Genomic alterations in abnormal neutrophils isolated from adult patients with systemic lupus erythematosus
© Singh et al.; licensee BioMed Central Ltd. 2014
Received: 12 March 2014
Accepted: 18 July 2014
Published: 8 August 2014
Patients with systemic lupus erythematosus (SLE) have an abnormal population of neutrophils, called low-density granulocytes (LDGs), that express the surface markers of mature neutrophils, yet their nuclear morphology resembles an immature cell. Because a similar discrepancy in maturation status is observed in myelodysplasias, and disruption of neutrophil development is frequently associated with genomic alterations, genomic DNA isolated from autologous pairs of LDGs and normal-density neutrophils was compared for genomic changes.
Alterations in copy number and losses of heterozygosity (LOH) were detected by cytogenetic microarray analysis. Microsatellite instability (MSI) was detected by capillary gel electrophoresis of fluorescently labeled PCR products.
Control neutrophils and normal-density SLE neutrophils had similar levels of copy number variations, while the autologous SLE LDGs had an over twofold greater number of copy number alterations per genome. The additional copy number alterations found in LDGs were prevalent in six of the thirteen SLE patients, and occurred preferentially on chromosome 19, 17, 8, and X. These same SLE patients also displayed an increase in LOH. Several SLE patients had a common LOH on chromosome 5q that includes several cytokine genes and a DNA repair enzyme. In addition, three SLE patients displayed MSI. Two patients displayed MSI in greater than one marker, and one patient had MSI and increased copy number alterations. No correlations between genomic instability and immunosuppressive drugs, disease activity or disease manifestations were apparent.
The increased level of copy number alterations and LOH in the LDG samples relative to autologous normal-density SLE neutrophils suggests somatic alterations that are consistent with DNA strand break repair, while MSI suggests a replication error-prone status. Thus, the LDGs isolated have elevated levels of somatic alterations that are consistent with genetic damage or genomic instability. This suggests that the LDGs in adult SLE patients are derived from cell progenitors that are distinct from the autologous normal-density neutrophils, and may reflect a role for genomic instability in the disease.
Systemic lupus erythematosus (SLE) is an autoimmune disease of complex etiology. Intense and ongoing research efforts into the genetics of SLE have greatly advanced our understanding of the susceptibility to and development of the disease [1, 2]. More recently, research emphasis has shifted toward the identification and characterization of causative genetic alterations that convey the associated risk linkages in human SLE , as well as mouse models of disease . As research into the genetics of SLE continues, and the resolution of analysis becomes more refined, it is becoming increasingly apparent that many of the identified susceptibility intervals provide a rather limited contribution to disease incidence when considered individually . As such, models of SLE development generally propose that in the majority of cases, it is the inheritance of a combination of multiple susceptibility intervals that actually drives the development of disease in any one individual [6, 7]. The profile of these inherited genetic intervals has also been proposed to influence the manifestations of the disease, such as time to onset, disease progression and target organ involvement . Despite all of these advances that have established the role of genetics in SLE, inheritance alone rarely accounts for the incidence of SLE in an individual, suggesting that there are additional influences that contribute to the disease.
Because SLE is typically characterized by the progressive development of autoantibodies that recognize components of the cell nucleus , it is frequently considered to result from a disruption in the regulation of the adaptive immune system . However, recent evidence supports additional contributions from components of the innate immune system . Research toward defining the importance of additional cell lineages in the development of SLE is ongoing, and alterations in granulocyte function have been identified in both pediatric and adult SLE [12–15]. In this regard, an intriguing population of abnormal granulocytes has been identified and isolated from SLE patients [12–14, 16, 17]. These low-density granulocytes (LDGs) contribute the granulocyte signature observed in gene expression arrays from the mononuclear cell fraction of pediatric lupus patients . In adults, LDGs mediate enhanced proinflammatory and cytotoxic responses compared to those of autologous normal-density neutrophils [12, 13]. These LDGs readily induce endothelial cell death and spontaneously form neutrophil extracellular traps (NETs) [12, 13]. Despite these advances in our understanding of the function of LDGs, their developmental origins remain undefined. One model proposes that LDGs arise as a consequence of in situ activation of normal neutrophils . However, direct gene expression array analysis and bioinfomatic pathway comparisons between autologous pairs of LDGs and normal-density neutrophils isolated from SLE patients were not entirely consistent with an in situ activation model . The expression of genes associated with mature neutrophils did not differ between the LDGs and autologous normal-density neutrophils, nonetheless genes related to azurophilic granules, as well as cytoskeleton and adhesion molecules, were altered . Thus, mechanisms other than in situ activation may contribute to the development of LDGs in SLE patients.
One such alternate mechanism for the production of LDGs would be a disruption in granulocyte development. While the initial characterizations of LDGs suggested that they were immature granulocytes, based upon their lobulated or ovoid nuclei [14, 17], further characterization of the surface molecule expression on LDGs revealed a profile that is more consistent with a fully mature developmental state [12, 13]. This apparent inconsistency in maturation phenotype has also been described in patients with myelodysplasias . While the genetics of SLE is a topic of intense interest, the potential contributions of genetic instability and somatic mutations in SLE have received far less attention , in large part due to the difficulties associated with clearly identifying altered cell lineages and applying techniques that are suitable for analysis [20–22]. Since we have previously developed techniques to isolate highly enriched autologous pairs of normal-density neutrophils and LDGs from individual SLE patients [12, 13], it was now possible to apply genomic techniques currently utilized in cancer research to examine SLE LDGs for evidence of genomic instability . We hypothesized that the LDGs arise from a process that is similar to myelodysplasia, and therefore genomic alterations should exist between the autologous pairs of LDGs and normal-density neutrophils isolated from individual SLE patients. We report herein that there is clear evidence for genetic instability within the LDG lineage in SLE patients, with multiple types of genomic abnormalities detected in some SLE patients.
Recruitment of SLE patients and healthy controls
The Institutional Review Boards at Temple University and the University of Michigan approved this study. Subjects gave informed consent in accordance with the Declaration of Helsinki. Lupus patients fulfilled the revised American College of Rheumatology criteria for SLE and enrollment was open to all patients examined at the outpatient rheumatology clinics at Temple University and the University of Michigan . Disease activity was assessed by the SLE disease activity index (SLEDAI) . Female healthy controls were recruited by advertisement. Demographic and clinical information for the lupus patients enrolled in the study (including medications) were extracted from patient charts.
Isolation of LDGs and neutrophils
LDGs and autologous neutrophils were isolated from the blood of SLE patients as described previously [12, 13]. Briefly, venous blood (approximately 60 ml) was collected in heparinized tubes and separated by discontinuous density gradient centrifugation using Ficoll-Hypaque. LDGs were isolated from the PBMC layer by negative selection of lymphocytes and monocytes using a panel of biotinylated antibodies recognizing CD3, CD7, CD19, CD56, CD79b, CD86, MHC class II, and erythrophorin (Ancell, Bayport, MN, USA). The labeled cells were depleted using paramagnetic beads coupled with an anti-biotin antibody and a magnetic column (Miltenyi, Bergisch Gladbach, Germany). Normal density neutrophils were recovered from the corresponding erythrocyte fraction of the Ficoll-Hypaque gradient by dextran sedimentation of erythrocytes and lysis of residual red blood cells . The resultant cell purity of LDGs and autologous neutrophils exceeded 90% as assessed by flow cytometric analysis using the monocyte marker CD14 and the neutrophil marker CD15 .
Isolation of genomic DNA
Purified LDGs and neutrophils (5 to 20 X 106) were incubated at 65°C overnight in 0.4 ml of cell lysis buffer containing proteinase K (100 mMTris, pH 8.0, 0.2% sodium dodecyl sulfate, 5 mM EDTA, 200 mMNaCl, 0.4 mg proteinase K/mL (Sigma-Aldrich, St Louis, MO, USA)) . After cooling, denatured proteins were removed by phenol-chloroform extraction, and the aqueous phase was collected. Total nucleic acids were precipitated by addition of an equal volume of isopropanol, and recovered by centrifugation. The pellet was washed once in 70% ethanol, air-dried, dissolved in water, and treated with DNAse-free RNAse (Promega Madison, WI, USA) for 30 min at 37°C. Purified genomic (g)DNA was precipitated by addition of three volumes of ethanol, incubated at −20°C overnight, recovered by centrifugation, and the pellet stored in 70% ethanol at −20°C. The purity and integrity of the gDNA was assessed by agarose gel electrophoresis. All samples of gDNA were free of residual RNA and displayed a single band of greater the 24 kb (see Additional file 1).
Cytogenetic microarray analysis
Cytogenetic microarray analysis was performed by the Cytogenetics and Chromosomal Microarray core at the Fox Chase Cancer Center, using the Affymetrix 2.7 M Cytogenetics array chip, and genomic alterations were identified using Affymetrix Chromosome Analysis Suite software (Version 2.1) (Affymetrix, Santa Clara, CA, USA). This microarray chip evaluates genomic segments and single nucleotide polymorphism (SNP) markers, thus it is capable of simultaneously identifying both copy number alterations, such as duplications and deletions, as well as copy number-neutral losses of heterozygosity (LOH) [28–31]. Copy number alterations that were at least 9 kb in length and detected by a minimum of 10 consecutive markers with 80% confidence were included. Copy number alterations that spanned the centromere were excluded. Likewise, since only female subjects were used in this study, any interval that was localized to the Y chromosome was eliminated. Previously established and novel genomic variations were included in the analysis in order to distinguish inherited copy number variants from somatic alterations in the SLE patients. Each pair of SLE LDG and neutrophil samples was processed and analyzed together to minimize variability. The SNP markers on the microarray chip were also used to identify copy number-neutral LOH. Intervals greater than 2 Mb in length and detected with a minimum of 80% confidence were included in the analysis. Regions of LOH were compared between each SLE patient’s LDG and neutrophil samples to identify constitutional LOH from somatic mutations.
PCR analysis of JAK2V617F mutation and Flt3 alterations
Somatic mutations resulting in the conversion of wild-type JAK2 to a dominant activated form (JAK2V617F) were assessed in the pairs of LDGs and normal-density neutrophils by tetra-primer amplification refractory mutational screening using established primers and PCR conditions [32, 33]. The JAK2V617F positive cell line HEL served as a control. Flt3 mutation within the kinase domain activation loop was also tested by PCR . The introduction of an aspartate at amino acid position 835 was examined by the loss of an EcoRV restriction site encoded in Flt3 . Flt3 internal tandem duplications in the juxtamembrane region were evaluated by an alteration in the size of the PCR amplicon in controls and SLE samples .
Microsatellite instability (MSI) assays
A total of six microsatellites were analyzed using fluorescence-labeled PCR primers and capillary gel electrophoresis. The primer sequences and PCR protocol for five quasimonomorphic microsatellites (NR21, NR22, NR24, BAT25 and BAT26) and one polymorphic microsatellite (BAT40) have been described previously [36–39]. PCR products for both the LDGs and autologous neutrophils were compared. MSI was determined based upon differences in the main PCR product peak identified for each amplicon from the autologous pairs of LDGs and normal-density neutrophils for each SLE patient. A sample of genomic DNA isolated from the replication error-prone cell line Jurkat was amplified and analyzed in parallel with each set of patient samples to confirm the reproducibility of the MSI assay .
Because the distribution of copy number alterations is noncontinuous, only nonparametric analysis could be applied. Pairwise comparisons between autologous sets of LDGs and normal-density neutrophils were performed using Wilcoxon signed-rank test, with a one-tailed P value <0.05 considered statistically significant.
Copy number alterations are present in LDGs isolated from human SLE patients
Closer inspection of the individual SLE sample pairs revealed two distinct profiles for the copy number alterations in the LDGs (Figure 1C). The majority of the alterations were found in a subset of SLE patients. Because healthy donors had an average of number of copy number alterations of 7.67 ± 2.58 (mean ± standard deviation (SD)), we considered a SLE LDG sample as ‘change in copy number variation high’ (∆CNVhi) if it possessed a total number of copy number alterations that exceeded four standard deviations above the mean number of sites present in control neutrophils. Thus, any SLE LDG sample that had 18 or more copy number alterations was considered ∆CNVhi. Using this criterion, seven of the thirteen SLE samples had levels of copy number variations in their LDGs that were equivalent to autologous normal-density neutrophils and healthy controls (see Additional file 2). The remaining six SLE patient samples had levels of copy number alterations in their LDG fraction that exceeded the benchmark of eighteen (range 18 to 52). It was noteworthy that the level of copy number alterations detected in the normal-density neutrophils isolated from the ∆CNVhi subset of SLE patients was similar to healthy donors (Figure 1C). Therefore, the changes in copy number seen in lupus were restricted to the LDGs, with the corresponding normal-density neutrophils isolated from these SLE patients possessing similar levels of copy number variations as healthy controls, or samples from the ∆CNVneg SLE patients (Figure 1C). Therefore, there was a marked increased frequency of alterations in copy number alterations in six of the thirty SLE samples, consistent with genomic instability.
Copy number alterations in LDGs are localized to chromosomes and genomic intervals
Copy number-neutral losses of heterozygosity (LOH) are also present in LDGs isolated from human SLE patients
Activating mutations in JAK2 and Flt3 are not observed in LDGs
Due to the genomic alterations within the LDGs isolated from SLE patients, it is possible these cells also possess specific genomic alterations that affect neutrophil development. Myeloproliferative disorders are associated with a somatic mutation in the JAK2 kinase . JAK2 V617F displays constitutive activation that promotes the expansion of the erythroid and myeloid compartments . The LDGs and autologous normal-density neutrophils isolated from SLE patients were examined for JAK2 V617F mutation by tetra-primer amplification refractory mutation system (ARMS) assay (see Additional file 3). None of the samples displayed the JAK2 mutation, indicating that the LDGs did not possess the activated form of the JAK2 kinase. In addition, mutations in the Flt3 receptor kinase domain were examined by PCR . An activating point mutation at D835 within the kinase domain and internal tandem repeats of the juxtamembrane region were assayed, but again none of the sample pairs displayed either of these alterations (see Additional file 4). Thus, while a subset of the LDGs has an increased frequency of somatic errors including duplications, deletions, and LOH, specific mutations in either the JAK2 kinase or Flt3 kinase that have been associated with myeloproliferative disorders or acute myeloid leukemia were not detected.
Microsatellite instability (MSI) is present in LDGs isolated from human SLE patients
We have found evidence for multiple forms of genomic instability within an abnormal pool of neutrophils isolated from human SLE patients. Cytogenetic microarray analysis revealed genomic instability within the LDGs of SLE patients (see Additional file 6). Of the thirteen patients analyzed, six had pronounced alterations in copy number within their LDG fraction relative to autologous normal-density neutrophils. This is consistent with reports in patients with myelodysplastic syndromes, where cytogenetic microarray analysis detects an increased frequency of somatic duplications and deletions in myeloid progenitors, particularly in cases where classical cytogenetics is uninformative [53–58]. The copy number alterations and LOH are consistent with an increase in DNA strand break repair within the LDGs [59, 60]. In addition, three of the thirteen SLE patients also displayed MSI, a feature associated with replication error-prone cells [61, 62]. Thus, there was evidence for multiple types of DNA damage in the LDGs consistent with genomic instability in SLE. It is unlikely these genomic alterations occur secondary to in situ activation of the LDGs, resulting in NETosis and random damage of genomic DNA, which is subsequently detected as a genomic alteration. This alternative mechanism is not supported due to the presence of genomic alterations beyond deletions. The cytogenetic microarrays identified significant increases in the levels of copy number gains and LOH, and MSI was detected by an independent assay technique. The extent and types of genomic alterations that are found in the LDGs are not consistent with detection of activation-induced damage. The notion that genomic instability can be associated with SLE is supported by several observations. SLE patients are at an increased risk for certain cancers, including lymphomas and myeloid leukemia, beyond that associated with drug therapy for the disease [63, 64]. Lymphoblastoid cell lines prepared from a subset of pediatric SLE patients display an increased susceptibility to irradiation-induced double-stranded DNA breaks , an observation that is consistent with the alterations in copy number that are present in the LDGs.
The copy number alterations were selectively distributed on chromosomes 19, 17, 8 and X, and the copy number alterations on chromosome 19 were clustered within a few genomic intervals, consistent with a nonrandom pattern of damage. In addition to the accumulated somatic copy number alterations, these SLE patients also had an increased frequency of LOH. Several patients had an LOH that included several genes on chromosome 5q. This particular interval encodes several cytokines, the DNA repair enzyme RAD50, and IRF1. The transcription factor IRF1 contributes to the development autoimmunity in animal models [65–67], and loss of IRF1 tumor suppressor function has been proposed to promote myelodysplasias and the development of myelodysplasia-associated autoimmunity [49, 50, 68]. The region of LOH at chromosome 5q is contained within a larger interval that is associated with a distinct type myelodysplasia, 5q-syndrome [50, 68, 69]. 5q-syndrome is distinguished from other myelodysplasias in that it typically has a milder clinical course, infrequently converts to acute myeloid leukemia, is more prevalent in females, and is responsive to lenalidomide therapy [70, 71].
While previous studies have examined the functional differences between LDGs and autologous normal-density neutrophils, their developmental basis remained unexplored. We examined a model in which the LDGs arise from abnormal myeloid development in a manner resembling myelodysplasia, thus the techniques relied on the comparison of each patient’s LDGs to their autologous normal-density neutrophils. This experimental design is better suited for interpretation of data from individual SLE patients, rather than from a pooled cohort of patients, since it is differentiates genomic copy number variants from somatic alterations [72–74]. While the genomic techniques utilized in this study are suitable for evaluation of genome-wide alterations, they lack the necessary degree of fine specificity required for an associated functional analysis. For example, the consequence of a copy number loss within a heterozygous lupus susceptibility interval may depend upon whether the wild-type or the risk allele was lost. Thus, cytogenetic microarray analysis alone may not be sufficient to establish the relationship between genomic alterations and functional consequences. In addition, the incidence of microsatellite instability is consistent with the potential to accumulate point mutations that cannot be detected by the genomic microarray. Analysis of point mutations would necessitate the use of a next-generation sequencing-based screening panel, or whole exome sequencing. Although this study has focused on abnormal neutrophil development, it is certainly feasible to design related studies to examine genomic alterations in other cell lineages, including isolated subsets of abnormal T- and B-lymphocytes. This genomic analysis may provide similar insights into the role of genomic alterations in the development of autoimmunity as recently described for autoimmune lymphoproliferative syndrome, or ALPS [75–77].
The similarity between the alterations in myeloid development in myelodysplasia and SLE has been reported previously. Bone marrow biopsies from SLE patients resemble those from MDS patients diagnosed with refractory anemia, with abnormal regions of myeloid precursors and alterations in neutrophil morphology [78, 79], and the diagnostic criteria for MDS exclude SLE as a cause of observed cytopenia. Recent advances in myelodysplasia research have identified several new genomic alterations that may also be relevant to SLE. Genome-wide exome sequencing has revealed that patients with myelodysplasia frequently harbor somatic mutations in proteins that form the spliceosome complex [80, 81], and these mutations are strongly associated with the type of myelodysplasia and long-term prognosis. The possibility that spliceosome proteins may also be mutated in LDGs opens an exciting new area for future research, and a more direct and detailed analysis of specific spliceosome proteins in SLE seems warranted. In addition to promoting abnormal immune cell development, genetic alterations in the spliceosome machinery may also lead to dysregulated expression of autoantigens, and the subsequent development of autoimmunity, a feature that has been associated with myeloid leukemias.
The advances in the genetics of SLE are occurring in conjunction with research defining a key role for excessive activation of the Type 1 interferon pathway [2, 82]. Type 1 interferons participate in anti-viral immune responses, and the relationship between Type 1 interferon gene expression signature and the development of SLE is observed in several mouse models and in many SLE patients with active disease [17, 83–88]. As such, genes that regulate the expression of, or the response to, Type 1 interferons are frequently given high priority as candidate genes in genetic analysis [89–91]. While this strategy has identified variants and haplotypes of signal transducer and activator of transcription 4 (STAT4) and interferon regulatory factor 5 (IRF5) [92, 93], definitive associations within other genetic intervals, including the prominent association within the MHC locus [94–96], have yet to be established through this candidate gene selection process. Because the relative risk of disease that is associated with any one interval in isolation, it is generally interpreted as supportive evidence of the polygenetic nature of the disease. However, it is also possible that the variant that conveys the true lupus susceptibility within the interval may not have been identified. Because the screening of candidate genes within the larger susceptibility intervals generally focuses on genes associated with immune cell function or inflammatory responses, a potential selection bias may be introduced into the screening process.
Influences beyond genetics are also thought to be critical for the development of SLE. Despite the current interest in genetics, the disease concordance in identical twins is relatively low compared to other inherited diseases. This is typically attributed to a role for environmental influences in SLE, however, the exact nature of the environmental factor that drives disease development in a genetically susceptible individual remains unresolved. Our results suggest that one of the as yet undefined environmental components may be related to developmental alterations that are attributable to genetic instability or DNA damage. Recent high-resolution mapping of the MHC locus has identified a susceptibility interval that includes the DNA repair gene MSH5, consistent with a role for DNA damage and repair in the development of SLE [94, 97, 98].
We have identified multiple types of genomic alterations in LDGs isolated from human SLE patients (copy number gains and losses, copy number-neutral LOH, and MSI) and found that these alterations are clustered on certain chromosomes in areas that are potentially involved in granulocyte development and immune response regulation. A recent study has found that SLE patients have an increased risk of developing myelodysplastic disorders and myeloid leukemias . One of the implications of this research is that candidate genes related to DNA damage repair should be included in the interpretation of genome-wide association studies, with affected individuals harboring the susceptibility gene likely displaying a mutator phenotype . The use of cytogenetic approaches that have been instrumental in understanding the development of cancer may also be applicable to understand role of genetic instability in SLE, and to guide the development of potential new therapeutic strategies for controlling the disease and its manifestations. Although the current emphasis for new chemotherapeutic agents for the treatment of SLE is focused almost exclusively on developing antagonists of cytokines and growth factors that are associated with disease severity, this research suggests a role for the use of anti-myelodysplastic agents as well.
The peripheral blood mononuclear cell fraction isolated from patients with SLE contains a pool of low-density granulocytes (LDGs). Previous studies have proposed that these abnormal neutrophils are either immature polymorphonuclear cells, or neutrophils that have been activated in situ. However, since LDGs express surface markers that are characteristic of a fully mature neutrophil, and have a gene expression profile that is not consistent with marked activation, an alternative mechanism likely mediates the presence of LDGs. Because LDGs resemble the abnormal neutrophils present in myelodysplasias, we applied a genomic analysis approach that is more commonly used in cancer research to determine whether LDGs display evidence of genomic instability. Numerous genomic alterations were identified in LDGs isolated from SLE patients, including copy number alterations, losses of heterozygosity, and microsatellite instability. Taken together, this supports a model whereby genomic damage contributes to the development of an abnormal population of neutrophils. Moreover, the presence of genomic instability suggests a confounding factor in the interpretation of genetic association studies. These findings also suggest that therapeutic approaches designed to control myelodysplasias may also be beneficial in SLE.
amplification refractory mutation system
copy number variation
loss of heterozygosity
systemic lupus erythematosus.
The authors are grateful for excellent technical support provided by Dr.Jianming Pei and the Cytogenetic Microarray Core facility at Fox Chase Cancer Center (supported by P30 CA006927). We also appreciate the many suggestions and helpful comments of Dr. Brendan Hilliard. This research was supported by a grant from the Lupus Research Institute to MJK and a Target Identification in Lupus grant from the Alliance for Lupus Research to MFD. This study was performed while MJK was employed at the University of Michigan. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. MFD was also supported in part by a research supplement to R01 DE017590 (PLC), NIAMS New Investigator Award R03 AR061026, and a Faculty Research Development Award from the Department of Medicine at Temple University. Research conducted by NS and PT in partial fulfillment of the requirements for fellows participating in the Rheumatology Research Training Program at Temple University.
- Tsokos GC: Systemic lupus erythematosus. N Engl J Med. 2011, 365: 2110-2121.View ArticlePubMedGoogle Scholar
- Banchereau J, Pascual V: Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006, 25: 383-392.View ArticlePubMedGoogle Scholar
- Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO: Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008, 40: 204-210.PubMed CentralView ArticlePubMedGoogle Scholar
- Xu Z, Morel L: Genetics of systemic lupus erythematosus: contributions of mouse models in the era of human genome-wide association studies. Discov Med. 2010, 10: 71-78.PubMedGoogle Scholar
- Guerra SG, Vyse TJ, Cunninghame Graham DS: The genetics of lupus: a functional perspective. Arthritis Res Ther. 2012, 14: 211-PubMed CentralView ArticlePubMedGoogle Scholar
- Hughes T, Adler A, Kelly JA, Kaufman KM, Williams AH, Langefeld CD, Brown EE, Alarcon GS, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Boackle SA, Stevens AM, Reveille JD, Sanchez E, Martin J, Niewold TB, Vila LM, Scofield RH, Gilkeson GS, Gaffney PM, Criswell LA, Moser KL, Merrill JT, Jacob CO, Tsao BP, James JA, Vyse TJ, Alarcon-Riquelme ME: Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum. 2012, 64: 485-492.PubMed CentralView ArticlePubMedGoogle Scholar
- Koga M, Kawasaki A, Ito I, Furuya T, Ohashi J, Kyogoku C, Ito S, Hayashi T, Matsumoto I, Kusaoi M, Takasaki Y, Hashimoto H, Sumida T, Tsuchiya N: Cumulative association of eight susceptibility genes with systemic lupus erythematosus in a Japanese female population. J Hum Genet. 2011, 56: 503-507.View ArticlePubMedGoogle Scholar
- Alonso-Perez E, Suarez-Gestal M, Calaza M, Ordi-Ros J, Balada E, Bijl M, Papasteriades C, Carreira P, Skopouli FN, Witte T, Endreffy E, Marchini M, Migliaresi S, Sebastiani GD, Santos MJ, Suarez A, Blanco FJ, Barizzone N, Pullmann R, Ruzickova S, Lauwerys BR, Gomez-Reino JJ, Gonzalez A: Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study. PLoS One. 2012, 7: e45356-PubMed CentralView ArticlePubMedGoogle Scholar
- Arbuckle MR, James JA, Dennis GJ, Rubertone MV, McClain MT, Kim XR, Harley JB: Rapid clinical progression to diagnosis among African-American men with systemic lupus erythematosus. Lupus. 2003, 12: 99-106.View ArticlePubMedGoogle Scholar
- Choi J, Kim ST, Craft J: The pathogenesis of systemic lupus erythematosus-an update. Curr Opin Immunol. 2012, 24: 651-657.PubMed CentralView ArticlePubMedGoogle Scholar
- Liu Z, Davidson A: Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med. 2012, 18: 871-882.PubMed CentralView ArticlePubMedGoogle Scholar
- Denny MF, Yalavarthi S, Zhao W, Thacker SG, Anderson M, Sandy AR, McCune WJ, Kaplan MJ: A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol. 2010, 184: 3284-3297.PubMed CentralView ArticlePubMedGoogle Scholar
- Villanueva E, Yalavarthi S, Berthier CC, Hodgin JB, Khandpur R, Lin AM, Rubin CJ, Zhao W, Olsen SH, Klinker M, Shealy D, Denny MF, Plumas J, Chaperot L, Kretzler M, Bruce AT, Kaplan MJ: Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol. 2011, 187: 538-552.PubMed CentralView ArticlePubMedGoogle Scholar
- Hacbarth E, Kajdacsy-Balla A: Low density neutrophils in patients with systemic lupus erythematosus, rheumatoid arthritis, and acute rheumatic fever. Arthritis Rheum. 1986, 29: 1334-1342.View ArticlePubMedGoogle Scholar
- Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ, Banchereau J, Pascual V: Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011, 3: 73ra20-PubMed CentralView ArticlePubMedGoogle Scholar
- Kaplan MJ: Neutrophils in the pathogenesis and manifestations of SLE. Nat Rev Rheumatol. 2011, 7: 691-699.PubMed CentralView ArticlePubMedGoogle Scholar
- Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J, Banchereau J, Pascual V: Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003, 197: 711-723.PubMed CentralView ArticlePubMedGoogle Scholar
- Catenacci DV, Schiller GJ: Myelodysplasic syndromes: a comprehensive review. Blood Rev. 2005, 19: 301-319.View ArticlePubMedGoogle Scholar
- Bernatsky S, Ramsey-Goldman R, Labrecque J, Joseph L, Boivin JF, Petri M, Zoma A, Manzi S, Urowitz MB, Gladman D, Fortin PR, Ginzler E, Yelin E, Bae SC, Wallace DJ, Edworthy S, Jacobsen S, Gordon C, Dooley MA, Peschken CA, Hanly JG, Alarcon GS, Nived O, Ruiz-Irastorza G, Isenberg D, Rahman A, Witte T, Aranow C, Kamen DL, Steinsson K: Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun. 2013, 42: 130-135.PubMed CentralView ArticlePubMedGoogle Scholar
- Bassi C, Xavier D, Palomino G, Nicolucci P, Soares C, Sakamoto-Hojo E, Donadi E: Efficiency of the DNA repair and polymorphisms of the XRCC1, XRCC3 and XRCC4 DNA repair genes in systemic lupus erythematosus. Lupus. 2008, 17: 988-995.View ArticlePubMedGoogle Scholar
- Davies RC, Pettijohn K, Fike F, Wang J, Nahas SA, Tunuguntla R, Hu H, Gatti RA, McCurdy D: Defective DNA double-strand break repair in pediatric systemic lupus erythematosus. Arthritis Rheum. 2012, 64: 568-578.View ArticlePubMedGoogle Scholar
- Lee HM, Sugino H, Aoki C, Nishimoto N: Underexpression of mitochondrial-DNA encoded ATP synthesis-related genes and DNA repair genes in systemic lupus erythematosus. Arthritis Res Ther. 2011, 13: R63-PubMed CentralView ArticlePubMedGoogle Scholar
- Shaffer LG, Ballif BC, Schultz RA: The use of cytogenetic microarrays in myelodysplastic syndrome characterization. Methods Mol Biol. 2013, 973: 69-85.View ArticlePubMedGoogle Scholar
- Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997, 40: 1725-View ArticlePubMedGoogle Scholar
- Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH: Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992, 35: 630-640.View ArticlePubMedGoogle Scholar
- Clark RA, Nauseef WM: Isolation and functional analysis of neutrophils. Current Protocols in Immunology. Edited by: Coligan JE. 2003, New York: John Wiley & Sons, 7-23.21-27.23.17Google Scholar
- Wang Z, Storm DR: Extraction of DNA from mouse tails. Biotechniques. 2006, 41: 410-412.View ArticlePubMedGoogle Scholar
- Maciejewski JP, Tiu RV, O’Keefe C: Application of array-based whole genome scanning technologies as a cytogenetic tool in haematological malignancies. Br J Haematol. 2009, 146: 479-488.View ArticlePubMedGoogle Scholar
- Tiu RV, Gondek LP, O’Keefe CL, Huh J, Sekeres MA, Elson P, McDevitt MA, Wang XF, Levis MJ, Karp JE, Advani AS, Maciejewski JP: New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia. J Clin Oncol. 2009, 27: 5219-5226.PubMed CentralView ArticlePubMedGoogle Scholar
- Howell KB, Kornberg AJ, Harvey AS, Ryan MM, Mackay MT, Freeman JL, Rodriguez Casero MV, Collins KJ, Hayman M, Mohamed A, Ware TL, Clark D, Bruno DL, Burgess T, Slater H, McGillivray G, Leventer RJ: High resolution chromosomal microarray in undiagnosed neurological disorders. J Paediatr Child Health. 2013, 49: 716-724.View ArticlePubMedGoogle Scholar
- Tiu R, Gondek L, O’Keefe C, Maciejewski JP: Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. Leukemia. 2007, 21: 1648-1657.View ArticlePubMedGoogle Scholar
- Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D’Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG: Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005, 7: 387-397.View ArticlePubMedGoogle Scholar
- Moliterno AR, Williams DM, Rogers O, Isaacs MA, Spivak JL: Phenotypic variability within the JAK2 V617F-positive MPD: roles of progenitor cell and neutrophil allele burdens. Exp Hematol. 2008, 36: 1480-1486.PubMed CentralView ArticlePubMedGoogle Scholar
- Kussick SJ, Stirewalt DL, Yi HS, Sheets KM, Pogosova-Agadjanyan E, Braswell S, Norwood TH, Radich JP, Wood BL: A distinctive nuclear morphology in acute myeloid leukemia is strongly associated with loss of HLA-DR expression and FLT3 internal tandem duplication. Leukemia. 2004, 18: 1591-1598.View ArticlePubMedGoogle Scholar
- Sheikhha MH, Awan A, Tobal K, Liu Yin JA: Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J. 2003, 4: 41-46.View ArticlePubMedGoogle Scholar
- Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K, Seruca R, Iacopetta B, Hamelin R: Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002, 123: 1804-1811.View ArticlePubMedGoogle Scholar
- Ma SK, Kong CT, Wan TS, Au WY, Chan JC, Yip SF, Chan LC: Absence of microsatellite instability in primary myelodysplastic syndrome. Int J Mol Med. 2000, 5: 159-163.PubMedGoogle Scholar
- Pyatt R, Chadwick RB, Johnson CK, Adebamowo C, de la Chapelle A, Prior TW: Polymorphic variation at the BAT-25 and BAT-26 loci in individuals of African origin, Implications for microsatellite instability testing. Am J Pathol. 1999, 155: 349-353.PubMed CentralView ArticlePubMedGoogle Scholar
- Sheikhha MH, Tobal K, Liu Yin JA: High level of microsatellite instability but not hypermethylation of mismatch repair genes in therapy-related and secondary acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol. 2002, 117: 359-365.View ArticlePubMedGoogle Scholar
- Levati L, Marra G, Lettieri T, D’Atri S, Vernole P, Tentori L, Lacal PM, Pagani E, Bonmassar E, Jiricny J, Graziani G: Mutation of the mismatch repair gene hMSH2 and hMSH6 in a human T-cell leukemia line tolerant to methylating agents. Genes Chromosomes Cancer. 1998, 23: 159-166.View ArticlePubMedGoogle Scholar
- MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW: The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2013, 42: D986-D992.PubMed CentralView ArticlePubMedGoogle Scholar
- Szekanecz E, Szucs G, Szekanecz Z, Tarr T, Antal-Szalmas P, Szamosi S, Szanto J, Kiss E: Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: associations with organ manifestations, immunolaboratory markers and disease activity indices. J Autoimmun. 2008, 31: 372-376.View ArticlePubMedGoogle Scholar
- Grimwood J, Gordon LA, Olsen A, Terry A, Schmutz J, Lamerdin J, Hellsten U, Goodstein D, Couronne O, Tran-Gyamfi M, Aerts A, Altherr M, Ashworth L, Bajorek E, Black S, Branscomb E, Caenepeel S, Carrano A, Caoile C, Chan YM, Christensen M, Cleland CA, Copeland A, Dalin E, Dehal P, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D: The DNA sequence and biology of human chromosome 19. Nature. 2004, 428: 529-535.View ArticlePubMedGoogle Scholar
- Olsen A, Teglund S, Nelson D, Gordon L, Copeland A, Georgescu A, Carrano A, Hammarstrom S: Gene organization of the pregnancy-specific glycoprotein region on human chromosome 19: assembly and analysis of a 700-kb cosmidcontig spanning the region. Genomics. 1994, 23: 659-668.View ArticlePubMedGoogle Scholar
- van Leeuwen BH, Martinson ME, Webb GC, Young IG: Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5. Blood. 1989, 73: 1142-1148.PubMedGoogle Scholar
- Yang YC, Kovacic S, Kriz R, Wolf S, Clark SC, Wellems TE, Nienhuis A, Epstein N: The human genes for GM-CSF and IL 3 are closely linked in tandem on chromosome 5. Blood. 1988, 71: 958-961.PubMedGoogle Scholar
- Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, Suzuki M, Nagasaki M, Ohtsuki M, Ono M, Furukawa H, Nagashima M, Yoshino S, Mabuchi A, Sekine A, Saito S, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet. 2003, 35: 341-348.View ArticlePubMedGoogle Scholar
- Lobachev KS, Gordenin DA, Resnick MA: The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell. 2002, 108: 183-193.View ArticlePubMedGoogle Scholar
- Willman CL, Sever CE, Pallavicini MG, Harada H, Tanaka N, Slovak ML, Yamamoto H, Harada K, Meeker TC, List AF, Taniguchi T: Deletion of IRF-1, mapping to chromosome 5q31.1, in human leukemia and preleukemicmyelodysplasia. Science. 1993, 259: 968-971.View ArticlePubMedGoogle Scholar
- Boultwood J, Fidler C, Lewis S, MacCarthy A, Sheridan H, Kelly S, Oscier D, Buckle VJ, Wainscoat JS: Allelic loss of IRF1 in myelodysplasia and acute myeloid leukemia: retention of IRF1 on the 5q- chromosome in some patients with the 5q- syndrome. Blood. 1993, 82: 2611-2616.PubMedGoogle Scholar
- Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005, 352: 1779-1790.View ArticlePubMedGoogle Scholar
- Passamonti F, Rumi E, Pietra D, Della Porta MG, Boveri E, Pascutto C, Vanelli L, Arcaini L, Burcheri S, Malcovati L, Lazzarino M, Cazzola M: Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood. 2006, 107: 3676-3682.View ArticlePubMedGoogle Scholar
- Suela J, Alvarez S, Cigudosa JC: DNA profiling by arrayCGH in acute myeloid leukemia and myelodysplastic syndromes. Cytogenet Genome Res. 2007, 118: 304-309.View ArticlePubMedGoogle Scholar
- Babicz M, Kowalczyk JR, Winnicka D, Gaworczyk A, Lejman M, Dmowski R, Kaczanowska K: The effectiveness of high-resolution-comparative genomic hybridization in detecting the most common chromosomal abnormalities in pediatric myelodysplastic syndromes. Cancer Genet Cytogenet. 2005, 158: 49-54.View ArticlePubMedGoogle Scholar
- Kim MH, Stewart J, Devlin C, Kim YT, Boyd E, Connor M: The application of comparative genomic hybridization as an additional tool in the chromosome analysis of acute myeloid leukemia and myelodysplastic syndromes. Cancer Genet Cytogenet. 2001, 126: 26-33.View ArticlePubMedGoogle Scholar
- Thiel A, Beier M, Ingenhag D, Servan K, Hein M, Moeller V, Betz B, Hildebrandt B, Evers C, Germing U, Royer-Pokora B: Comprehensive array CGH of normal karyotype myelodysplastic syndromes reveals hidden recurrent and individual genomic copy number alterations with prognostic relevance. Leukemia. 2011, 25: 387-399.View ArticlePubMedGoogle Scholar
- Graubert TA, Payton MA, Shao J, Walgren RA, Monahan RS, Frater JL, Walshauser MA, Martin MG, Kasai Y, Walter MJ: Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis. PLoS One. 2009, 4: e4583-PubMed CentralView ArticlePubMedGoogle Scholar
- Ahmad A, Iqbal MA: Significance of genome-wide analysis of copy number alterations and UPD in myelodysplastic syndromes using combined CGH - SNP arrays. Curr Med Chem. 2012, 19: 3739-3747.View ArticlePubMedGoogle Scholar
- Moynahan ME, Jasin M: Loss of heterozygosity induced by a chromosomal double-strand break. Proc Natl Acad Sci U S A. 1997, 94: 8988-8993.PubMed CentralView ArticlePubMedGoogle Scholar
- Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW: Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Res. 2000, 60: 3884-3892.PubMedGoogle Scholar
- Parsons R, Li GM, Longley MJ, Fang WH, Papadopoulos N, Jen J, de la Chapelle A, Kinzler KW, Vogelstein B, Modrich P: Hypermutability and mismatch repair deficiency in RER + tumor cells. Cell. 1993, 75: 1227-1236.View ArticlePubMedGoogle Scholar
- Horii A, Han HJ, Shimada M, Yanagisawa A, Kato Y, Ohta H, Yasui W, Tahara E, Nakamura Y: Frequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers. Cancer Res. 1994, 54: 3373-3375.PubMedGoogle Scholar
- Bernatsky S, Clarke A, Ramsey-Goldman R: Risk of lymphoma in autoimmune rheumatic conditions. Arch Intern Med. 2006, 166: 1233-1234. author reply 1234View ArticlePubMedGoogle Scholar
- Bernatsky S, Clarke AE, Labrecque J, von Scheven E, Schanberg LE, Silverman ED, Brunner HI, Haines KA, Cron RQ ONKM, O’Neil KM, Oen K, Rosenberg AM, Duffy CM, Joseph L, Lee JL, Kale M, Turnbull EM, Ramsey-Goldman R: Cancer risk in childhood-onset systemic lupus. Arthritis Res Ther. 2013, 15: R198-PubMed CentralView ArticlePubMedGoogle Scholar
- Tada Y, Ho A, Matsuyama T, Mak TW: Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking interferon regulatory factor-1. J Exp Med. 1997, 185: 231-238.PubMed CentralView ArticlePubMedGoogle Scholar
- Nakazawa T, Satoh J, Takahashi K, Sakata Y, Ikehata F, Takizawa Y, Bando SI, Housai T, Li Y, Chen C, Masuda T, Kure S, Kato I, Takasawa S, Taniguchi T, Okamoto H, Toyota T: Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1. J Autoimmun. 2001, 17: 119-125.View ArticlePubMedGoogle Scholar
- Reilly CM, Olgun S, Goodwin D, Gogal RM, Santo A, Romesburg JW, Ahmed SA, Gilkeson GS: Interferon regulatory factor-1 gene deletion decreases glomerulonephritis in MRL/lpr mice. Eur J Immunol. 2006, 36: 1296-1308.View ArticlePubMedGoogle Scholar
- Harada H, Kondo T, Ogawa S, Tamura T, Kitagawa M, Tanaka N, Lamphier MS, Hirai H, Taniguchi T: Accelerated exon skipping of IRF-1 mRNA in human myelodysplasia/leukemia; a possible mechanism of tumor suppressor inactivation. Oncogene. 1994, 9: 3313-3320.PubMedGoogle Scholar
- Cavalli LR, Riggins RB, Wang A, Clarke R, Haddad BR: Frequent loss of heterozygosity at the interferon regulatory factor-1 gene locus in breast cancer. Breast Cancer Res Treat. 2010, 121: 227-231.PubMed CentralView ArticlePubMedGoogle Scholar
- Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ, Astrand-Grundstrom I, Strombeck B, Horvat A, Ferry H, Dhanda RS, Hast R, Ryden T, Vyas P, Gohring G, Schlegelberger B, Johansson B, Hellstrom-Lindberg E, List A, Nilsson L, Jacobsen SE: Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl J Med. 2010, 363: 1025-1037.View ArticlePubMedGoogle Scholar
- Fenaux P, Kelaidi C: Treatment of the 5q- syndrome. Hematology Am Soc Hematol Educ Program. 2006, 2006: 192-198.View ArticleGoogle Scholar
- Olsson LM, Holmdahl R: Copy number variation in autoimmunity-importance hidden in complexity?. Eur J Immunol. 2012, 42: 1969-1976.View ArticlePubMedGoogle Scholar
- Ptacek T, Li X, Kelley JM, Edberg JC: Copy number variants in genetic susceptibility and severity of systemic lupus erythematosus. Cytogenet Genome Res. 2008, 123: 142-147.View ArticlePubMedGoogle Scholar
- Schaschl H, Aitman TJ, Vyse TJ: Copy number variation in the human genome and its implication in autoimmunity. Clin Exp Immunol. 2009, 156: 12-16.PubMed CentralView ArticlePubMedGoogle Scholar
- Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB, Puck JM, Jaffe ES, Pittaluga S, Cohen JI, Fleisher TA, Rao VK: Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood. 2010, 115: 5164-5169.PubMed CentralView ArticlePubMedGoogle Scholar
- Hauck F, Magerus-Chatinet A, Vicca S, Rensing-Ehl A, Roesen-Wolff A, Roesler J, Rieux-Laucat F: Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation. Clin Immunol. 2013, 147: 61-68.View ArticlePubMedGoogle Scholar
- Magerus-Chatinet A, Neven B, Stolzenberg MC, Daussy C, Arkwright PD, Lanzarotti N, Schaffner C, Cluet-Dennetiere S, Haerynck F, Michel G, Bole-Feysot C, Zarhrate M, Radford-Weiss I, Romana SP, Picard C, Fischer A, Rieux-Laucat F: Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. J Clin Invest. 2011, 121: 106-112.PubMed CentralView ArticlePubMedGoogle Scholar
- Oka Y, Kameoka J, Hirabayashi Y, Takahashi R, Ishii T, Sasaki T, Harigae H: Reversible bone marrow dysplasia in patients with systemic lupus erythematosus. Intern Med. 2008, 47: 737-742.View ArticlePubMedGoogle Scholar
- Voulgarelis M, Giannouli S, Tasidou A, Anagnostou D, Ziakas PD, Tzioufas AG: Bone marrow histological findings in systemic lupus erythematosus with hematologic abnormalities: a clinicopathological study. Am J Hematol. 2006, 81: 590-597.View ArticlePubMedGoogle Scholar
- Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, Pellagatti A, Wainscoat JS, Hellstrom-Lindberg E, Gambacorti-Passerini C, Godfrey AL, Rapado I, Cvejic A, Rance R, McGee C, Ellis P, Mudie LJ, Stephens PJ, McLaren S, Massie CE, Tarpey PS, Varela I, Nik-Zainal S, Davies HR, Shlien A, Jones D, Raine K, Hinton J, Butler AP, Teague JW: Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011, 365: 1384-1395.PubMed CentralView ArticlePubMedGoogle Scholar
- Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H: Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011, 478: 64-69.View ArticlePubMedGoogle Scholar
- Ronnblom L, Eloranta ML, Alm GV: The type I interferon system in systemic lupus erythematosus. Arthritis Rheum. 2006, 54: 408-420.View ArticlePubMedGoogle Scholar
- Pascual V, Farkas L, Banchereau J: Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol. 2006, 18: 676-682.View ArticlePubMedGoogle Scholar
- Theofilopoulos AN, Baccala R, Beutler B, Kono DH: Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005, 23: 307-336.View ArticlePubMedGoogle Scholar
- Liu Z, Davidson A: IFNalpha inducible models of murine SLE. Front Immunol. 2013, 4: 306-PubMed CentralPubMedGoogle Scholar
- Ramanujam M, Kahn P, Huang W, Tao H, Madaio MP, Factor SM, Davidson A: Interferon-alpha treatment of female (NZW x BXSB)F(1) mice mimics some but not all features associated with the Yaa mutation. Arthritis Rheum. 2009, 60: 1096-1101.PubMed CentralView ArticlePubMedGoogle Scholar
- Fairhurst AM, Mathian A, Connolly JE, Wang A, Gray HF, George TA, Boudreaux CD, Zhou XJ, Li QZ, Koutouzov S, Banchereau J, Wakeland EK: Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice. Eur J Immunol. 2008, 38: 1948-1960.PubMed CentralView ArticlePubMedGoogle Scholar
- Mathian A, Weinberg A, Gallegos M, Banchereau J, Koutouzov S: IFN-alpha induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB/c mice. J Immunol. 2005, 174: 2499-2506.View ArticlePubMedGoogle Scholar
- Kyogoku C, Tsuchiya N: A compass that points to lupus: genetic studies on type I interferon pathway. Genes Immun. 2007, 8: 445-455.View ArticlePubMedGoogle Scholar
- Bronson PG, Chaivorapol C, Ortmann W, Behrens TW, Graham RR: The genetics of type I interferon in systemic lupus erythematosus. Curr Opin Immunol. 2012, 24: 530-537.View ArticlePubMedGoogle Scholar
- Deng Y, Tsao BP: Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol. 2010, 6: 683-692.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang C, Sandling JK, Hagberg N, Berggren O, Sigurdsson S, Karlberg O, Ronnblom L, Eloranta ML, Syvanen AC: Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4. Ann Rheum Dis. 2013, 72: 96-103.View ArticlePubMedGoogle Scholar
- Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, Eloranta ML, Gunnarsson I, Svenungsson E, Sturfelt G, Bengtsson AA, Jonsen A, Truedsson L, Rantapaa-Dahlqvist S, Eriksson C, Alm G, Goring HH, Pastinen T, Syvanen AC, Ronnblom L: A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet. 2008, 17: 2868-2876.PubMed CentralView ArticlePubMedGoogle Scholar
- Morris DL, Taylor KE, Fernando MM, Nititham J, Alarcon-Riquelme ME, Barcellos LF, Behrens TW, Cotsapas C, Gaffney PM, Graham RR, Pons-Estel BA, Gregersen PK, Harley JB, Hauser SL, Hom G, Langefeld CD, Noble JA, Rioux JD, Seldin MF, Criswell LA, Vyse TJ: Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. Am J Hum Genet. 2012, 91: 778-793.PubMed CentralView ArticlePubMedGoogle Scholar
- Gaffney PM, Kearns GM, Shark KB, Ortmann WA, Selby SA, Malmgren ML, Rohlf KE, Ockenden TC, Messner RP, King RA, Rich SS, Behrens TW: A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci U S A. 1998, 95: 14875-14879.PubMed CentralView ArticlePubMedGoogle Scholar
- Relle M, Schwarting A: Role of MHC-linked susceptibility genes in the pathogenesis of human and murine lupus. Clin Dev Immunol. 2012, 2012: 584374-PubMed CentralView ArticlePubMedGoogle Scholar
- Barcellos LF, May SL, Ramsay PP, Quach HL, Lane JA, Nititham J, Noble JA, Taylor KE, Quach DL, Chung SA, Kelly JA, Moser KL, Behrens TW, Seldin MF, Thomson G, Harley JB, Gaffney PM, Criswell LA: High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet. 2009, 5: e1000696-PubMed CentralView ArticlePubMedGoogle Scholar
- Sanchez E, Comeau ME, Freedman BI, Kelly JA, Kaufman KM, Langefeld CD, Brown EE, Alarcon GS, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Reveille JD, Vila LM, Merrill JT, Tsao BP, Kamen DL, Gilkeson GS, James JA, Vyse TJ, Gaffney PM, Jacob CO, Niewold TB, Richardson BC, Harley JB, Alarcon-Riquelme ME, Sawalha AH: Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study. Arthritis Rheum. 2011, 63: 3493-3501.PubMed CentralView ArticlePubMedGoogle Scholar
- Lu M, Bernatsky S, Ramsey-Goldman R, Petri M, Manzi S, Urowitz MB, Gladman D, Fortin PR, Ginzler EM, Yelin E, Bae SC, Wallace DJ, Jacobsen S, Dooley MA, Peschken CA, Alarcón GS, Nived O, Gottesman L, Criswell LA, Sturfelt G, Dreyer L, Lee JL, Clarke AE: Non-lymphoma hematological malignancies in systemic lupus erythematosus. Oncology. 2013, 85: 235-240.View ArticlePubMedGoogle Scholar
- Loeb LA, Bielas JH, Beckman RA: Cancers exhibit a mutator phenotype: clinical implications. Cancer Res. 2008, 68: 3551-3557. discussion 3557View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.