A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus

Systemic lupus erythematosus is an autoimmune disease characterized by autoantibody production against nuclear Ags. Recent studies suggest that the Cr2 gene, which encodes for complement receptor (CR)1 and CR2, is important in disease susceptibility. Because the precise disease phenotype related to this gene, in isolation or in relation to other genetic loci, is not known, we analyzed C57BL/6 mice with a targeted mutation in Cr2 (C57BL/6.Cr2(-/-)) with or without a concomitant mutation in Fas (C57BL/6.lpr Cr2(-/-)). The Cr2(null) mutation in a C57BL/6.lpr background markedly increases the serum concentrations of IgG1 and IgG2b and the levels of antinuclear and anti-dsDNA Abs as compared with C57BL/6.lpr controls. There is also a trend for higher concentrations of IgG2a and IgG3. In contrast, isolated deficiencies in either these CRs or Fas have a limited effect in the production of anti-dsDNA Abs. Moreover, the Cr2(null) mutation does not affect other disease manifestations. These findings demonstrate that abnormalities in CR1 and CR2 may be linked to the production of autoantibodies by modifying the effect of other systemic lupus erythematosus susceptibility genes. Phenotypic expression of other disease manifestations need additional Cr2-independent genetic factors.     

Genetic background of cutaneous forms of lupus erythematosus: update on current evidence

This article reviews and updates current information on the possible genetic basis for cutaneous lupus erythematosus. The aetiology of this condition remains unknown and is believed to be multifactorial, involving genetic, environmental and retroviral factors. A genetic predisposition is probably the greatest risk factor for this condition. Individual susceptibility to lupus erythematosus may be determined by a combination of specific polymorphisms of genes encoding multiple cytokines, adhesion molecules, and cellular proteins. This condition may lead to an abnormal expression of immunoregulatory molecules and finally results in the development or exacerbation of the disease. Recently also the role of endogenous retroviral sequences in the pathogenesis of autoimmunity has been discussed.     

Genetic susceptibility to autoimmune disorders: clues from gene association and gene expression studies

Susceptibility to autoimmune disorders results from the interaction of multiple genetic factors that regulate the threshold of autoreactivity. Genome-wide microsatellite screens and large-scale single nucleotide polymorphism (SNP) association studies have identified chromosomal loci that are associated with specific disorders including systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, multiple sclerosis, and diabetes. Numerous candidate gene association studies have in turn investigated the association of specific genes within these chromosomal regions, with susceptibility to autoimmune diseases (e.g. FcgammaReceptors, TYK2 and systemic lupus). More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus). In the future, integrated analyses of gene (and protein) expression together with SNP data will allow us to sketch an intelligible picture of the genesis of autoimmunity in humans. This review sets out to illustrate how the most recent advances in the field of systemic lupus erythematosus, rheumatoid arthritis and juvenile arthritis have led to a better understanding of these disorders.     

Spontaneous autoimmunity in 129 and C57BL/6 mice-implications for autoimmunity described in gene-targeted mice

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 × C57BL/6) model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE.     

Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms (SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes—the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes—we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10^-7) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.     

Profiles of gene expression in human autoimmune disease

Human autoimmune diseases arise from complex interactions between genetic and environmental factors, result from immune attack upon target tissues, and affect 3–5% of the population. We compared gene expression profiles (>4000 genes) in the peripheral blood mononuclear cells of normal individuals after immunization to individuals with four different autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes mellitus, and multiple sclerosis). All autoimmune individuals, including unaffected first-degree relatives, share a common gene expression profile that is completely distinct from the immune profile. Therefore, this expression pattern is not simply a recapitulation of the immune response to nonself, is not a result of the disease process, and results, as least in part, from genetic factors. Surprisingly, these genes are clustered in chromosomal domains suggesting there is some genomewide logic to this unique expression pattern. These data argue that that there is a constant pattern of gene expression in autoimmunity that is independent of the specific autoimmune disease and clinical parameters associated with any individual autoimmune disease.     

Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.KEY WORDS: Lupus, SLE, Human genetics, Mouse models, Susceptibility genes     

Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted Mice

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 × C57BL/6) model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE.     

B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity.

B cells are required for both the expression of lupus nephritis and spontaneous T cell activation/memory cell accumulation in MRL-Faslpr mice (MRL/lpr). Autoimmunity in the MRL/lpr strain is the result of Fas-deficiency and multiple background genes; however, the precise roles of background genes vs Fas-deficiency have not been fully defined. Fas-deficiency (i.e., the lpr defect) is required in B cells for optimal autoantibody expression, raising the possibility that the central role for B cells in MRL/lpr mice may not extend to MRL/+ mice and, thus, to lupus models that do not depend on Fas-deficiency ("polygenic lupus"). To address this issue, B cell-deficient, Fas-intact MRL/+ mice (JHd-MRL/) were created; and disease was evaluated in aged animals (>9 mo). The JHd-MRL/+ animals did not develop nephritis or vasculitis at a time when the B cell-intact littermates had severe disease. In addition, while activated/memory CD4+ and CD8+ T cells accumulated in B cell-intact mice, such accumulation was substantially inhibited in the absence of B cells. This effect appeared to be restricted to the MRL strain because it was not seen in B cell-deficient BALB/c mice (JHd-BALB) of similar ages. The results indicate that B cells are essential in promoting systemic autoimmunity in a Fas-independent model. Therefore, B cells have an important role in pathogenesis, generalizable to lupus models that depend on multiple genes even when Fas expression is intact. The results provide further rationale for B cell suppression as therapy for systemic lupus erythematosus.     

Limited evidence that cancer susceptibility regions are preferential targets for somatic mutation

BackgroundGenome wide-association studies have successfully identified several hundred independent loci harboring common cancer susceptibility alleles that are distinct from the more than 110 cancer predisposition genes. The latter are generally characterized by disruptive mutations in coding genes that have been established as ‘drivers’ of cancer in large somatic sequencing studies. We set out to determine whether, similarly, common cancer susceptibility loci map to genes that have altered frequencies of mutation.ResultsIn our analysis of the intervals defined by the cancer susceptibility markers, we observed that cancer susceptibility regions have gene mutation frequencies comparable to background mutation frequencies. Restricting analyses to genes that have been determined to be pleiotropic across cancer types, genes affected by expression quantitative trait loci, or functional genes indicates that most cancer susceptibility genes classified into these subgroups do not display mutation frequencies that deviate from those expected. We observed limited evidence that cancer susceptibility regions that harbor common alleles with small estimated effect sizes are preferential targets for altered somatic mutation frequencies.ConclusionsOur findings suggest a complex interplay between germline susceptibility and somatic mutation, underscoring the cumulative effect of common variants on redundant pathways as opposed to driver genes. Complex biological pathways and networks likely link these genetic features of carcinogenesis, particularly as they relate to distinct polygenic models for each cancer type.     

牛疾病相关基因的DNA变异及遗传控制

牛基因组中一些重要基因的DNA突变通过改变基因的表达和蛋白质功能来影响机体对疾病的抗性或易感性。控制牛疾病的DNA变异主要分为单基因座及多基因座两类。导致疾病的单基因座类型亦称因果突变,其遗传基础较简单,突变一般位于基因编码区或非编码区,多为单碱基或少数几个碱基的突变,这些突变导致氨基酸的错义突变、翻译提前终止或部分外显子缺失等。相比而言,多基因相关疾病的遗传基础较为复杂,遗传-病原体-环境间的互作是导致这类复杂疾病的主要原因。文章综述了由单基因座和多基因座遗传变异所控制的牛主要疾病的研究和应用现状,以及在牛育种及生产中为降低这些疾病的发生所采用的遗传控制策略。     

Complex genetic association of 6q23 with autoimmune rheumatic conditions

In the paper by Dieguez-Gonzalez and colleagues in the present issue of Arthritis Research & Therapy, the results of a detailed genetic investigation of the recently identified rheumatoid arthritis and systemic lupus erythematosus susceptibility region at 6q23 containing the TNFAIP3 gene are reported. Their data confirm the complex nature of the association involving both the TNFAIP3 locus and a region >150 kb upstream that does not encode any known gene. These data are consistent with recent studies of systemic lupus erythematosus susceptibility confirming the presence of several independent genetic contributions to autoimmune rheumatic diseases arising from 6q23.     

A single-nucleotide polymorphism of the TNFAIP3 gene is associated with systemic lupus erythematosus in Chinese Han population

Systemic lupus erythematosus (SLE) is a complex systemic disease influenced by genetic and environmental factors. The exact pathogenesis of SLE is still unknown. Recently, several genome-wide association studies (GWA) in European population have found many novel susceptibility genes for SLE including TNFAIP3. In order to examine whether TNFAIP3 is associated with SLE in Chinese Han population, we genotyped one of its non-synonymous mutation SNP rs2230926, showing significant association evidence with SLE in European population, with 1,420 cases and 4,461 controls of Chinese Han by using Sequenom MassArray system. Highly significant association between SNP rs2230926 and SLE of Chinese Han was detected [OR = 1.65, 95% confidence interval (CI): 1.392–1.986, P = 2.03 × 10⁻⁸]. Interestingly, rs2230926 of TNFAIP3 was also associated with arthritis, ANA and some other subphenotypes of the disease. Our findings suggest that SNP rs2230926 in the TNFAIP3 might be a common genetic factor for SLE within different populations in terms of Chinese Han and European population.     

The neurobiological context of autism

Autistic disorder (AD) is a complex neuropsychiatric disorder of neurodevelopmental origin, where multiple genetic and environmental factors may interact, resulting in a clinical continuum. The genetic component is best described by a multilocus model that takes into account epistatic interactions between several susceptibility genes. In the past ten years enormous progress has been made in identifying chromosomal regions in linkage with AD, but moving from chromosomal regions to candidate genes has proven to be tremendously difficult. Neuroanatomical findings point to early dysgenetic events taking place in the cerebral cortex, cerebellum, and brainstem. At the cellular level, disease mechanisms may include altered cell migration, increased cell proliferation, decreased cell death, or altered synapse elimination. Neurochemical findings in AD point to involvement of multiple neurotransmitter systems. The serotoninergic system has been intensively investigated in AD, but other neurotransmitter systems (e.g., the GABAergic and the cholinergic system) are also coming under closer scrutiny. The role of environmental factors is still poorly characterized. It is not clear yet whether environmental factors act merely as precipitating agents, always requiring an underlying genetic liability, or whether they represent an essential component of a pathogenetic process where genetic liability alone does not lead to the full-blown autism phenotype. A third potential player in the pathogenesis of autism, in addition to genetic and environmental factors, is developmental variability due to “random” factors, e.g. small fluctuations of gene expression and complex, non-deterministic interactions between genes during brain development. These considerations suggest that a non-deterministic conceptual framework is highly appropriate for autism research.     

Genetics of rheumatic disease

Many of the chronic inflammatory and degenerative disorders that present to clinical rheumatologists have a complex genetic aetiology. Over the past decade a dramatic improvement in technology and methodology has accelerated the pace of gene discovery in complex disorders in an exponential fashion. In this review, we focus on rheumatoid arthritis, systemic lupus erythematosus and ankylosing spondylitis and describe some of the recently described genes that underlie these conditions and the extent to which they overlap. The next decade will witness a full account of the main disease susceptibility genes in these diseases and progress in establishing the molecular basis by which genetic variation contributes to pathogenesis.     

Genetic variants of microRNA-146a gene: an indicator of systemic lupus erythematosus susceptibility,lupus nephritis,and disease activity

Genetic variations of microRNA encoding genes influence various sorts of diseases by modifying the expression or activity of microRNAs. MicroRNA 146a is an epigenetic regulator of immune response through controlling the type I interferon (IFN) and nuclear factor kappa B (NF-κB) pathways. Genetic variations of microRNA 146a impact the susceptibility to systemic lupus erythematosus (SLE) and its clinical presentations. This study aimed to investigate the polymorphisms of microRNA-146a gene (rs2431697 and rs57095329) in patients with SLE and its association with disease activity. Sixty-five patients with SLE and 40 apparently healthy controls were enrolled in this study. Patients were subjected to history taking, clinical examination, and disease activity evaluation by SLEDAI score. The microRNA-146a variants were determined by allele discrimination real-time PCR method in all participants. We found a statistically significant association between rs2431697 T allele and SLE (P-value?<?0.05), but there was no significant association between rs57095329 and SLE. The T/T genotype of microRNA-146a rs2431697 was associated with lupus nephritis, higher disease activity, and autoantibodies production. The microRNA-146a rs2431697 T allele could be a potential risk factor that contributes to SLE susceptibility, development of lupus nephritis, and disease activity.

     

Identification of possible candidate genes regulating Sjögren's syndrome-associated autoimmunity: a potential role for <Emphasis Type="Italic">TNFSF4</Emphasis>in autoimmune exocrinopathy

Introduction

Sjögren syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, two genetic regions, one on chromosome 1 (designated autoimmune exocrinopathy 2 or Aec2) and the second on chromosome 3 (designated autoimmune exocrinopathy 1 or Aec1) derived from nonobese diabetic (NOD) mice, have been shown to be necessary and sufficient to replicate SjS-like disease in nonsusceptible C57BL/6 mice.

Methods

Starting with the SjS-susceptible C57BL/6-derived mouse, referred to as C57BL/6.NOD-Aec1Aec2, we generated a large set of recombinant inbred (RI) lines containing portions of Aec2 as a means of identifying more precisely the genetic elements of chromosome 1 responsible for disease development.

Results

Disease profiling of these RI lines has revealed that the SjS susceptibility genes of Aec2 lie within a region located at approximately 79 ± 5 cM distal to the centromere, as defined by microsatellite markers. This chromosomal region contains several sets of genes known to correlate with various immunopathological features of SjS as well as disease susceptibility genes for both type 1 diabetes and systemic lupus erythematosus in mice. One gene in particular, tumor necrosis factor (ligand) superfamily member 4 (or Ox40 ligand), encoding a product whose biological functions correlate with both physiological homeostasis and immune regulations, could be a potential candidate SjS susceptibility gene.

Conclusions

These new RI lines represent the first step not only in fine mapping SjS susceptibility loci but also in identifying potential candidate SjS susceptibility genes. Identification of possible candidate genes permits construction of models describing underlying molecular pathogenic mechanisms in this model of SjS and establishes a basis for construction of specific gene knockout mice.

     

Identification of molecular genetic factors that influence migraine

Migraine is a common neurological disorder with a strong genetic basis. However, the complex nature of the disorder has meant that few genes or susceptibility loci have been identified and replicated consistently to confirm their involvement in migraine. Approaches to genetic studies of the disorder have included analysis of the rare migraine subtype, familial hemiplegic migraine with several causal genes identified for this severe subtype. However, the exact genetic contributors to the more common migraine subtypes are still to be deciphered. Genome-wide studies such as genome-wide association studies and linkage analysis as well as candidate genes studies have been employed to investigate genes involved in common migraine. Neurological, hormonal and vascular genes are all considered key factors in the pathophysiology of migraine and are a focus of many of these studies. It is clear that the influence of individual genes on the expression of this disorder will vary. Furthermore, the disorder may be dependent on gene–gene and gene–environment interactions that have not yet been considered. In addition, identifying susceptibility genes may require phenotyping methods outside of the International Classification of Headache Disorders II criteria, such as trait component analysis and latent class analysis to better define the ambit of migraine expression.     

Meta-analysis for microarray studies of the genetics of complex traits

In comparison to other complex disease traits, alcoholism and alcohol abuse are influenced by the combined effects of many genes that alter susceptibility, phenotypic expression and associated morbidity, respectively. Many genetic studies, in both animal models and humans, have identified genetic intervals containing genes that influence alcoholism or behavioral responses to ethanol. Concurrently, a growing number of microarray studies have identified gene expression differences related to ethanol drinking or other ethanol behaviors. However, concerns about the statistical power of these experiments, combined with the complexity of the underlying phenotypes, have greatly hampered the identification of candidate genes underlying ethanol behaviors. Meta-analysis approaches using recent compilations of large datasets of microarray, behavioral and genetic data promise improved statistical power for detecting the genes or gene networks affecting ethanol behaviors and other complex traits.