupus Erythematosus

The Journal of Rheumatology, 2008

ObjectiveMelanoma-associated antigen gene B2 (MAGE-B2) encodes an embryonic antigen normally sile... more ObjectiveMelanoma-associated antigen gene B2 (MAGE-B2) encodes an embryonic antigen normally silenced after birth except in testis and placenta. We identified the MAGE-B2 gene and autoantibodies in pediatric patients with systemic lupus erythematosus (SLE) glomerulonephritis. We investigated the prevalence of MAGE-B2 autoantibodies in association with active SLE, to determine a pathogenetic role of MAGE-B2 protein through its distribution in cells and tissues.MethodsAcross-sectional study analyzed the frequency of MAGE-B2 autoantibodies in 40 patients with pediatric SLE, 23 adult controls, and 16 patients with pediatric juvenile rheumatoid arthritis (JRA) using Western blots containing recombinant MAGE-B2. SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG) index measured SLE disease activity. Tissue distribution of MAGE-B2 protein was assessed by immunohistochemistry, immunofluorescence, and Western blots.ResultsSeventeen (43%) of 40 pediatr...

Research paper thumbnail of Identification of new SLE-associated genes with a two-step Bayesian study design

Genes and Immunity, 2009

In our previous study, we utilized a Bayesian design to probe the association of ~1,000 genes (~1... more In our previous study, we utilized a Bayesian design to probe the association of ~1,000 genes (~10,000 SNPs) with SLE on a moderate number of trios of parents and children with SLE. Two genes associated with SLE with a multitest corrected False Discovery Rate (FDR) of <0.05. were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In the present report, using a large population of controls and adultor-childhood onset SLE cases, we have extended the previous investigation to explore the SLE association of ten of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit significant (FDR < 0.05) association with SLE, both confirming some genes that have previously been found to be associated with SLE (PTPN22 and IRF5) and novel findings of genes (KLRG1, IL-16, PTPRT, TLR8 and CASP10) which have not been previously reported. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Research paper thumbnail of Osteopontin Polymorphisms in Juvenile Idiopathic Arthritis and Pediatric Systemic Lupus Erythematosus

Clinical Immunology, 2010

Background: The concept of polarization describes macrophage heterogeneity under specific microen... more Background: The concept of polarization describes macrophage heterogeneity under specific microenvironmental

Research paper thumbnail of F.80. Polymorphism in IL-1 Alpha (-889 C to T Substitution) in Patients with JRA and SLE Fails to Show An Association with Clinical Presentation

Clinical Immunology, 2006

Research paper thumbnail of Etanercept associated optic neuropathy

Clinical & Experimental Ophthalmology, 2007

We report the case of a 14-year-old boy who developed optic neuropathy subsequent to the use of e... more We report the case of a 14-year-old boy who developed optic neuropathy subsequent to the use of etanercept. There have been 15 reported cases of anti-TNF-alpha-associated optic neuropathy to date and their characteristics are reviewed in this report, as well as possible pathophysiologic mechanisms behind such phenomenon. Such cases demonstrate the importance of prompt ophthalmologic evaluation of visual changes in patients being treated with anti-TNF-alpha antagonists.

Research paper thumbnail of Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus

Arthritis Care & Research, 2012

Objective-To formulate consensus treatment plans (CTPs) for induction therapy of newlydiagnosed p... more Objective-To formulate consensus treatment plans (CTPs) for induction therapy of newlydiagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).

Research paper thumbnail of Defective DNA double-strand break repair in pediatric systemic lupus erythematosus

Arthritis & Rheumatism, 2012

Objective. Previous reports of cells from patients with systemic lupus erythematosus (SLE) note t... more Objective. Previous reports of cells from patients with systemic lupus erythematosus (SLE) note that repair of single-strand breaks is delayed, and these lesions may be converted to double-strand breaks (DSBs) at DNA replication forks. We undertook this study to assess the integrity of DSB recognition, signaling, and repair mechanisms in B lymphoblastoid cell lines derived from patients with pediatric SLE. Methods. Nine assays were used to interrogate DSB repair and recognition in lymphoblastoid cell lines from patients with pediatric SLE, including the neutral comet assay (NCA), colony survival assay (CSA), irradiation-induced foci formation for ␥-H2AX and 53BP1 proteins, kinetics of phosphorylation of structural maintenance of chromosomes protein 1 (SMC1), postirradiation bromodeoxyuridine incorporation to evaluate S phase checkpoint integrity, monoubiquitination of Fanconi protein D2, ATM protein expression, and non-homologous DNA end joining protein expression and function. Results. Three of the 9 assays revealed abnormal patterns of response to irradiation-induced DNA damage. The NCA and CSA yielded aberrant results in the majority of SLE lymphoblastoid cell lines. Abnormal prolongation of SMC1 phosphorylation was also noted in 2 of 16 SLE lymphoblastoid cell lines. Conclusion. Our data suggest that DSB repair is defective in some lymphoblastoid cell lines from pediatric patients with SLE, especially when assessed by both NCA and CSA. Since these studies are nonspecific, further studies of DNA repair and kinetics are indicated to further delineate the underlying pathogenesis of SLE and possibly identify therapeutic targets.

Research paper thumbnail of Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform

Arthritis & Rheumatism, 2007

Objective. Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patie... more Objective. Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. Methods. Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. Results. Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P ‫؍‬ 5.74 ؋ 10 ؊6) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P ‫؍‬ 9.58 ؋ 10 ؊6). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. Conclusion. SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.

Research paper thumbnail of High prevalence of iga rheumatoid factor in severe polyarticular-onset juvenile rheumatoid arthritis, but not in systemic-onset or pauciarticular-onset disease

Arthritis & Rheumatism, 1990

The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in a... more The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in adult rheumatoid arthritis (RA), but IgA-RF has not been reported in juvenile rheumatoid arthritis (JRA). In the present study, IgA-RF was assayed by an enzyme-linked immunosorbent assay and was found in the sera of 14 of 24 children (58%) with active polyarticular JRA. The presence of IgA-RF correlated with the degree of functional disability. In contrast, IgA-RF was not found in the sera of systemic-onset disease patients, regardless of the degree of dysfunction. IgA-RF was detected in only 1 patient with pauciarticular disease, despite the fact that several patients in this group had severe disease. The presence of IgA-RF in polyarticular JRA did not correlate with serum IgA levels, but did correlate with the presence and the level of serum IgM-RF. Thus, the presence of IgA-RF appears to be specific for polyarticular JRA, and shows a correlation with severe disease in this group.

Research paper thumbnail of Premature atherosclerosis in pediatric systemic lupus erythematosus: Risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort

Arthritis & Rheumatism, 2009

Objective-To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population.... more Objective-To evaluate risk factors of sub-clinical atherosclerosis in a pediatric SLE population. Methods-A prospective multicenter cohort of 221 patients underwent baseline measurements of carotid intima medial thickening (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess thickness of the bilateral common carotids and mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT that were examined in multivariable linear regression modeling. Results-Based on mean-mean common or mean-max CIMT as the dependent variable, univariable analysis showed significant associations with increased CIMT: increasing age, longer SLE duration, minority status, higher BMI, male sex, increased creatinine clearance, higher Lp(a), proteinuria, azathioprine use, and prednisone dose. Azathioprine use (P=0.005 for mean-mean common; P=0.102 for mean-max model) and male sex (P< 0.001) were both associated with increases in mean-max CIMT. Moderate dose prednisone (0.15-0.4 mg/kg/day) was associated with decreases in mean-max CIMT (P=0.024) while high or low dose prednisone was associated with mean-mean common CIMT (P=0.021) or mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031), remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing Lp(a) (P=0.005) were associated with increased mean-max CIMT. Conclusion-Traditional as well as non-traditional risk factors are associated with increased CIMT in pediatric SLE patients in this cohort. Azathioprine treatment was associated with increased CIMT. The relationship of CIMT with prednisone dose may not be linear. Over the last 3 decades, lupus-related mortality has decreased in all categories except cardiovascular disease (1). The lack of improvement in cardiovascular morbidity and

Research paper thumbnail of A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis

Arthritis & Rheumatism, 2007

Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind stu... more Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo ClinicalTrials.gov identifier: NCT00036374.

Research paper thumbnail of Coronary arthritis in mice following the systemic injection of group bLactobacillus casei cell walls in aqueous suspension

Arthritis & Rheumatism, 1985

We describe the induction of an asymmetric, focal, inflammatory coronary arteritis by a single in... more We describe the induction of an asymmetric, focal, inflammatory coronary arteritis by a single intraperitoneal injection of group B Lactobacillus casei cell wall fragments in various inbred mouse strains. This coronary arteritis resembles the arteritis which is responsible for the 1-2% fatality rate among children with mucocutaneous lymph node syndrome. Coronary arteritis developed in 18 of 26 C57BL/6, 14 of 26 AIJ, 7 of 15 Balbk, and 8 of 15 C3HeblFeJ mice injected. It also developed in 2 of 4 "nude" AIJ background mice and 3 of 4 "nude" C57BL/6 mice, but in 0 of 15 C3WHeJ mice. Lesions were evident as early as 3 days following injection. The development of arteritis was accompanied by disruption of the arterial intima and media with true aneurysm formation. Measurement of serial IgG and

Research paper thumbnail of Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice

Arthritis & Rheumatism, 2009

Objective-To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an impor... more Objective-To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an important autoantigen that drives the production of certain IgG-anticardiolipin (aCL) antibodies in patients with the antiphospholipid syndrome. Methods-BALB/cJ and MRL/MpJ mice were immunized with Freund's complete adjuvant in the presence or absence of human plasmin. The mouse sera were analyzed for production of IgGantiplasmin, IgG-aCL, and IgG-anti-β 2-glycoprotein I (anti-β 2 GPI) antibodies. IgG monoclonal antibodies (mAb) were generated from the plasmin-immunized MRL/MpJ mice with high titers of aCL, and these 10 mAb were studied for their binding properties and functional activity in vitro. Results-Plasmin-immunized BALB/cJ mice produced high titers of IgG-antiplasmin only, while plasmin-immunized MRL/MpJ mice produced high titers of IgG-antiplasmin, IgG-aCL, and IgGanti-β 2 GPI. Both strains of mice immunized with the adjuvant alone did not develop IgG-antiplasmin or IgG-aCL. All 10 of the IgG mAb bound to human plasmin and cardiolipin, while 4 of 10 bound to β 2 GPI, 3 of 10 bound to thrombin, and 4 of 10 bound to the activated coagulation factor X (FXa). Functionally, 4 of the 10 IgG mAb inhibited plasmin activity, 1 of 10 hindered inactivation of thrombin by antithrombin III (AT), and 2 of 10 inhibited inactivation of FXa by AT. Conclusion-Plasmin immunization leads to production of the IgG mAb antiplasmin, aCL, and anti-β 2 GPI in MRL/MpJ mice, but leads to production of only IgG-antiplasmin in BALB/cJ mice. IgG mAb generated from the plasmin-immunized MRL/MpJ mice bind to various antigens and exhibit procoagulant activity in vitro. These results suggest that plasmin may drive the potentially prothrombotic activities of aCL in genetically susceptible individuals. The antiphospholipid syndrome (APS) is characterized by clinical manifestations of vascular thrombosis and pregnancy loss associated with the presence of persistently and significantly increased titers of antiphospholipid antibodies (aPL) (1-6). The antigenic specificities of aPL have been the subject of a number of studies, and these studies have shown that aPL represent a heterogeneous group of immunologically and functionally distinct antibodies that recognize

Research paper thumbnail of High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups

Arthritis & Rheumatism, 2009

Objective-Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with ... more Objective-Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.

Research paper thumbnail of Classification, presentation, and initial treatment of Wegener's granulomatosis in childhood

Arthritis & Rheumatism, 2009

Methods. Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis")... more Methods. Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.