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1.
Mol Ther ; 26(5): 1354-1365, 2018 05 02.
Article in English | MEDLINE | ID: mdl-29606504

ABSTRACT

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.


Subject(s)
Antibodies, Monoclonal/pharmacology , Glioblastoma/immunology , Glioblastoma/metabolism , Receptors, CXCR/antagonists & inhibitors , Temozolomide/pharmacology , Animals , Antibodies, Monoclonal/metabolism , Antibody Affinity/immunology , Antineoplastic Agents, Immunological/pharmacology , Cell Line, Tumor , Cytotoxicity, Immunologic/drug effects , Disease Models, Animal , Drug Synergism , Glioblastoma/diagnosis , Glioblastoma/mortality , Humans , Magnetic Resonance Imaging , Mice , Mortality , Protein Binding/immunology , Receptors, CXCR/metabolism , Xenograft Model Antitumor Assays
2.
PLoS One ; 9(12): e112925, 2014.
Article in English | MEDLINE | ID: mdl-25437209

ABSTRACT

Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated ß-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. α-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof-of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Naphthalenes/pharmacology , Quaternary Ammonium Compounds/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Arrestins/metabolism , Brain/drug effects , Brain/metabolism , Cell Movement/drug effects , Chemokines/metabolism , Drug Evaluation, Preclinical , Drug Stability , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Leukocytes/drug effects , Mice , Mice, Inbred C57BL , Naphthalenes/adverse effects , Naphthalenes/chemistry , Naphthalenes/therapeutic use , Quaternary Ammonium Compounds/adverse effects , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/therapeutic use , Receptors, Chemokine , Safety , Spinal Cord/drug effects , Spinal Cord/metabolism , Structure-Activity Relationship , beta-Arrestins
3.
J Immunol Methods ; 413: 69-73, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25066631

ABSTRACT

Due to low numbers of endogenous dendritic cells (DCs) in vivo, exogenous DC-poietin Fms-like tyrosine kinase 3-ligand (FLT3L) is routinely used to generate DC for subsequent studies. We engineered a novel FLT3L-FC DNA construct that, when combined with hydrodynamic gene transfer (HDT), induced robust DC expansion in mice. DC generated in vivo by FLT3L-FC HDT produced cytokines in response to stimulation by an array of TLR agonists and promoted T cell proliferation. The FLT3L-FC protein produced in vivo spontaneously homodimerized to enable effective FLT signaling and the FC-domain enhanced its plasma half-life, providing an improved reagent and method to boost DC numbers.


Subject(s)
Dendritic Cells/immunology , Gene Transfer Techniques , Membrane Proteins/genetics , Plasmids/metabolism , Recombinant Fusion Proteins/genetics , Animals , Cell Count , Cell Proliferation , Dendritic Cells/cytology , Female , Gene Expression , Half-Life , Hydrodynamics , Membrane Proteins/immunology , Mice , Mice, Inbred BALB C , Protein Multimerization , Recombinant Fusion Proteins/immunology , Signal Transduction
4.
Immunology ; 141(1): 111-22, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24116850

ABSTRACT

The concentration of CXCL12/SDF-1 in the bloodstream is tightly regulated, given its central role in leucocyte and stem/progenitor cell egress from bone marrow and recruitment to sites of inflammation or injury. The mechanism responsible for this regulation is unknown. Here we show that both genetic deletion and pharmacological inhibition of CXCR7, a high-affinity CXCL12 receptor, caused pronounced increases in plasma CXCL12 levels. The rise in plasma CXCL12 levels was associated with an impairment in the ability of leucocytes to migrate to a local source of CXCL12. Using a set of complementary and highly sensitive techniques, we found that CXCR7 protein is expressed at low levels in multiple organs in both humans and mice. In humans, CXCR7 was detected primarily on venule endothelium and arteriole smooth muscle cells. CXCR7 expression on venule endothelium was also documented in immunodeficient mice and CXCR7(+/lacZ) mice. The vascular expression of CXCR7 therefore gives it immediate access to circulating CXCL12. These studies suggest that endothelial CXCR7 regulates circulating CXCL12 levels and that CXCR7 inhibitors might be used to block CXCL12-mediated cell migration for therapeutic purposes.


Subject(s)
Chemokine CXCL12/immunology , Endothelium, Vascular/immunology , Gene Expression Regulation/immunology , Human Umbilical Vein Endothelial Cells/immunology , Receptors, CXCR/immunology , Animals , Cell Movement/immunology , Chemokine CXCL12/blood , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Leukocytes/cytology , Leukocytes/immunology , Leukocytes/metabolism , Mice , Organ Specificity/immunology , Receptors, CXCR/biosynthesis
5.
J Immunol ; 189(2): 956-67, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22696441

ABSTRACT

Chemokine (CC motif) receptor-like 2 (CCRL2) binds leukocyte chemoattractant chemerin and can regulate local levels of the attractant, but does not itself support cell migration. In this study, we show that CCRL2 and VCAM-1 are upregulated on cultured human and mouse vascular endothelial cells (EC) and cell lines by proinflammatory stimuli. CCRL2 induction is dependent on NF-κB and JAK/STAT signaling pathways, and activated endothelial cells specifically bind chemerin. In vivo, CCRL2 is constitutively expressed at high levels by lung endothelial cells and at lower levels by liver endothelium; and liver but not lung EC respond to systemic LPS injection by further upregulation of the receptor. Plasma levels of total chemerin are elevated in CCRL2(-/-) mice and are significantly enhanced after systemic LPS treatment in CCRL2(-/-) mice compared with wild-type mice. Following acute LPS-induced pulmonary inflammation in vivo, chemokine-like receptor 1 (CMKLR1)(+) NK cell recruitment to the airways is significantly impaired in CCRL2(-/-) mice compared with wild-type mice. In vitro, chemerin binding to CCRL2 on endothelial cells triggers robust adhesion of CMKLR1(+) lymphoid cells through an α(4)ß(1) integrin/VCAM-1-dependent mechanism. In conclusion, CCRL2 is expressed by EC in a tissue- and activation-dependent fashion, regulates circulating chemerin levels and its bioactivity, and enhances chemerin- and CMKLR1-dependent lymphocyte/EC adhesion in vitro and recruitment to inflamed airways in vivo. Its expression and/or induction on EC by proinflammatory stimuli provide a novel and specific mechanism for the local enrichment of chemerin at inflammatory sites, regulating the recruitment of CMKLR1(+) cells.


Subject(s)
Endothelium, Vascular/immunology , Endothelium, Vascular/metabolism , Receptors, CCR/biosynthesis , Animals , CHO Cells , Cell Movement/immunology , Chemokines , Chemotactic Factors/blood , Cricetinae , Endothelium, Vascular/pathology , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Intercellular Signaling Peptides and Proteins/blood , Janus Kinases/physiology , Mice , Mice, Inbred BALB C , Mice, Knockout , NF-kappa B/physiology , Receptors, CCR/deficiency , Receptors, CCR/physiology , STAT Transcription Factors/physiology , Signal Transduction/immunology , Up-Regulation/immunology , Vascular Cell Adhesion Molecule-1/biosynthesis
6.
Mol Cancer ; 10: 73, 2011 Jun 14.
Article in English | MEDLINE | ID: mdl-21672222

ABSTRACT

BACKGROUND: Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects. METHODS: The human Burkitt's lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM behavior by various concentrations of the various cognate chemokines for the above-mentioned receptors, placed in either the source or target wells of modified Boyden chamber migration plates, was assessed by quantifying the number of cells migrated under each experimental condition. RESULTS: Exposure of CXCR4⁺CXCR7⁺ cancer cells to CXCL12 greatly potentiated their TEM towards the chemokines CCL19 and CXCL13. This CXCL12-potentiated TEM was inhibited by the second CXCR7 chemokine ligand, CXCL11, as well as CXCR7-specific small molecule antagonists and antibodies. In contrast, the CXCR4 antagonist AMD3100 was less effective at inhibiting CXCL12-potentiated TEM. Thus, CXCR7 antagonists may be effective therapeutic agents for blocking CXCL12-mediated migration of CXCR4⁺CXCR7⁺ tumor cells into lymph nodes, regardless of whether the cancer cells follow a CXCL12 gradient or whether serum CXCL12 stimulates their migration towards CCR7 and CXCR5 chemokines in the lymph nodes.


Subject(s)
Neoplasms/physiopathology , Receptors, CXCR/metabolism , Transendothelial and Transepithelial Migration/genetics , Antibodies/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemokines/pharmacology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Profiling , Gene Silencing , Humans , Lymphoma, B-Cell/physiopathology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptors, CCR7/metabolism , Receptors, CXCR/antagonists & inhibitors , Receptors, CXCR5/metabolism , Transendothelial and Transepithelial Migration/drug effects
7.
J Immunol ; 185(9): 5130-9, 2010 Nov 01.
Article in English | MEDLINE | ID: mdl-20889540

ABSTRACT

Since the discovery that CXCR7 binds to CXCL12/SDF-1α, the role of CXCR7 in CXCL12-mediated biological processes has been under intensive scrutiny. However, there is no consensus in the literature on the expression of CXCR7 protein by peripheral blood cells. In this study we analyzed human and mouse leukocytes and erythrocytes for CXCR7 protein expression, using a competitive CXCL12 binding assay as well as by flow cytometry and immunohistochemistry using multiple CXCR7 Abs. CXCR7(-/-) mice were used as negative controls. Together, these methods indicate that CXCR7 protein is not expressed by human peripheral blood T cells, B cells, NK cells, or monocytes, or by mouse peripheral blood leukocytes. CXCR7 protein is, however, expressed on mouse primitive erythroid cells, which supply oxygen to the embryo during early stages of development. These studies therefore suggest that, whereas CXCR7 protein is expressed by primitive RBCs during murine embryonic development, in adult mammals CXCR7 protein is not expressed by normal peripheral blood cells.


Subject(s)
Erythrocytes/metabolism , Leukocytes/metabolism , Receptors, CXCR/biosynthesis , Adult , Animals , Cell Separation , Embryo, Mammalian , Flow Cytometry , Hematopoiesis/genetics , Hematopoietic Stem Cells/metabolism , Humans , Immunohistochemistry , Mice , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction
8.
J Rheumatol ; 37(3): 574-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20080916

ABSTRACT

OBJECTIVE: We examined the genetic association of the promoter insertion/deletion (indel) in IRF5 gene with systemic lupus erythematosus (SLE) in distinct populations and assessed its role in gene expression. METHODS: Four IRF5 polymorphisms were genotyped in 1488 SLE patients and 1466 controls. Gene expression was analyzed by quantitative real-time PCR using RNA from peripheral blood mononuclear cells (PBMC). RESULTS: The promoter indel and rs2070197 had independent genetic effects, which accounted for the association of rs2004640 and rs10954213. Gene expression analysis revealed that rs10954213 exerted the greatest influence on IRF5 transcript levels. CONCLUSION: We corroborated the association of the promoter indel with SLE in 5 different populations and revealed that rs10954213 is the main single-nucleotide polymorphism responsible for altered IRF5 expression in PBMC.


Subject(s)
Genetic Predisposition to Disease/genetics , INDEL Mutation/genetics , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Leukocytes, Mononuclear/metabolism , Lupus Erythematosus, Systemic/genetics , Promoter Regions, Genetic/genetics , Argentina , Case-Control Studies , Gene Expression Regulation , Gene Frequency , Genotype , Germany , Humans , Italy , Lupus Erythematosus, Systemic/ethnology , Mexico , Polymorphism, Single Nucleotide/genetics , Spain
9.
Oncol Lett ; 1(5): 845-847, 2010 Sep.
Article in English | MEDLINE | ID: mdl-22966392

ABSTRACT

Metastatic breast cancer is the leading cause of cancer-related death in women worldwide and, despite recent therapeutic advances, the disease remains incurable. A critical step in cancer cell metastasis is the degradation of extracellular matrix components by matrix metalloproteinases (MMPs), which permits malignant cells to separate from the primary tumor and access circulatory conduits for seeding distant organs. This study reports a correlation between the elevated secretion of MMP-3 by breast cancer cells and the expression of CCR7 protein, a recently discovered non-classical chemokine receptor that may play a role in metastasis by regulating tumor cell transendothelial migration. MMP-3 secretion is increased in human mammary tumor cells that overexpress CXCR7, and is reduced in mouse breast cancer cells in which the endogenous CXCR7 expression has been knocked down via RNAi. The correlation between CXCR7 and MMP-3 expression in breast cancer may provide additional therapeutic rationale for targeting CXCR7 in order to prevent metastatic disease.

10.
J Immunol ; 183(5): 3204-11, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19641136

ABSTRACT

CXCR7 binds chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1) but does not act as a classical chemoattractant receptor. Using CCX771, a novel small molecule with high affinity and selectivity for CXCR7, we found that, although CXCR7 is dispensable for "bare filter" in vitro chemotaxis, CXCR7 plays an essential role in the CXCL12/CXCR4-mediated transendothelial migration (TEM) of CXCR4(+)CXCR7(+) human tumor cells. Importantly, although CXCL11 is unable to stimulate directly the migration of these cells, it acts as a potent antagonist of their CXCL12-induced TEM. Furthermore, even though this TEM is driven by CXCR4, the CXCR7 ligand CCX771 is substantially more potent at inhibiting it than the CXCR4 antagonist AMD3100, which is more than 100 times weaker at inhibiting TEM when compared with its ability to block bare filter chemotaxis. Far from being a "silent" receptor, we show that CXCR7 displays early hallmark events associated with intracellular signaling. Upon cognate chemokine binding, CXCR7 associates with beta-arrestin2, an interaction that can be blocked by CXCR7-specific mAbs. Remarkably, the synthetic CXCR7 ligand CCX771 also potently stimulates beta-arrestin2 recruitment to CXCR7, with greater potency and efficacy than the endogenous chemokine ligands. These results indicate that CXCR7 can regulate CXCL12-mediated migratory cues, and thus may play a critical role in driving CXCR4(+)CXCR7(+) tumor cell metastasis and tissue invasion. CXCR7 ligands, such as the chemokine CXCL11 and the newly described synthetic molecule CCX771, may represent novel therapeutic opportunities for the control of such cells.


Subject(s)
Cell Migration Inhibition/immunology , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/physiology , Receptors, CXCR/antagonists & inhibitors , Receptors, CXCR/physiology , Signal Transduction/immunology , Animals , CHO Cells , Cell Line , Cell Line, Tumor , Chemokine CXCL12/antagonists & inhibitors , Chemokine CXCL12/metabolism , Chemotaxis, Leukocyte/immunology , Cricetinae , Cricetulus , Endothelium, Vascular/metabolism , Humans , Ligands , Receptors, CXCR/biosynthesis , Receptors, CXCR/metabolism , Receptors, CXCR4/biosynthesis , U937 Cells
11.
Cancer Immunol Immunother ; 57(4): 507-15, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17786443

ABSTRACT

Tumor associated macrophages (TAMs) are well known to play a very important role in tumor angiogenesis and metastasis. The suppression of TAMs in the tumor-microenvironment (TME) provides a novel strategy to inhibit tumor growth and dissemination by remodeling the tumor's stroma. Here, we tested our hypothesis that suppression of TAMs can be achieved in syngeneic BALB/c mice with oral minigene vaccines against murine MHC class I antigen epitopes of Legumain, an asparaginyl endopeptidase and a member of the C13 family of cystine proteases which is overexpressed on TAMs in the tumor stroma. Vaccine vectors were constructed and transformed into attenuated Salmonella typhimurium (Dam ( - ) , AroA ( - )) for oral delivery. Groups of mice received either the expression vectors encoding the Legumain H-2D or 2K epitopes or the control empty vector by gavage. The efficacy of the minigene vaccines was determined by their ability to protect mice from lethal tumor cell challenges, the induction of a specific CTL response as well as IFN-gamma release, and inhibition of tumor angiogenesis. We demonstrated that the Legumain minigene vaccine provided effective protection against tumor cell challenge by inducing a specific CD8+ T-cell response against Legumain+ TAMs in our breast tumor model. The protection, induced by this T-cell response, mediated by the Legumain Kd minigene, is also responsible for lysing D2F2 breast carcinoma cells in syngeneic BALB/c mice and for suppressing tumor angiogenesis. Importantly, in a prophylactic setting, the minigene vaccine proved to be of similar anti-tumor efficacy as a vaccine encoding the entire Legumain gene. Together, our findings establish proof of concept that a Legumain minigene vaccine provides a more flexible alternative to the whole gene vaccine, which may facilitate the future design and clinical applications of such a vaccine for cancer prevention.


Subject(s)
Cancer Vaccines/immunology , Cysteine Endopeptidases/immunology , Macrophages/immunology , Mammary Neoplasms, Experimental/prevention & control , Neovascularization, Pathologic/immunology , Vaccines, DNA/immunology , Animals , Cysteine Endopeptidases/genetics , Cytotoxicity, Immunologic , Female , Histocompatibility Antigens Class I/immunology , Macrophages/metabolism , Mammary Neoplasms, Experimental/blood supply , Mammary Neoplasms, Experimental/immunology , Mice , Mice, Inbred BALB C , T-Lymphocytes, Cytotoxic/immunology
12.
Arthritis Rheum ; 56(4): 1234-41, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17393452

ABSTRACT

OBJECTIVE: To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. METHODS: Peripheral blood mononuclear cells were obtained from SLE patients and healthy controls from Argentina, Spain, and Germany and from trio families from Spain and Denmark. A reporter assay was used to investigate the role of SNP no. rs2004640. IRF5 expression in relation to the genotypes of functional SNPs was analyzed using quantitative polymerase chain reaction. Sequencing and genotyping of the IRF5 gene was performed. RESULTS: Sequencing of complementary DNA from individuals with different genotypes showed 4 basic isoforms transcribed from all 5'-untranslated regions (5'-UTRs), suggesting no preferential isoform transcription based on rs2004640 genotypes. Analysis of translation efficiency showed that exon 1A was the most efficient in initiating protein synthesis. We identified a novel polymorphic insertion/deletion that defines the pattern of expression of isoforms of IRF5. The insertion consists of 4 repeats in exon 6 affecting the protein interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5'-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon-alpha. The SNP most strongly associated with SLE was SNP no. rs2070197 (P=5.2x10(-11)), which is a proxy of the risk haplotype, but does not appear to be functional. CONCLUSION: None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor splice site, and its functional importance appears to be small. Our results suggest that there may be other functional polymorphisms, yet to be identified, in IRF5. We did not observe evidence of epistatic interaction between the functional SNPs.


Subject(s)
Gene Expression Regulation/physiology , Interferon Regulatory Factors/genetics , Lupus Erythematosus, Systemic/genetics , Mutagenesis, Insertional/genetics , Sequence Deletion , 5' Untranslated Regions/genetics , 5' Untranslated Regions/metabolism , Base Sequence , Family Health , Female , Haplotypes , Humans , Interferon Regulatory Factors/biosynthesis , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Male , Molecular Sequence Data , Nuclear Family , Polymorphism, Single Nucleotide , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , RNA Splicing/physiology , Reverse Transcriptase Polymerase Chain Reaction , Reverse Transcription , Risk Factors , Sequence Analysis, DNA
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