Restricted accessResearch articleFirst published online 2022-8
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
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.
JogNRJamesJA. Epstein Barr virus and autoimmune responses in systemic lupus erythematosus. Front Immunol2021; 11: 1–11.
2.
SjaksteTKalninaJ. Disease-specific and common HLA and non-HLA genetic markers in susceptibility to rheumatoid arthritis, type 1 diabetes mellitus and multiple sclerosis. J Mol Genet Med2016; 10: 1–6.
3.
NiuZZhangPTongY. Value of HLA-DR genotype in systemic lupus erythematosus and lupus nephritis: a meta-analysis. Int J Rheum Dis2015; 18: 17–28.
4.
MosaadYMHammadAYoussefHM, et al.HLA-DRB1*15 confers susceptibility to juvenile sle but is not associated with disease presentation: an Egyptian study. Immunol Invest2010; 39: 235–244.
5.
ShimaneKKochiYSuzukiA, et al.An association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes. Rheumatol (United Kingdom)2013; 52: 1172–1182.
6.
Al-MotweeSJawdatDJehaniGS, et al.Association of HLA-DRB1*15 and HLADQB1*06 with SLE in saudis. Ann Saudi Med2013; 33: 229–234.
7.
DianeLK. Environmental influences on systemic lupus erythematosus expression. Rheum Dis Clin North Am2014; 40: 1–14.
8.
CavalcantePGalbardiBFranziS, et al.Increased expression of toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein-Barr virus infection. Immunobiology2016; 221: 516–527.
9.
BarzilaiORamMShoenfeldY. Viral infection can induce the production of autoantibodies. Curr Opin Rheumatol2007; 19: 636–643.
10.
HarleyJBZollerEE. Editorial: what caused all these troubles, anyway? Epstein-Barr virus in Sjögren’s syndrome reevaluated. Arthritis Rheumatol2014; 66: 2328–2330.
11.
De PaschaleMClericiP. Serological diagnosis of Epstein-Barr virus infection: problems and solutions. World J Virol2012; 1: 31–43.
12.
ChoMSMilmanGHaywardSD. A second Epstein-Barr virus early antigen gene in BamHI fragment M encodes a 48- to 50-kilodalton nuclear protein. J Virol1985; 56: 860–866.
13.
ZhangQHongYDorskyD, et al.Functional and physical interactions between the Epstein-Barr virus (EBV) proteins BZLF1 and BMRF1: effects on EBV transcription and lytic replication. J Virol1996; 70: 5131–5142.
14.
BabcockGJHochbergDThorley-LawsonDA. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity2000; 13: 497–506.
15.
TsurumiTFujitaMKudohA. Latent and lytic Epstein-Barr virus replication strategies. Rev Med Virol2005; 15: 3–15.
16.
HanlonPAvenellAAucottLM. Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. Arthritis Res Ther2014; 16: R3.
17.
KluttsJSFordBAPerezNR, et al.Evidence-based approach for interpretation of Epstein-Barr virus serological patterns. J Clin Microbiol2009; 47: 3204–3210.
18.
VistaESWeismanMHIshimoriML, et al.Strong viral associations with SLE among Filipinos. Lupus Sci Med2017; 4: e000214.
19.
MeenakshiSD TheresePA. Seroprevalence of Epstein Barr virus in patients with systemic lupus erythematosus. Indian J Appl Res2019; 9: 3–4.
20.
ChouguleDNadkarMRajadhyakshaA, et al.Association of clinical and serological parameters of systemic lupus erythematosus patients with Epstein-Barr virus antibody profile. J Med Virol2018; 90: 559–563.
21.
McClainMTHeinlenLDDennisGJ, et al.Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med2005; 11: 85–89.
22.
PooleBDScofieldRHHarleyJB. Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity2006; 39: 63–70.
23.
DraborgAHDuusKHouenG. Epstein-Barr virus and systemic lupus erythematosus. Clin Dev Immunol2012; 2012: 1–11.
24.
JamesJARobertsonJM. Lupus and Epstein-Barr. Curr Opin Rheumatol2012; 24: 383–388.
25.
RasmussenNDraborgANielsenC, et al.Antibodies to early EBV, CMV, and HHV6 antigens in systemic lupus erythematosus patients. Scand J Rheumatol2015; 44: 143–149.
26.
Van GrunsvenWMJNabbeAMiddeldorpJM. Identification and molecular characterization of two diagnostically relevant marker proteins of the Epstein-Barr virus capsid antigen complex. J Med Virol1993; 40: 161–169.
27.
LarsenMSauceDDebackC, et al.Exhausted cytotoxic control of Epstein-Barr virus in human lupus. Plos Pathog2011; 7: e1002328.
28.
HanlonPAvenellAAucottL, et al.Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. Arthritis Res Ther2014; 16: R3. DOI: 10.1186/ar4429
29.
JamesJANeasBRMoserKL, et al.Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum2001; 44: 1122–1126.
30.
McClainMTPooleBDBrunerBF, et al.An altered immune response to Epstein-Barr nuclear antigen 1 in pediatric systemic lupus erythematosus. Arthritis Rheum2006; 54: 360–368.
31.
MuraoSMakinoHKainoY, et al.Differences in the contribution of HLA-DR and -DQ haplotypes to susceptibility to adult-and childhood-onset type 1 diabetes in Japanese patients. Diabetes2004; 53: 2684–2690.
32.
PandoMLarribaJFernandezGC, et al.Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition. Hepatology1999; 30: 1374–1380.
33.
ShankarkumarUGhoseUBadakereSS, et al.HLA-DRB1*03 and DQB1*0302 associations in a subset of patients severely affected with systemic lupus erythematosus from western India. Ann Rheum Dis2003; 62: 92–93.
34.
KatkamSKRajasekharLKutalaVK. The influence of functional polymorphic positions of HLA-DRβ1 molecules on risk for South Indian systemic lupus erythematosus patients. Lupus2018; 27: 991–1000.
35.
MehraNKPandeITanejaV. Major histocompatibility complex genes and susceptibility systemic lupus erythematosus in Northern India. Lupus1993; 2: 313–314.
36.
LipsitchMBergstromCTAntiaR. Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures. BMC Med Genet2003; 4: 2. DOI: 10.1186/1471-2350-4-2
37.
WordsworthPPileKDBuckelyJD, et al.HLA heterozygosity contributes to susceptibility to rheumatoid arthritis. Am J Hum Genet1992; 51: 585–591.
38.
EerlighPvan LummelMZaldumbideA, et al.Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes. Genes Immun2011; 12: 415–427.
39.
PenderMP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol2003; 24: 584–588.
40.
SundqvistESundströmP.LindénM, et al.Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun2012; 13: 14–20.
41.
XiaoDYeXZhangN, et al.A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis. Sci Rep2015; 5: 18083.
42.
KularLLiuYRuhrmannS, et al.DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat Commun2018; 9: 2397.
43.
OoiJDPetersenJTanYH, et al.Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature2017; 545: 243–247.
44.
MartinJEAssassiSDiaz-GalloLM, et al.A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet2013; 22: 4021–4029.
45.
MöhlBSChenJSathiyamoorthyK, et al.Structural and mechanistic insights into the tropism of Epstein-Barr virus. Mol Cell2016; 39: 286–291.
46.
FarinaACironeMYorkM, et al.Epstein–Barr virus infection induces aberrant TLR activation pathway and fibroblast–myofibroblast conversion in scleroderma. J Invest Dermatol2014; 134: 954–964.
47.
Bar-OrAPenderMPKhannaR, et al.Epstein–Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends Mol Med2020; 26: 296–310.
48.
AfrasiabiAKeaneJTOngLTC, et al.Genetic and transcriptomic analyses support a switch to lytic phase in Epstein Barr virus infection as an important driver in developing systemic lupus erythematosus. J Autoimmun2022; 127: 102781.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
