Genetic and transcriptomic analyses support a switch to lytic phase in Epstein Barr virus infection as an important driver in developing Systemic Lupus Erythematosus

Afrasiabi, Ali; Keane, Jeremy T; Ong, Lawrence; Alinejad‐Rokny, Hamid; Fewings, Nicole; Booth, David R.; Parnell, Grant P; Swaminathan, Sanjay

doi:10.1016/j.jaut.2021.102781

Cited by 12 publications

(9 citation statements)

References 96 publications

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“…EBV and autoimmunity in SLE are thus strongly linked. The present study is therefore a proof of concept study of great need to further understand the interaction of EBV, HLA and non-HLA genes 48 in development and progression of SLE. It also points at need for understanding epigenetic regulation of this complex host-virus interaction.…”

Section: Discussionmentioning

confidence: 98%

Association of Human Leucocyte Antigen Class II, with viral load and immune response to Epstein–Barr virus in adult and pediatric Systemic lupus erythematosus patients

Das

Minz

Saikia

et al. 2022

Lupus

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Objective Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, which is known to be associated with HLA-DRB1 and Epstein–Barr virus (EBV) infection. In the Indian subcontinent where there is high seroendemicity of EBV, we postulated that the association of this virus in adult SLE (aSLE) and pediatric SLE (pSLE) patients would be different and differentially associate with the HLA-DRB1 susceptibility and protective genes. Methods A total of 109 aSLE, 52 pSLE, 215 adult healthy and 63 pediatric healthy controls were recruited. HLA-DRB1 genotyping by PCR-SSP, EBV load estimation by real-time PCR and antibody profiling (IgG & IgM) to EBV antigens by line blot assay were performed. Results DRB1*15 was found predominant in pSLE patients and DRB1*03 in aSLE patients. DRB1*15/X heterozygous was predominant in overall SLE patients, although disease severity, like hypocomplementemia, higher autoantibody levels and more organ involvement was observed in *15/*15 homozygous state. EBV strongly associated with pSLE patients showing higher percent of EA-D IgG ( p < 0.0001) and p22 IgG ( p = 0.035) along with higher viral load ( p = 0.001) as compared to healthy controls. In addition, the higher EBV DNA load significantly associated with anti-EA-D IgG ( p = 0.013) and DRB1*15/*15 ( p = 0.007) in pSLE patients as compared to aSLE patients. Conclusions This study therefore indicates that different HLA-DRB1 allotypes confer susceptibility to SLE in children and adults and disease may be triggered by increased EBV reactivation.

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Section: Discussionmentioning

confidence: 98%

Association of Human Leucocyte Antigen Class II, with viral load and immune response to Epstein–Barr virus in adult and pediatric Systemic lupus erythematosus patients

Das

Minz

Saikia

et al. 2022

Lupus

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“…The EBV gene product and transcription co-factor, EBNA2, is concentrated at SLE and MS risk loci, including BLK (Harley et al, 2018, p. 2;Yin et al, 2021). Recently, Afrasiabi et al (2022), have extended these observations by showing that BLK and FAM167A are bound by EBNA2 and the products of both genes are differentially expressed as eQTLs in greater magnitude in LCLs than in B cells that are not EBV infected, with BLK and FAM167A being affected in opposing directions. Both BLK and FAM167A are correlated with EBV DNA copy number per cell, with the association with FAM167A being much more convincing.…”

Section: Discussionmentioning

confidence: 99%

Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1

et al. 2022

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A major goal of genetics research is to elucidate mechanisms explaining how genetic variation contributes to phenotypic variation. The genetic variants identified in genome-wide association studies (GWASs) generally explain only a small proportion of heritability of phenotypic traits, the so-called missing heritability problem. Recent evidence suggests that additional common variants beyond lead GWAS variants contribute to phenotypic variation; however, their mechanistic underpinnings generally remain unexplored. Herein, we undertake a study of haplotype-specific mechanisms of gene regulation at 8p23.1 in the human genome, a region associated with a number of complex diseases. The FAM167A-BLK locus in this region has been consistently found in the genome-wide association studies (GWASs) of systemic lupus erythematosus (SLE) in all major ancestries. Our haplotype-specific chromatin interaction (Hi-C) experiments, allele-specific enhancer activity measurements, genetic analyses, and epigenome editing experiments revealed that: 1) haplotype-specific long-range chromatin interactions are prevalent in 8p23.1; 2) BLK promoter and cis-regulatory elements cooperatively interact with haplotype-specificity; 3) genetic variants at distal regulatory elements are allele-specific modifiers of the promoter variants at FAM167A-BLK; 4) the BLK promoter interacts with and, as an enhancer-like promoter, regulates FAM167A expression and 5) local allele-specific enhancer activities are influenced by global haplotype structure due to chromatin looping. Although systemic lupus erythematosus causal variants at the FAM167A-BLK locus are thought to reside in the BLK promoter region, our results reveal that genetic variants at distal regulatory elements modulate promoter activity, changing BLK and FAM167A gene expression and disease risk. Our results suggest that global haplotype-specific 3-dimensional chromatin looping architecture has a strong influence on local allelic BLK and FAM167A gene expression, providing mechanistic details for how regional variants controlling the BLK promoter may influence disease risk.

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“…For example, in most EBV‐associated cancers, the latency I (Hodgkin lymphoma) or II (Burkitt's lymphoma) programmes are involved, 101 while diseases associated with immune deficiencies or autoimmunity are associated with the latency III programme 102 . According to one proposed model, EBV lytic switching may contribute to the pathogenesis of Systemic Lupus Erythematosus (SLE), 103 contrary to the proposed model for MS, 80 which suggests that latency III plays a greater role in MS development. Since there are some shared risk genetic loci between MS and SLE, particularly those genes that are linked to EBV molecular processes such as CD40 , 104,105 therapeutic advantage may be gained by focusing on targeting EBV elements that arrest latency III but do not induce lytic activation.…”

Section: Targeting Ebv Therapeuticallymentioning

confidence: 99%

The interaction between Epstein–Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities

et al. 2023

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Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease, characterised by the demyelination of neurons in the central nervous system. Whilst it is unclear what precisely leads to MS, it is believed that genetic predisposition combined with environmental factors plays a pivotal role. It is estimated that close to half the disease risk is determined by genetic factors. However, the risk of developing MS cannot be attributed to genetic factors alone, and environmental factors are likely to play a significant role by themselves or in concert with host genetics. Epstein-Barr virus (EBV) infection is the strongest known environmental risk factor for MS. There has been increasing evidence that leaves little doubt that EBV is necessary, but not sufficient, for developing MS. One plausible explanation is EBV may alter the host immune response in the presence of MS risk alleles and this contributes to the pathogenesis of MS. In this review, we discuss recent findings regarding how EBV infection may contribute to MS pathogenesis via interactions with genetic risk loci and discuss possible therapeutic interventions.

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Genetic and transcriptomic analyses support a switch to lytic phase in Epstein Barr virus infection as an important driver in developing Systemic Lupus Erythematosus

Cited by 12 publications

References 96 publications

Association of Human Leucocyte Antigen Class II, with viral load and immune response to Epstein–Barr virus in adult and pediatric Systemic lupus erythematosus patients

Association of Human Leucocyte Antigen Class II, with viral load and immune response to Epstein–Barr virus in adult and pediatric Systemic lupus erythematosus patients

Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1

The interaction between Epstein–Barr virus and multiple sclerosis genetic risk loci: insights into disease pathogenesis and therapeutic opportunities

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