Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals

Neelakshi R. Jog, Kendra A. Young, Melissa E. Munroe, Michael T. Harmon, Joel M. Guthridge, Jennifer A. Kelly, Diane L. Kamen, Gary S. Gilkeson, Michael H. Weisman, David R Karp, Patrick M. Gaffney, John B. Harley, Daniel J. Wallace, Jill M. Norris, Judith A. James

Research output: Contribution to journalArticle

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Abstract

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. Methods: SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. Results: Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. Conclusion: Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

Original languageEnglish (US)
JournalAnnals of the Rheumatic Diseases
DOIs
StatePublished - Jan 1 2019

Fingerprint

Human Herpesvirus 4
Viruses
Systemic Lupus Erythematosus
Antigens
Viral Antigens
Immunoglobulin G
Capsid
Polymorphism
Interleukin-10
Nucleotides
Genes
Viral Antibodies
Single Nucleotide Polymorphism
Antibodies
Autoantibodies
Immunoglobulin A
Virus Latency
Blood
Cells
Autoimmune Diseases

Keywords

  • autoimmunity
  • epstein-barr virus
  • systemic lupus erythematosus

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals. / Jog, Neelakshi R.; Young, Kendra A.; Munroe, Melissa E.; Harmon, Michael T.; Guthridge, Joel M.; Kelly, Jennifer A.; Kamen, Diane L.; Gilkeson, Gary S.; Weisman, Michael H.; Karp, David R; Gaffney, Patrick M.; Harley, John B.; Wallace, Daniel J.; Norris, Jill M.; James, Judith A.

In: Annals of the Rheumatic Diseases, 01.01.2019.

Research output: Contribution to journalArticle

Jog, NR, Young, KA, Munroe, ME, Harmon, MT, Guthridge, JM, Kelly, JA, Kamen, DL, Gilkeson, GS, Weisman, MH, Karp, DR, Gaffney, PM, Harley, JB, Wallace, DJ, Norris, JM & James, JA 2019, 'Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals', Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2019-215361
Jog, Neelakshi R. ; Young, Kendra A. ; Munroe, Melissa E. ; Harmon, Michael T. ; Guthridge, Joel M. ; Kelly, Jennifer A. ; Kamen, Diane L. ; Gilkeson, Gary S. ; Weisman, Michael H. ; Karp, David R ; Gaffney, Patrick M. ; Harley, John B. ; Wallace, Daniel J. ; Norris, Jill M. ; James, Judith A. / Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals. In: Annals of the Rheumatic Diseases. 2019.
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abstract = "Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. Methods: SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13{\%}) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. Results: Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95{\%} CI 1.07 to 1.53, p=0.007, OR 1.43 95{\%} CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. Conclusion: Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.",
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T1 - Association of Epstein-Barr virus serological reactivation with transitioning to systemic lupus erythematosus in at-risk individuals

AU - Jog, Neelakshi R.

AU - Young, Kendra A.

AU - Munroe, Melissa E.

AU - Harmon, Michael T.

AU - Guthridge, Joel M.

AU - Kelly, Jennifer A.

AU - Kamen, Diane L.

AU - Gilkeson, Gary S.

AU - Weisman, Michael H.

AU - Karp, David R

AU - Gaffney, Patrick M.

AU - Harley, John B.

AU - Wallace, Daniel J.

AU - Norris, Jill M.

AU - James, Judith A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. Methods: SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. Results: Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. Conclusion: Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

AB - Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. Methods: SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. Results: Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. Conclusion: Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

KW - autoimmunity

KW - epstein-barr virus

KW - systemic lupus erythematosus

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