Humoral response to Epstein-Barr virus in patients with multiple sclerosis treated with B cell depletion therapy. 2023

Brit Ellen Rød, and Stig Wergeland, and Kjetil Bjørnevik, and Trygve Holmøy, and Elling Ulvestad, and Gro Njølstad, and Kjell-Morten Myhr, and Øivind Torkildsen
Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: brit.ellen.rod@helse-bergen.no.

BACKGROUND B cell depletion therapy is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, the precise underlying mechanisms of action for its biological effects in MS have still not been clarified. Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. EBV resides latently in the memory B cells, and may not only increase the risk of developing MS, but also contribute to disease activity and disability progression. Therefore, the effects of B cell depletion in MS could be associated with the depletion of EBV-infected cells and the altered immune response to the virus. In this study, we investigate the impact of B cell depletion on the humoral immune response specific to EBV in patients with MS. METHODS Newly diagnosed, treatment-naïve patients with RRMS were followed up to 18 months after initiation of B-cell depletion therapy in the Overlord-MS study, a phase III trial (NCT04578639). We analyzed serum sampled before treatment and after 3, 6, 12 and 18 months for immunoglobulin γ (IgG) against Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr viral capsid antigen (VCA). We analyzed antibodies to cytomegalovirus (CMV) and total IgG in serum, as controls for viral and overall humoral immunity. The risk allele, HLA-DRB1*15:01, and the protective allele, HLA-A*02:01, were determined in all participants. In addition, polymerase chain reaction (PCR) for circulating EBV-DNA was performed in the first 156 samples drawn. The associations between time on B cell-depletion therapy and serum anti-EBV antibody levels were estimated using linear mixed-effects models. RESULTS A total of 290 serum samples from 99 patients were available for analysis. After 6, 12 and 18 months, the EBNA1 IgG levels decreased by 12.7 % (95 % CI -18.8 to -6.60, p < 0.001), 12.1 % (95 % CI -19.8 to -3.7, p = 0.006) and 14.6 % (95 % CI to -25.3 to -2.4, p = 0.02) respectively, compared to baseline level. Carriers of the HLA-DRB1*15:01 allele had higher EBNA1 IgG levels at baseline (p = 0.02). The VCA IgG levels significantly increased by 13.7 % (95 % CI 9.4 to 18.1, p < 0.001) after 3 months, compared to baseline, and persisted at this level throughout the follow-up. CMV IgG levels decreased, but to a lesser extent than the decrease of EBNA1 IgG, and total IgG levels decreased during therapy. Circulating EBV-DNA was found in only three of 156 samples from 64 patients. CONCLUSIONS EBNA1 IgG levels decreased, while VCA IgG levels increased, during B cell depletion therapy. This supports the hypothesis that the mechanism of action for B cell depletion therapy might be mediated by effects on EBV infection, which, in turn, mitigate immune cross-reactivity and disease perpetuation.

UI MeSH Term Description Entries
D009103 Multiple Sclerosis An autoimmune disorder mainly affecting young adults and characterized by destruction of myelin in the central nervous system. Pathologic findings include multiple sharply demarcated areas of demyelination throughout the white matter of the central nervous system. Clinical manifestations include visual loss, extra-ocular movement disorders, paresthesias, loss of sensation, weakness, dysarthria, spasticity, ataxia, and bladder dysfunction. The usual pattern is one of recurrent attacks followed by partial recovery (see MULTIPLE SCLEROSIS, RELAPSING-REMITTING), but acute fulminating and chronic progressive forms (see MULTIPLE SCLEROSIS, CHRONIC PROGRESSIVE) also occur. (Adams et al., Principles of Neurology, 6th ed, p903) MS (Multiple Sclerosis),Multiple Sclerosis, Acute Fulminating,Sclerosis, Disseminated,Disseminated Sclerosis,Sclerosis, Multiple
D003586 Cytomegalovirus Infections Infection with CYTOMEGALOVIRUS, characterized by enlarged cells bearing intranuclear inclusions. Infection may be in almost any organ, but the salivary glands are the most common site in children, as are the lungs in adults. CMV Inclusion,CMV Inclusions,Congenital CMV Infection,Congenital Cytomegalovirus Infection,Cytomegalic Inclusion Disease,Cytomegalovirus Colitis,Cytomegalovirus Inclusion,Cytomegalovirus Inclusion Disease,Cytomegalovirus Inclusions,Inclusion Disease,Perinatal CMV Infection,Perinatal Cytomegalovirus Infection,Renal Tubular Cytomegalovirus Inclusion,Renal Tubular Cytomegalovirus Inclusions,Salivary Gland Virus Disease,Severe Cytomegalovirus Infection,Severe Cytomegalovirus Infections,Infections, Cytomegalovirus,CMV Infection, Congenital,CMV Infection, Perinatal,Colitis, Cytomegalovirus,Congenital CMV Infections,Congenital Cytomegalovirus Infections,Cytomegalic Inclusion Diseases,Cytomegalovirus Colitides,Cytomegalovirus Inclusion Diseases,Cytomegalovirus Infection,Cytomegalovirus Infection, Congenital,Cytomegalovirus Infection, Perinatal,Cytomegalovirus Infection, Severe,Cytomegalovirus Infections, Severe,Disease, Cytomegalic Inclusion,Disease, Cytomegalovirus Inclusion,Diseases, Cytomegalovirus Inclusion,Inclusion Disease, Cytomegalic,Inclusion Disease, Cytomegalovirus,Inclusion Diseases,Inclusion Diseases, Cytomegalovirus,Inclusion, CMV,Inclusion, Cytomegalovirus,Infection, Congenital CMV,Infection, Congenital Cytomegalovirus,Infection, Cytomegalovirus,Infection, Perinatal CMV,Infection, Perinatal Cytomegalovirus,Infection, Severe Cytomegalovirus,Perinatal CMV Infections,Perinatal Cytomegalovirus Infections
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004854 Herpesvirus 4, Human The type species of LYMPHOCRYPTOVIRUS, subfamily GAMMAHERPESVIRINAE, infecting B-cells in humans. It is thought to be the causative agent of INFECTIOUS MONONUCLEOSIS and is strongly associated with oral hairy leukoplakia (LEUKOPLAKIA, HAIRY;), BURKITT LYMPHOMA; and other malignancies. Burkitt Herpesvirus,Burkitt Lymphoma Virus,E-B Virus,EBV,Epstein-Barr Virus,Human Herpesvirus 4,Infectious Mononucleosis Virus,Burkitt's Lymphoma Virus,HHV-4,Herpesvirus 4 (gamma), Human,Burkitts Lymphoma Virus,E B Virus,E-B Viruses,Epstein Barr Virus,Herpesvirus, Burkitt,Infectious Mononucleosis Viruses,Lymphoma Virus, Burkitt,Mononucleosis Virus, Infectious,Mononucleosis Viruses, Infectious
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000914 Antibodies, Viral Immunoglobulins produced in response to VIRAL ANTIGENS. Viral Antibodies
D059811 HLA-DRB1 Chains A subtype of HLA-DRB beta chains that includes over one hundred allele variants. The HLA-DRB1 subtype is associated with several of the HLA-DR SEROLOGICAL SUBTYPES. HLA DRB1,HLA-DRB1,HLA-DRB1 Antigen,Antigen, HLA-DRB1,Chains, HLA-DRB1,HLA DRB1 Antigen,HLA DRB1 Chains
D019309 Epstein-Barr Virus Nuclear Antigens Nuclear antigens encoded by VIRAL GENES found in HUMAN HERPESVIRUS 4. At least six nuclear antigens have been identified. EBV Nuclear Antigen,EBV Nuclear Antigens,Epstein-Barr Virus Nuclear Antigen,Herpesvirus 4, Human Nuclear Antigens,Nuclear Antigens, Herpesvirus 4, Human,Antigen, EBV Nuclear,Epstein Barr Virus Nuclear Antigen,Epstein Barr Virus Nuclear Antigens,Nuclear Antigen, EBV,Nuclear Antigens, EBV
D020031 Epstein-Barr Virus Infections Infection with human herpesvirus 4 (HERPESVIRUS 4, HUMAN); which may facilitate the development of various lymphoproliferative disorders. These include BURKITT LYMPHOMA (African type), INFECTIOUS MONONUCLEOSIS, and oral hairy leukoplakia (LEUKOPLAKIA, HAIRY). EBV Infections,Epstein-Barr Virus Infection,Herpesvirus 4 Infections, Human,Human Herpes Virus 4 Infections,Human Herpesvirus 4 Infections,Infections, EBV,Infections, Epstein-Barr Virus,EBV Infection,Epstein Barr Virus Infection,Epstein Barr Virus Infections,Infection, EBV,Infection, Epstein-Barr Virus,Virus Infection, Epstein-Barr,Virus Infections, Epstein-Barr
D020529 Multiple Sclerosis, Relapsing-Remitting The most common clinical variant of MULTIPLE SCLEROSIS, characterized by recurrent acute exacerbations of neurologic dysfunction followed by partial or complete recovery. Common clinical manifestations include loss of visual (see OPTIC NEURITIS), motor, sensory, or bladder function. Acute episodes of demyelination may occur at any site in the central nervous system, and commonly involve the optic nerves, spinal cord, brain stem, and cerebellum. (Adams et al., Principles of Neurology, 6th ed, pp903-914) Multiple Sclerosis, Acute Relapsing,Relapsing-Remitting Multiple Sclerosis,Acute Relapsing Multiple Sclerosis,Remitting-Relapsing Multiple Sclerosis,Multiple Sclerosis, Relapsing Remitting,Multiple Sclerosis, Remitting-Relapsing,Relapsing Remitting Multiple Sclerosis,Remitting Relapsing Multiple Sclerosis

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