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Frank C Arnett

Publications and source records attributed to Frank C Arnett.

At least 19 recordsLinked to original sources
PubMed2006

Induction of apoptosis and fibrillin 1 expression in human dermal endothelial cells by scleroderma sera containing anti-endothelial cell antibodies.

OBJECTIVE: Sera from patients with scleroderma (systemic sclerosis [SSc]) contain anti-endothelial cell antibodies (AECAs) capable of inducing endothelial cell apoptosis. We sought to determine whether SSc sera containing anticentromere antibodies (ACAs) or anti-topoisomerase I antibodies (or, anti-Scl-70 antibodies) contain subsets of AECAs that trigger distinct pathways of apoptosis and gene expression in normal adult human dermal endothelial cells (HDECs). METHODS: Adult HDECs were grown to subconfluence and treated with control or SSc patient sera. Apoptosis was investigated by differential interference contrast (DIC) microscopy, microarrays of proapoptotic gene expression, caspase 3 protease activity, and flow cytometry for phosphatidyl serine translocation. RESULTS: Flow cytometry and DIC microscopy demonstrated that HDECs exposed to SSc sera containing either SSc autoantibody underwent apoptosis at much higher levels than those treated with control sera. While unique gene expression profiles were induced in HDECs by stimulation with SSc sera containing the respective autoantibody, similar patterns of increased gene expression of transcripts for the proapoptotic protease caspase 3 as well as the SSc autoantigen fibrillin 1 were demonstrated. Caspase 3 gene expression correlated with increased protease activity, and targeted inhibition of this protease partly blocked SSc serum-induced apoptosis. Immunohistochemistry studies of serum-stimulated HDECs demonstrated the aberrant expression of fibrillin 1 protein only in apoptotic endothelial cells treated with SSc sera containing AECAs. CONCLUSION: There are distinct AECA subsets in the sera of patients with limited SSc (with ACAs) and diffuse SSc (with anti-Scl-70) that induce unique patterns of HDEC gene expression in the setting of apoptosis associated with increased caspase 3 activity and the reexpression of endothelial cell fibrillin 1.

Adult↗
PubMed2006

Attenuation of collagen production with small interfering RNA of SPARC in cultured fibroblasts from the skin of patients with scleroderma.

OBJECTIVE: Recently, it was observed that SPARC (secreted protein, acidic and rich in cysteine) is overexpressed in the fibroblasts of skin biopsy specimens obtained from patients with systemic sclerosis (SSc; scleroderma), and that specific inhibition of SPARC expression in normal human fibroblasts attenuated the profibrotic effect of transforming growth factor beta (TGFbeta). The purpose of this study was to examine whether inhibition of SPARC with small interfering RNA (siRNA) can be used to ameliorate the overproduction of major extracellular matrix components in SSc fibroblasts. METHODS: Fibroblasts obtained from biopsy specimens of the unaffected skin of 3 patients with diffuse SSc and 3 age- and sex-matched healthy controls were cultured and transfected with SPARC siRNA. Before and after transfection, real-time quantitative reverse transcription-polymerase chain reaction, immunostaining, and Western blotting were used to examine the transcription and/or protein levels of SPARC, connective tissue growth factor (CTGF), type I collagen, type II collagen, TGFbeta receptor 1 (TGFbetaR1), and Smad3. Student's paired t-tests were used to determine the significance of the results. RESULTS: SSc fibroblasts showed overexpression of SPARC, COL1A2, COL3A1, and CTGF, which is consistent with an activated fibroblast phenotype. Upon inhibition of SPARC with siRNA, these activated SSc fibroblasts showed decreased gene expression of COL1A2, COL3A1, and CTGF (43%, 54%, and 58%, respectively). In addition, the overproduction of type I collagen protein in SSc fibroblasts was inhibited and was shown to parallel levels of SPARC expression. In contrast, the expression of TGFBR1 and Smad3 did not change significantly nor was the level of phosphorylation of Smad3 reduced upon SPARC siRNA silencing in unstimulated cultured SSc fibroblasts. CONCLUSION: Overproduction of collagens in SSc skin fibroblasts can be attenuated through SPARC silencing. This inhibition may be associated either with direct interaction between SPARC and collagens or with inhibition of CTGF, which is a downstream effector of TGFbeta signaling. However, SPARC silencing in SSc fibroblasts appears not to be associated with TGFBR1- and Smad3-dependent processes. Application of SPARC silencing represents a potential therapeutic approach to SSc.

Activin Receptors, Type I↗
PubMed2006

Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma.

OBJECTIVE: To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc). METHODS: Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups. RESULTS: The frequency of the -173*C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173*C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype. CONCLUSION: Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc.

Female↗
PubMed2006

Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis.

OBJECTIVE: To determine any associations of the PTPN22 R620W single-nucleotide polymorphism (SNP) with systemic sclerosis (SSc) or with anticentromere antibody (ACA)-positive or anti-topoisomerase I (anti-topo I) antibody-positive SSc, in a case-control study of US white, black, Hispanic, and Choctaw Indian individuals. METHODS: A total of 850 white, 130 black, 120 Hispanic, and 20 Choctaw Indian patients with SSc were compared with 430 white, 164 black, 146 Hispanic, and 76 Choctaw Indian control subjects, respectively. All subjects were living in the US. PTPN22 SNP (rs2476601) genotyping was performed by TaqMan 5' allelic discrimination assay and pyrosequencing. RESULTS: The PTPN22 CT/TT genotype showed significant association with anti-topo I antibody-positive SSc in white patients (odds ratio [OR] 2.21, 95% confidence interval [95% CI] 1.3-3.7) and with ACA-positive white patients with SSc (OR 1.70, 95% CI 1.1-2.7). Frequency of the PTPN22*T allele also showed significant association with anti-topo I antibody-positive SSc in white patients (OR 2.03, 95% CI 1.3-3.2). When data for patients in the 3 ethnic groups (black, white, and Hispanic) were combined, a significant association with both genotype and allele frequencies was observed, suggesting a trend toward association in ACA-positive and anti-topo I antibody-positive SSc. Stepwise logistic regression analysis (controlled for the confounding effects of sex and race) showed that the PTPN22 CT/TT genotype was associated with a significantly higher risk of SSc compared with the CC genotype (for patients with SSc, OR 1.64, 95% CI 1.2-2.2; for ACA-positive patients with SSc, OR 1.63, 95% CI 1.0-2.6; for anti-topo I antibody-positive SSc, OR 2.33, 95% CI 1.5-3.7). CONCLUSION: Our results indicate that the PTPN22 R620W polymorphism is associated with ACA-positive and anti-topo I antibody-positive subsets of SSc and represents a risk factor in both white patients and black patients. The association of subsets of SSc with the PTPN22 R620W polymorphism further strengthens the classification of SSc within the spectrum of autoimmune diseases and strongly suggests the involvement of common susceptibility genes and similarly disordered immunoregulatory pathways.

Autoantibodies↗
PubMed2006

HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies.

OBJECTIVE: To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. METHODS: Molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). RESULTS: In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti-Jo-1 autoantibodies shared the risk factor HLA-DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American-, anti-Mi-2-associated risk factor DRB1*0701 were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. CONCLUSION: These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene-environment interactions.

Adenosine Triphosphatases↗
PubMed2006

A mariner with crippling arthritis and bleeding eyes.

A 41-year-old mariner developed acute arthritis affecting his legs more than his arms or hands during a violent storm on his return from the first of four voyages of discovery. He experienced repeated attacks of the arthritis over the ensuing 14 years, which on at least two occasions were accompanied by painful eyes "much affected with bleeding." He died shortly before his 55 birthday "quite paralyzed and bedridden." Who was he, and what was the likely etiology of his disorder?

Arthritis, Reactive↗
PubMed2006

Is scleroderma an autoantibody mediated disease?

PURPOSE OF REVIEW: Research into the pathogenesis of systemic sclerosis and other fibrotic conditions is becoming increasingly broad and sophisticated. In the past year, several provocative studies have presented evidence that autoantibodies may actually cause the vascular damage and fibrosis characteristic of systemic sclerosis. These autoantibodies include antiendothelial cell, antifibrillin-1, anti-matrix metalloproteinases 1 and 3, and antiplatelelet-derived growth factor beta, each having its own unique mechanism. Such reports provide novel avenues to pursue in understanding this enigmatic disease.

Autoantibodies↗
PubMed2006

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1, and -DQA1 allelic profiles distinguish European American patients with different myositis autoantibodies.

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases defined by chronic muscle inflammation and weakness associated with autoimmunity. We have performed low to high resolution molecular typing to assess the genetic variability of major histocompatibility complex loci (HLA-A, -B, -Cw, -DRB1, and -DQA1) in a large population of European American patients with IIM (n = 571) representing the major myositis autoantibody groups. We established that alleles of the 8.1 ancestral haplotype (8.1 AH) are important risk factors for the development of IIM in patients producing anti-synthetase/anti-Jo-1, -La, -PM/Scl, and -Ro autoantibodies. Moreover, a random forests classification analysis suggested that 8.1 AH-associated alleles B*0801 and DRB1*0301 are the principal HLA risk markers. In addition, we have identified several novel HLA susceptibility factors associated distinctively with particular myositis-specific (MSA) and myositis-associated autoantibody (MAA) groups of the IIM. IIM patients with anti-PL-7 (anti-threonyl-tRNA synthetase) autoantibodies have a unique HLA Class I risk allele, Cw*0304 (pcorr = 0.046), and lack the 8.1 AH markers associated with other anti-synthetase autoantibodies (for example, anti-Jo-1 and anti-PL-12). In addition, HLA-B*5001 and DQA1*0104 are novel potential risk factors among anti-signal recognition particle autoantibody-positive IIM patients (pcorr = 0.024 and p = 0.010, respectively). Among those patients with MAA, HLA DRB1*11 and DQA1*06 alleles were identified as risk factors for myositis patients with anti-Ku (pcorr = 0.041) and anti-La (pcorr = 0.023) autoantibodies, respectively. Amino acid sequence analysis of the HLA DRB1 third hypervariable region identified a consensus motif, 70D (hydrophilic)/71R (basic)/74A (hydrophobic), conferring protection among patients producing anti-synthetase/anti-Jo-1 and -PM/Scl autoantibodies. Together, these data demonstrate that HLA signatures, comprising both risk and protective alleles or motifs, distinguish IIM patients with different myositis autoantibodies and may have diagnostic and pathogenic implications. Variations in associated polymorphisms for these immune response genes may reflect divergent pathogenic mechanisms and/or responses to unique environmental triggers in different groups of subjects resulting in the heterogeneous syndromes of the IIM.

Alleles↗
PubMed2005

A systems biology approach to genetic studies of complex diseases.

Revealing mechanisms underlying complex diseases poses great challenges to biologists. The traditional linkage and linkage disequilibrium analysis that have been successful in the identification of genes responsible for Mendelian traits, however, have not led to similar success in discovering genes influencing the development of complex diseases. Emerging functional genomic and proteomic ('omic') resources and technologies provide great opportunities to develop new methods for systematic identification of genes underlying complex diseases. In this report, we propose a systems biology approach, which integrates omic data, to find genes responsible for complex diseases. This approach consists of five steps: (1) generate a set of candidate genes using gene-gene interaction data sets; (2) reconstruct a genetic network with the set of candidate genes from gene expression data; (3) identify differentially regulated genes between normal and abnormal samples in the network; (4) validate regulatory relationship between the genes in the network by perturbing the network using RNAi and monitoring the response using RT-PCR; and (5) genotype the differentially regulated genes and test their association with the diseases by direct association studies. To prove the concept in principle, the proposed approach is applied to genetic studies of the autoimmune disease scleroderma or systemic sclerosis.

Genomics↗
PubMed2005

Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the "scleroderma phenotype".

Fibroblasts from patients with systemic sclerosis (SSc) are activated producing excessive amounts of extracellular matrix (ECM) components. Recently, we identified a new SSc-specific autoantibody against portions of fibrillin-1, a major component of ECM microfibrils and regulator of TGF-beta1 signaling. To examine a potential pathogenic role of anti-fibrillin-1 autoantibodies, normal human fibroblasts were treated with affinity-purified autoantibodies isolated from SSc sera and then examined for alterations in gene and protein expression levels using microarrays, quantitative RT-PCR, immunoblots, and immunofluorescence. Compared with fibroblasts cultured in normal medium or in medium containing normal human IgG, anti-fibrillin-1 autoantibody-treated normal dermal fibroblasts showed increased expression of COL and several other ECM components characteristically overexpressed in SSc fibroblasts. This was accompanied by phosphorylation and nuclear translocation of Smad3. Neutralization of TGF-beta1 with anti-TGF-beta1 Abs significantly diminished the activation of fibroblasts by anti-fibrillin-1 autoantibodies. These data indicate that anti-fibrillin-1 autoantibodies can induce the activation of normal dermal fibroblasts into a profibrotic phenotype resembling that of SSc by potentially causing the release of sequestered TGF-beta1 from fibrillin-1-containing microfibrils in the ECM.

Active Transport, Cell Nucleus↗
PubMed2005

Small interfering RNA inhibition of SPARC attenuates the profibrotic effect of transforming growth factor beta1 in cultured normal human fibroblasts.

OBJECTIVE: SPARC (secreted protein, acidic and rich in cysteine), or osteonectin, is a matricellular protein. Recently, it was observed to be overexpressed in fibroblasts obtained from the skin of patients with scleroderma, as well as in different tissues from patients with several other fibrotic disorders. Moreover, a genetic polymorphism in SPARC has been associated with susceptibility to scleroderma. Transforming growth factor beta1 (TGFbeta1) is a profibrotic cytokine that stimulates excessive collagen production in patients with scleroderma or other fibrotic diseases. The purpose of this study was to examine whether specific inhibition of SPARC can influence the expression of type I collagen and ameliorate the profibrotic activity of TGFbeta1 on normal human fibroblasts. METHODS: Fibroblasts obtained from the skin of 4 healthy individuals were cultured and transfected with SPARC small interfering RNA (siRNA). TGFbeta was used as a fibrosis stimulus in cultured fibroblasts. Real-time quantitative reverse transcriptase-polymerase chain reaction and Western blotting were used to measure transcription and protein levels of SPARC and type I collagen, respectively. RESULTS: The fibroblasts transfected with SPARC siRNA showed decreased expression of both SPARC and type I collagen. Exogenous TGFbeta1 induced increased expression of both SPARC and type I collagen in cultured normal human fibroblasts, but this response was significantly blunted in the fibroblasts transfected with SPARC siRNA. CONCLUSION: TGFbeta1 can induce increased expression of both SPARC and type I collagen. Specific inhibition of SPARC led to decreased expression of type I collagen and attenuated the profibrotic effect of TGFbeta1 in cultured normal human fibroblasts. Use of siRNA to silence SPARC represents a potential therapeutic approach to fibrotic disorders such as scleroderma.

Cells, Cultured↗
PubMed2005

Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease.

OBJECTIVE: To compare the transcriptosome of early-passage nonlesional dermal fibroblasts from systemic sclerosis (SSc) patients with diffuse disease and matched normal controls in order to gain further understanding of the gene activation patterns that occur in early disease. METHODS: Total RNA was isolated from early-passage fibroblasts obtained from nonlesional skin biopsy specimens from 21 patients with diffuse SSc (disease duration <5 years in all but 1) and 18 healthy controls who were matched to the cases by age (+/-5 years), sex, and race. Array experiments were performed on a 16,659-oligonucleotide microarray utilizing a reference experimental design. Supervised methods were used to select differentially expressed genes. Quantitative polymerase chain reaction (PCR) was used to independently validate the array results. RESULTS: Of the 8,324 genes that passed filtering criteria, classification analysis revealed that <5% were differentially expressed between SSc and normal fibroblasts. Individually, differentially expressed genes included COL7A1, COL18A1 (endostatin), DAF, COMP, and VEGFB. Using the panel of genes discovered through classification analysis, a set of model predictors that achieved reasonably high predictive accuracy was developed. Analysis of 1,297 gene ontology (GO) classes revealed 35 classes that were significantly dysregulated in SSc fibroblasts. These GO classes included anchoring collagen (30934), extracellular matrix structural constituent (5201), and complement activation (6958, 6956). Validation by quantitative PCR demonstrated that 7 of 7 genes selected were concordant with the array results. CONCLUSION: Fibroblasts cultured from nonlesional skin of patients with SSc already have detectable abnormalities in a variety of genes and cellular processes, including those involved in extracellular matrix formation, fibrillogenesis, complement activation, and angiogenesis.

Dermis↗
PubMed2005

Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups.

OBJECTIVE: To assess possible seasonal patterns in the onset of polymyositis (PM) and dermatomyositis (DM). METHODS: The study group comprised 503 patients who met the criteria for probable or definite PM or DM and for whom detailed data on the time of myositis onset were available. Statistical analyses were performed using a Poisson model that assessed associations of ethnicity, sex, autoantibody presence, and month of onset of muscle weakness. RESULTS: There were no significant seasonal patterns of disease onset in myositis patients as a whole or in the total PM or DM populations. Significant seasonal associations were present, however, in the serologically defined groups. In the 131 patients with antisynthetase autoantibodies who were categorized as non-black, myositis onset peaked in March-April (P = 0.03). Among the antisynthetase-positive patients, the association was predominantly in those with PM (n = 85; P = 0.05) and in men (n = 51; P = 0.042). Patients with anti-signal recognition particle autoantibodies, however, did not have a significant seasonal onset, which is in contrast to previous findings. Patients without myositis-specific autoantibodies showed a significant peak in summer, with myositis onset in June-July (n = 252; P = 0.03); this seasonal association was significant in women (n = 182; P = 0.005), whereas there was no seasonal pattern in men (P = 0.9). CONCLUSION: These findings, in conjunction with other data, suggest that diverse environmental agents, acting upon different immunogenetic backgrounds, result in distinct immune responses and clinical syndromes in the idiopathic inflammatory myopathies. Our results emphasize the importance of considering more homogeneous disease groups, based on clinicopathologic features, immune responses, ethnicity, and sex, when attempting to decipher the pathogeneses of autoimmune disorders.

Autoantibodies↗
PubMed2005

Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles.

OBJECTIVE: Fewer than 5% of monozygotic (MZ) and dizygotic (DZ) twin pairs are clinically concordant for systemic sclerosis (SSc), yet the majority of MZ twins are concordant for antinuclear antibodies. To discover genetic versus nongenetic molecular pathways important to the pathogenesis of SSc, we compared global gene expression patterns in twins discordant for SSc. METHODS: Total RNA from dermal fibroblasts of 15 discordant twin pairs (10 MZ and 5 DZ) and 5 normal controls were used in microarray analysis. Aberrantly expressed genes were confirmed using quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Lesional and nonlesional fibroblasts from SSc patients showed no significant differences in gene expression, while SSc patients had gene profiles that were significantly different from those of unaffected DZ twins and normal controls. Unaffected MZ twins, however, were not significantly different from SSc patients. Unsupervised hierarchical clustering segregated the fibroblast samples as originating from 2 major groups. Group A contained 5 discordant MZ twin pairs, 3 affected MZ twins, and 3 affected DZ twins. Group B contained all 5 normal population controls, all 5 healthy DZ twins, 2 discordant MZ twins, and 2 discordant DZ twin pairs. Normal fibroblasts incubated with serum from an SSc-affected patient or with serum from her unaffected MZ twin sister developed the increased expression of COL1A2, SPARC, and CTGF typically seen in SSc fibroblasts. CONCLUSION: These results demonstrate that dermal fibroblasts from SSc patients and from 40-50% of their genetically identical but clinically unaffected MZ twins exhibit a similar gene expression pattern which can be induced in normal fibroblasts by sera from both. Thus, a stronger genetic predisposition to SSc (than can be detected clinically) is apparent at the molecular level in skin fibroblasts.

Adult↗
PubMed2005

Spondyloarthritis: update on pathogenesis and management.

A great deal of progress has occurred in the past few years in elucidating the causes and designing new treatments for ankylosing spondylitis and other types of spondyloarthritis. In addition to the human leukocyte antigen (HLA)-B27 and other major histocompatibility complex (MHC) genes, chromosomal regions and genes elsewhere in the genome are being implicated both in disease susceptibility and severity. The various ways HLA-B27 may function in causing spondyloarthritis now are better understood to encompass not only antigen presentation but also other mechanisms, possibly all being operative in pathogenesis (misfolding of the HLA-B27 molecule, impaired intracellular killing of bacteria, and HLA-B27 itself serving as an autoantigen). Specific enteric and sexually acquired infections can trigger reactive arthritis, though no specific microbe has been identified in other forms of spondyloarthritis. Intestinal inflammation with impairment of the gut:blood barrier may be operative in driving ankylosing spondylitis and enteropathic arthritis. A number of treatments have been tried in spondyloarthritis, including older agents such as methotrexate and sulfasalazine but also newer drugs such as pamindronate. The recent introduction of tumor necrosis factor (TNF) blockers in the treatment of spondyloarthritis has offered the most hope in not only relieving symptoms and signs of both peripheral arthritis and enthesitis but also spinal disease, which often has been refractory to other agents. Their high cost and considerable side effect profile, however, have necessitated the establishment of guidelines for their use in these diseases in order to target the patient in whom they are likely to have the most benefit.

Anti-Bacterial Agents↗
PubMed2005

Immunogenetic risk and protective factors for the idiopathic inflammatory myopathies: distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 allelic profiles and motifs define clinicopathologic groups in caucasians.

The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif (KLPLFHRL) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (pc < 0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (pc = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (pc = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif (AGSHTLQWM) conferred significant risk (pc = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.

Adult↗
PubMed2004

cDNA microarrays reveal distinct gene expression clusters in idiopathic inflammatory myopathies.

BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are complex human diseases of autoimmune origin which cause progressive skeletal muscle weakness in adults and children. Histopathological studies of affected muscles suggest that cytotoxic T cell-induced injury predominates in PM, while humoral immune mechanisms seem more likely in DM. Early expression of MHC class I molecules on myocytes is a striking feature of both disorders. This study was to use gene microarray analysis of muscle biopsies from PM and DM patients to obtain a comprehensive view of molecules participating in disease pathogenesis. MATERIAL/METHODS: Muscle biopsies from 10 patients (6 PM and 4 DM) and 5 controls were selected for gene expression profiles. Microarray filters containing 4000 known human genes were used to hybridize with RNAs from muscle biopsies. Real-time RT-PCR assays were used to confirmed selected genes that showed changes in expression levels in PM and DM from microarray data. The t-statistic was used to measure any differences in the amount of gene expression in the normal versus myositis biopsies. RESULTS: Forty genes clustering into two major groups showed significantly altered expression levels in PM/DM compared to normal biopsies. One cluster of over-expressed genes was primarily of immune origin and included HLA-class I and II, interferon-inducible proteins, natural killer (NK) protein, immunoglobulins and complement. The other cluster of under-expressed genes were of muscle origin, especially those involved in the fast twitch response. PM and DM gene profiles appeared similar. CONCLUSIONS: PM and DM muscle biopsies show similar gene expression profiles despite reported differences in histopathological changes. Altered gene expressions of immune regulation and myofibrillar proteins are prominent in muscle biopsies of myositis.

Adult↗