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1.  The Type I Interferons: Basic Concepts and Clinical Relevance in Immune-mediated Inflammatory Diseases 
Gene  2015;576(1 0 1):14-21.
There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of “viral interference”, a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent.
PMCID: PMC4666791  PMID: 26410416
Interferon alpha; Interferon beta; Interferon signature; autoimmune diseases; systemic lupus erythematosus; rheumatoid arthritis; multiple sclerosis; idiopathic inflammatory myopathies
2.  Immunogenetics of Systemic Lupus Erythematosus: A Comprehensive Review 
Journal of autoimmunity  2015;64:125-136.
Our understanding of the genetic basis of systemic lupus erythematosus has progressed rapidly in recent years. While many genetic polymorphisms have been associated with disease susceptibility, the next major step involves integrating these genetic polymorphisms into the molecular mechanisms and cellular immunology of the human disease. In this review, we summarize some recent work in this area, including the genetics of the type I IFN response in SLE, including polygenic and monogenic factors, as well as epigenetic influences. Contributions of both HLA and non-HLA polymorphisms to the complex genetics of SLE are reviewed. We also review recent reports of specific gene deficits leading to monogenic SLE-like syndromes. The molecular functions of common SLE-risk variants are reviewed in depth, including regulatory variations in promoter and enhancer elements and coding-change polymorphisms, and studies which are beginning to define the molecular and cellular functions of these polymorphisms in the immune system. We discuss epigenetic influences on lupus, with an emphasis on micro-RNA expression and binding, as well as epigenetic modifications that regulate the expression levels of various genes involved in SLE pathogenesis and the ways epigenetic marks modify SLE susceptibility genes. The work summarized in this review provides a fascinating window into the biology and molecular mechanisms of human SLE. Understanding the functional mechanisms of causal genetic variants underlying the human disease greatly facilitates our ability to translate genetic associations toward personalized care, and may identify new therapeutic targets relevant to human SLE disease mechanisms.
PMCID: PMC4628859  PMID: 26324017
systemic lupus erythematosus; genetics; interferon; autoimmune diseases
3.  Advances in Lupus Genetics 
Current opinion in rheumatology  2015;27(5):440-447.
Purpose of Review
The field of systemic lupus erythematosus (SLE) genetics has been advancing rapidly in recent years. This review will summarize recent progress.
Recent Findings
Genome-wide association and follow up studies have greatly expanded the list of associated polymorphisms, and much current work strives to integrate these polymorphisms into immune system biology and the pathogenic mediators involved in the disease. This review covers some current areas of interest, including genetic studies in non-European SLE patient populations, studies of pathogenic immune system subphenotypes such as type I interferon (IFN) and autoantibodies, and a rapidly growing body of work investigating the functional consequences of the genetic polymorphisms associated with SLE.
These studies provide a fascinating window into human SLE disease biology. As the work proceeds from genetic association signal to altered human biology, we move closer to tailoring interventions based upon an individual’s genetic substrate.
PMCID: PMC4540605  PMID: 26218512
systemic lupus erythematosus; genetics; interferon; autoantibodies
4.  Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus 
Clinical immunology (Orlando, Fla.)  2015;161(2):157-162.
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
PMCID: PMC4658308  PMID: 26385092
systemic lupus erythematosus; leptin pathway; gene polymorphisms
5.  Folate metabolic pathway single nucleotide polymorphisms: a predictive pharmacogenetic marker of methotrexate response in Indian (Asian) patients with rheumatoid arthritis 
Pharmacogenomics  2015;16(18):2019-2034.
We evaluated the pharmacogenetic influence of genetic polymorphisms in folate pathway genes in Indian rheumatoid arthritis patients receiving methotrexate (MTX).
Patients & methods:
Twelve polymorphisms within nine folate pathway genes were analyzed for association with MTX response in 322 Indian rheumatoid arthritis (RA) patients and MTX pharmacokinetics in 94 RA patients.
Polymorphisms in GGH, SHMT1 and TS were associated with MTX-related adverse events while SNPs in MTHFR and RFC1/SLC19A1 were associated with MTX efficacy. TS5′UTR and SHMT1 polymorphisms were associated with higher plasma levels of MTX.
Polymorphisms in folate-MTX pathway genes contribute to MTX response and affect MTX concentrations in Indian RA patients. A toxicogenetic index could identify patients who develop adverse events to MTX.
PMCID: PMC4976849  PMID: 26616421
folate metabolism; homocysteine; Indians; methotrexate; pharmacogenomics; pharmacokinetics
6.  Widely Divergent Transcriptional Patterns Between SLE Patients of Different Ancestral Backgrounds in Sorted Immune Cell Populations 
Journal of autoimmunity  2015;60:51-58.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. We examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Peripheral blood was collected from African-American (AA) and European-American (EA) SLE patients and controls. CD4 T-cells, CD8 T-cells, monocytes, and B cells were purified by flow sorting, and each cell subset from each subject was run on a genome-wide expression array. Cases were compared to controls of the same ancestral background. The overlap in differentially expressed gene (DEG) lists between different cell types from the same ancestral background was modest (<10%), and only 5-8% overlap in DEG lists was observed when comparing the same cell type between different ancestral backgrounds. IFN-stimulated gene (ISG) expression was not up-regulated synchronously in all cell types from a given patient, for example a given subject could have high ISG expression in T and B cells, but not in monocytes. AA subjects demonstrated more concordance in ISG expression between cell types from the same individual, and AA patients demonstrated significant down-regulation of metabolic gene expression which was not observed in EA patients. ISG expression was significantly decreased in B cells in patients taking immunosuppressants, while ISGs in other cell types did not differ with medication use. In conclusion, gene expression was strikingly different between immune cell subsets and between ancestral backgrounds in SLE patients. These findings emphasize the critical importance of studying multiple ancestral backgrounds and multiple cell types in gene expression studies. Ancestral backgrounds which are not studied will not benefit from personalized medicine strategies in SLE.
PMCID: PMC4457613  PMID: 25921064
Systemic Lupus Erythematosus; Interferon; Ancestral Background; Gene Expression
7.  Autoimmune Disease Genetics 2013 
Journal of Immunology Research  2014;2014:487643.
PMCID: PMC4140134  PMID: 25165727
8.  Interferon Regulatory Factors: Critical Mediators of Human Lupus 
The pathogenesis of systemic lupus erythematosus (SLE) is multi-factorial, and the interferon regulatory factors (IRFs) play an important role. Autoantibodies formed in SLE target nuclear antigens, and immune complexes formed by these antibodies contain nucleic acid. These immune complexes can activate anti-viral pattern-recognition receptors (PRRs), resulting in the downstream activation of interferon regulatory factors (IRFs), which can induce type I interferon and other inflammatory mediators. Genetic variations in IRFs have been associated with susceptibility to SLE, and current evidence supports the idea that these polymorphisms are gain-of-function in humans. Recent studies suggest that these genetic variations contribute to the break in humoral tolerance that allows for nucleic acid binding autoantibodies, and that the same polymorphisms also augment type I IFN production in the presence of these autoantibody immune complexes, forming a feed-forward loop. In this review, we will outline major features of the PRR/IRF systems and describe the role of the IRFs in human SLE pathogenesis.
PMCID: PMC4306637  PMID: 25445206
9.  Autoimmune Disease Genetics 
PMCID: PMC3540923  PMID: 23320016
10.  Dysregulation of antiviral helicase pathways in systemic lupus erythematosus 
Frontiers in Genetics  2014;5:418.
In the autoimmune disease systemic lupus erythematosus (SLE), our normal antiviral defenses are inappropriately activated, resulting in over-activity of the type I interferon (IFN) pathway. This increased activity of the type I IFN pathway is an important primary pathogenic factor in the disease. Emerging evidence has implicated the antiviral helicases in this process. The antiviral helicases normally function as nucleic acid receptors in viral immunity. Genetic variations in antiviral helicase genes have been associated with SLE, supporting the idea that helicase pathways are involved in the primary pathogenesis of SLE. Studies have documented functional consequences of these genetic variations within the type I IFN pathway in human cell lines and SLE patients. In this review, we summarize the function of helicases in the anti-viral immune response, and how this response is dysregulated in SLE patients. In particular, we will focus on known functional genetic polymorphisms in the IFIH1 (MDA5) and mitochondrial antiviral signaling protein genes which have been implicated in human SLE. These data provide fascinating evidence for dysregulation of helicase-mediated innate immunity in SLE, and may support novel therapeutic strategies in the disease.
PMCID: PMC4243696  PMID: 25505487
antiviral helicase; systemic lupus erythematosus; interferon
11.  Genetic Association of CD247 (CD3ζ) with SLE in a Large-Scale Multiethnic Study 
Genes and immunity  2015;16(2):142-150.
A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
PMCID: PMC4371129  PMID: 25569266
Genes and immunity  2014;16(1):15-23.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 40–50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs. low IFN-α in over 1550 SLE cases, including GWAS and replication cohorts. In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (PMeta=2.75 × 10−8) and PNP rs1049564 (PMeta=1.24 × 10−7). We also found evidence for cross-ancestral background associations with the ANKRD44 and PLEKHF2 loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes an attractive strategy for genetic discovery in complex disease.
PMCID: PMC4305028  PMID: 25338677
Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-α) levels. We explored circulating TNF-α levels in SLE families to determine whether high levels of TNF-α were clustered in a heritable pattern. We measured TNF-α in 242 SLE patients, 361 unaffected family members, 23 unaffected spouses of SLE patients, and 62 unrelated healthy controls. Familial correlations and relative recurrence risk rates for the high TNF-α trait were assessed. SLE-affected individuals had the highest TNF-α levels, and TNF-α was significantly higher in unaffected first degree relatives than healthy unrelated subjects (P = 0.0025). No Mendelian patterns were observed, but 28.4% of unaffected first degree relatives of SLE patients had high TNF-α levels, resulting in a first degree relative recurrence risk of 4.48 (P = 2.9 × 10−5). Interestingly, the median TNF-α value in spouses was similar to that of the first degree relatives. Concordance of the TNF-α trait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-α in SLE pathogenesis, and TNF-α levels may relate with heritable factors. The high degree of concordance in SLE patients and their spouses suggests that environmental factors may also play a role in the observed familial aggregation.
PMCID: PMC3800640  PMID: 24187561
Gut  2015;65(3):456-464.
ATG16L1 is an autophagy gene known to control host immune responses to viruses and bacteria. Recently, a non-synonymous single-nucleotide polymorphism in ATG16L1 (Thr300Ala), previously identified as a risk factor in Crohn's disease (CD), was associated with more favourable clinical outcomes in thyroid cancer. Mechanisms underlying this observation have not been proposed, nor is it clear whether an association between Thr300Ala and clinical outcomes will be observed in other cancers. We hypothesised that Thr300Ala influences clinical outcome in human colorectal cancer (CRC) and controls innate antiviral pathways in colon cancer cells.
We genotyped 460 patients with CRC and assessed for an association between ATG16L1 Thr300Ala and overall survival and clinical stage. Human CRC cell lines were targeted by homologous recombination to examine the functional consequence of loss of ATG16L1, or introduction of the Thr300Ala variant.
We found an association between longer overall survival, reduced metastasis and the ATG16L1 Ala/Ala genotype. Tumour sections from ATG16L1 Ala/Ala patients expressed elevated type I interferons (IFN-I)-inducible, MxA, suggesting that differences in cytokine production may influence disease progression. When introduced into human CRC cells by homologous recombination, the Thr300Ala variant did not affect bulk autophagy, but increased basal production of type I IFN. Introduction of Thr300Ala resulted in increased sensitivity to the dsRNA mimic poly(I:C) through a mitochondrial antiviral signalling (MAVS)-dependent pathway.
The CD-risk allele, Thr300Ala, in ATG16L1 is associated with improved overall survival in human CRC, generating a rationale to genotype ATG16L1 Thr300Ala in patients with CRC. We found that Thr300A alters production of MAVS-dependent type I IFN in CRC cells, providing a mechanism that may influence clinical outcomes.
PMCID: PMC4789828  PMID: 25645662
Pediatrics  2011;127(5):e1239-e1246.
Familial aggregation of autoimmune diseases likely reflects shared pathogenic factors between different diseases. Familial aggregation of autoimmunity has not been examined in juvenile dermatomyositis. Interferon-α is thought to be a pathogenic factor in both systemic lupus erythematosus and juvenile dermatomyositis, and we have previously demonstrated familial aggregation of serum interferon-α.
Family histories were obtained from 304 families of children with juvenile dermatomyositis via 3-generation structured interviews performed by the same person. Rates of autoimmune disease in families of children with juvenile dermatomyositis were compared with published population rates. Serum interferon-α, tumor necrosis factor-α, and neopterin were measured using standard techniques.
A total of 51% of families of children with juvenile dermatomyositis reported at least 1 additional member affected by an autoimmune disease. In particular, both type 1 diabetes and systemic lupus erythematosus were significantly more common than would be expected (odds ratio >5, P ≤ 1 × 10−7 for both). Pedigree analysis showed particularly strong familial clustering of systemic lupus erythematosus with little decrease in incidence across generations, suggesting the possibility of rare causal genes with large effect. Untreated subjects with juvenile dermatomyositis with a family history of systemic lupus erythematosus had higher serum interferon-α than those who did not (P = .047).
We find strong familial aggregation of specific autoimmune diseases in families of children with juvenile dermatomyositis, suggesting that these conditions share pathogenic factors. Higher serum interferon-α in juvenile dermatomyositis patients with a family history of systemic lupus erythematosus suggesting that interferon-α is one such shared factor.
PMCID: PMC3081190  PMID: 21502224
juvenile dermatomyositis; systemic lupus erythematosus; diabetes mellitus type I; psoriasis; celiac disease; interferons
Annals of the Rheumatic Diseases  2014;75(1):242-252.
Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.
Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.
The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.
These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
PMCID: PMC4717392  PMID: 25180293
Systemic Lupus Erythematosus; Autoantibodies; Gene Polymorphism; B cells
Arthritis and rheumatism  2008;58(2):541-546.
The type I interferon (IFN) pathway is activated in many patients with systemic lupus erythematosus (SLE), and high serum levels of IFN are associated with anti-SSA/Ro autoantibodies. To investigate the clinical features associated with type I IFN production in vivo, we compared serum IFN activity in individuals with anti-SSA/Ro antibodies who were asymptomatic with that in individuals with clinical manifestations of SLE or Sjögren's syndrome (SS).
Antibody-positive sera from 84 mothers of children with manifestations of neonatal lupus were studied for type I IFN activity, using a functional reporter cell assay. Maternal health status was characterized as asymptomatic, SS, SLE, pauci-SLE, or pauci-SS, based on a screening questionnaire, telephone interview, and review of medical records. The prefix “pauci-” indicates symptoms insufficient for a formal classification of the disease.
Only 4% of asymptomatic mothers had high serum type I IFN activity, compared with 73% with pauci-SLE (P = 5.7 × 10−5), 35% with SLE (P = 0.011), and 32% of patients with SS (P = 0.032). One of the 4 patients with pauci-SS had high levels of IFN. The majority of patients for whom longitudinal data were available had stable type I IFN activity over time, and changes in IFN activity were not clearly accompanied by changes in the clinical diagnosis.
Patients with SLE, patients with pauci-SLE, and patients with SS are more likely to have high serum IFN activity than asymptomatic individuals with SSA/Ro autoantibodies, suggesting that these autoantibodies are insufficient for activation of the type I IFN pathway, and that disease-specific factors are important for type I IFN generation in vivo.
PMCID: PMC2755051  PMID: 18240214
Genes and immunity  2013;14(8):10.1038/gene.2013.42.
Alleles of IRF8 are associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While high type I interferon (IFN) is thought to be causal in SLE, type I IFN is used as a therapy in MS. We investigated whether IRF8 alleles were associated with type I IFN levels or serologic profiles in SLE and MS. Alleles which have been previously associated with SLE or MS were genotyped in SLE and MS patients. The MS-associated rs17445836G allele was associated with anti-dsDNA autoantibodies in SLE patients (meta-analysis OR=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and with decreased type I IFN-induced gene expression in PBMC from anti-dsDNA negative SLE patients. In secondary progressive MS patients, rs17445836G was associated with decreased serum type I IFN. Rs17445836G was associated with increased IRF8 expression in SLE patient B cells. In summary, IRF8 rs17445836G is associated with human autoimmune disease characterized by low type I IFN levels, and this may have pharmacogenetic relevance as type I IFN is modulated in SLE and MS. The association with autoantibodies and increased IRF8 expression in B cells supports a role for rs17445836G in humoral tolerance.
PMCID: PMC3856198  PMID: 23965942
systemic lupus erythematosus; type I interferon; autoantibodies; interferon regulatory factors
Annals of the rheumatic diseases  2012;72(4):596-601.
Hyperactivity of the type I interferon (IFN) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). Immunoglobulin like transcript (ILT3) is an immunohibitory transmembrane molecule which is induced by type I IFNs. ILT3 is expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. Given the pathogenic role of IFN in SLE, we hypothesised that the IFN-induced immunosuppressive ILT3 receptor may be dysfunctional in human SLE.
132 European-derived and 79 Hispanic-American SLE patients were genotyped for two coding-change single nucleotide polymorphisms (SNPs) predicted to interfere with protein folding in ILT3 (rs11540761 and rs1048801). 116 control DNA samples and sera from healthy controls were also studied. We detected associations between ILT3 genotype and serum cytokine profiles. ILT3 expression levels on PDCs and MDCs from 18 patients and 10 controls were studied by flow cytometry.
The rs11540761 SNP in the extracellular region was associated with decreased cell surface expression of ILT3 on circulating MDCs and to a lesser extent PDCs in SLE patients. The cytoplasmically located rs1048801 SNP was not associated with a change in dendritic cells expression of ILT3. Both SNPs were significantly and independently associated with increased levels of serum type I IFN activity in SLE patients. The rs1048801 SNP was also associated with increased serum levels of TNF-α.
Loss-of-function polymorphisms in ILT3 are associated with increased inflammatory cytokine levels in SLE, supporting a biological role for ILT3 in SLE.
PMCID: PMC3910490  PMID: 22904259
PMCID: PMC4074699  PMID: 25071767
interferons; systemic lupus erythematosus; Sjogren’s syndrome; multiple sclerosis; scleroderma; systemic; type I diabetes; autoimmune thyroid disease
Arthritis and rheumatism  2012;64(10):3383-3387.
Genetic variation in interferon regulatory factor 5 (IRF5) has been associated with risk of developing systemic lupus erythematosus (SLE), and this association is largely dependent upon anti-Ro autoantibodies. We studied a unique cohort of anti-Ro positive individuals with diverse diagnoses to determine if IRF5 genotype associated with maternal diagnosis or progression of autoimmunity.
We genotyped haplotype-tagging polymorphisms in IRF5 in 93 European ancestry subjects recruited to the Research Registry for Neonatal Lupus who all had high titer anti-Ro autoantibodies and a child with neonatal lupus (NL), and allele frequencies were compared to non-autoimmune controls. The mothers diagnoses included SLE, Sjogren’s syndrome (SS), undifferentiated autoimmune syndrome (UAS), and asymptomatic.
The SLE-risk haplotype of IRF5 was enriched in all anti-Ro positive subjects except those with SS (OR = 2.55, p=8.8×10−4). Even asymptomatic individuals with anti-Ro antibodies were enriched for the SLE-risk haplotype (OR=2.69, p=0.019). The same haplotype was more prevalent in subjects who were initially asymptomatic, but developed symptomatic SLE during follow up (OR=5.83, p=0.0024). Interestingly, SS was associated with two minor IRF5 haplotypes, and these same haplotypes were decreased in frequency in those with SLE and UAS.
The IRF5 SLE-risk haplotype was associated with anti-Ro antibodies in asymptomatic individuals as well as progression to SLE in asymptomatic anti-Ro positive individuals. SS in NL mothers was associated with different IRF5 haplotypes. These data suggest that IRF5 polymorphisms play a role in serologic autoimmunity in humans and may promote the progression to clinical autoimmunity.
PMCID: PMC3449035  PMID: 22674082
systemic lupus erythematosus; interferon; autoantibodies; neonatal lupus; Sjogren’s syndrome
Arthritis and rheumatism  2012;64(9):2947-2952.
SLE disease manifestations are highly variable between patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor alpha (TNF-α) is elevated in some SLE patients, and may play a role in disease pathogenesis. We detected associations between serum TNF-α, clinical manifestations, autoantibodies, and serum IFN-α in a large multi-ancestral SLE cohort.
We studied serum TNF-α in 653 SLE patients, including 214 African-American, 298 European-Americans and 141 Hispanic-American subjects. TNF-α was measured using ELISA, and IFN-α was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate.
Serum TNF-α levels were significantly higher in SLE patients than in nonautoimmune controls (p<5.0×10−3 for each ancestral background). High serum TNF-α was positively correlated with high serum IFN-α when tested in the same sample across all ancestral backgrounds (meta-analysis OR=1.8, p=1.2×10−3). While serum TNF-α levels alone did not differ significantly between SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high TNF-α and high IFN-α was highest in African-Americans and lowest in European-Americans (p=5.0×10−3). Serum TNF-α was not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at time of sample.
Serum TNF-α levels are high in many SLE patients, and we observed a positive correlation between serum TNF-α and IFN-α. These data support a role for TNF-α in SLE pathogenesis across all ancestral backgrounds, and suggest important cytokine subgroups within the disease.
PMCID: PMC3396783  PMID: 22488302
systemic lupus erythematosus; tumor necrosis factor alpha; autoantibodies, ancestry
Annals of the Rheumatic Diseases  2011;71(3):463-468.
High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.
1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.
In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE.
The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements.
SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.34
PMCID: PMC3307526  PMID: 22088620
Human Molecular Genetics  2014;23(15):4161-4176.
Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10−90, odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele (‘A’) relative to the non-risk allele (‘G’), in a dose-dependent fashion: (‘AA’ < ‘AG’ < ‘GG’). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the ‘A’ transcript than ‘G’ transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.
PMCID: PMC4082363  PMID: 24608226
Background: In systemic lupus erythematosus (SLE), antibodies directed at RNA-binding proteins (anti-RBP) are associated with high serum type I interferon (IFN), which plays an important role in SLE pathogenesis. African-Americans (AA) are more likely to develop SLE, and SLE is also more severe in this population. We hypothesized that peripheral blood gene expression patterns would differ between AA and European-American (EA) SLE patients, and between those with anti-RBP antibodies and those who lack these antibodies.
Methods: Whole blood RNA from 33 female SLE patients and 16 matched female controls from AA and EA ancestral backgrounds was analyzed on Affymetrix Gene 1.0 ST gene expression arrays. Ingenuity Pathway Analysis was used to compare the top differentially expressed canonical pathways amongst the sample groups. An independent cohort of 116 SLE patients was used to replicate findings using quantitative real-time PCR (qPCR).
Results: Both AA and EA patients with positive anti-RBP antibodies showed over-expression of similar IFN-related canonical pathways, such as IFN Signaling (P = 1.3 × 10−7 and 6.3 × 10−11 in AA vs. EA respectively), Antigen Presenting Pathway (P = 1.8 × 10−5 and 2.5 × 10−6), and a number of pattern recognition receptor pathways. In anti-RBP negative (RBP−) patients, EA subjects demonstrated similar IFN-related pathway activation, whereas no IFN-related pathways were detected in RBP−AA patients. qPCR validation confirmed similar results.
Conclusion: Our data show that IFN-induced gene expression is completely dependent on the presence of autoantibodies in AA SLE patients but not in EA patients. This molecular heterogeneity suggests differences in IFN-pathway activation between ancestral backgrounds in SLE. This heterogeneity may be clinically important, as therapeutics targeting this pathway are being developed.
PMCID: PMC3787392  PMID: 24101921
systemic lupus erythematosus; interferon alpha; autoantibodies; ancestral background; interferon gamma

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