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Characterisation of a human antibody that potentially links cytomegalovirus infection with systemic lupus erythematosus.
Sci Rep. 2019 07 10; 9(1):9998.SR

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been linked with the development of systemic lupus erythematosus (SLE). Thus far, molecular mimicry has been implicated as the principal mechanism that explains this association. In this study, we characterise a potential alternative process whereby HCMV contributes to SLE. In a cohort of SLE patients, we show a significant association between HCMV infection and SLE through a human antibody response that targets UL44. UL44 is an obligate nuclear-resident, non-structural viral protein vital for HCMV DNA replication. The intracellular nature of this viral protein complicates its targeting by the humoral response - the mechanism remains unresolved. To characterise this response, we present a thorough molecular analysis of the first human monoclonal antibody specific for UL44 derived from a HCMV seropositive donor. This human antibody immunoprecipitates UL44 from HCMV-infected cells together with known nuclear-resident SLE autoantigens - namely, nucleolin, dsDNA and ku70. We also show that UL44 is redistributed to the cell surface during virus-induced apoptosis as part of a complex with these autoantigens. This phenomenon represents a potential mechanism for the bystander presentation of SLE autoantigens to the humoral arm of our immune system under circumstances that favour a break in peripheral tolerance.

Authors+Show Affiliations

Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore. Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore. Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.Electron Microscopy Laboratory, Life Sciences Institute, National University of Singapore, Singapore, Singapore.Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Department of Medicine, National University Health System, Singapore, Singapore. Division of Rheumatology, Department of Medicine, National University Hospital, National University Health System, Singapore, Singapore. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore, Singapore. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore. Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.DSO National Laboratories, Singapore, Singapore.Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore. micpam@nus.edu.sg. Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. micpam@nus.edu.sg.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31292492

Citation

Neo, Jie Ying Jacklyn, et al. "Characterisation of a Human Antibody That Potentially Links Cytomegalovirus Infection With Systemic Lupus Erythematosus." Scientific Reports, vol. 9, no. 1, 2019, p. 9998.
Neo JYJ, Wee SYK, Bonne I, et al. Characterisation of a human antibody that potentially links cytomegalovirus infection with systemic lupus erythematosus. Sci Rep. 2019;9(1):9998.
Neo, J. Y. J., Wee, S. Y. K., Bonne, I., Tay, S. H., Raida, M., Jovanovic, V., Fairhurst, A. M., Lu, J., Hanson, B. J., & MacAry, P. A. (2019). Characterisation of a human antibody that potentially links cytomegalovirus infection with systemic lupus erythematosus. Scientific Reports, 9(1), 9998. https://doi.org/10.1038/s41598-019-46329-y
Neo JYJ, et al. Characterisation of a Human Antibody That Potentially Links Cytomegalovirus Infection With Systemic Lupus Erythematosus. Sci Rep. 2019 07 10;9(1):9998. PubMed PMID: 31292492.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterisation of a human antibody that potentially links cytomegalovirus infection with systemic lupus erythematosus. AU - Neo,Jie Ying Jacklyn, AU - Wee,Seng Yin Kelly, AU - Bonne,Isabelle, AU - Tay,Sen Hee, AU - Raida,Manfred, AU - Jovanovic,Vojislav, AU - Fairhurst,Anna-Marie, AU - Lu,Jinhua, AU - Hanson,Brendon J, AU - MacAry,Paul A, Y1 - 2019/07/10/ PY - 2019/03/27/received PY - 2019/06/26/accepted PY - 2019/7/12/entrez PY - 2019/7/12/pubmed PY - 2020/10/21/medline SP - 9998 EP - 9998 JF - Scientific reports JO - Sci Rep VL - 9 IS - 1 N2 - Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been linked with the development of systemic lupus erythematosus (SLE). Thus far, molecular mimicry has been implicated as the principal mechanism that explains this association. In this study, we characterise a potential alternative process whereby HCMV contributes to SLE. In a cohort of SLE patients, we show a significant association between HCMV infection and SLE through a human antibody response that targets UL44. UL44 is an obligate nuclear-resident, non-structural viral protein vital for HCMV DNA replication. The intracellular nature of this viral protein complicates its targeting by the humoral response - the mechanism remains unresolved. To characterise this response, we present a thorough molecular analysis of the first human monoclonal antibody specific for UL44 derived from a HCMV seropositive donor. This human antibody immunoprecipitates UL44 from HCMV-infected cells together with known nuclear-resident SLE autoantigens - namely, nucleolin, dsDNA and ku70. We also show that UL44 is redistributed to the cell surface during virus-induced apoptosis as part of a complex with these autoantigens. This phenomenon represents a potential mechanism for the bystander presentation of SLE autoantigens to the humoral arm of our immune system under circumstances that favour a break in peripheral tolerance. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/31292492/Characterisation_of_a_human_antibody_that_potentially_links_cytomegalovirus_infection_with_systemic_lupus_erythematosus_ L2 - https://doi.org/10.1038/s41598-019-46329-y DB - PRIME DP - Unbound Medicine ER -