Human cytomegalovirus pp65 peptide-induced autoantibodies cross-reacts with TAF9 protein and induces lupus-like autoimmunity in BALB/c mice

Wen-Yi Tseng,Yen-Fu Chen,I-Jun Chou,Ao-Ho Hsieh,Chang-Fu Kuo,Kuang-Hui Yu,Shue-Fen Luo

doi:10.1038/s41598-020-66804-1

Abstract

Human cytomegalovirus (HCMV) has been linked to the triggering of systemic lupus erythematosus (SLE). We proposed that B cell epitope region of HCMV phosphoprotein 65 (HCMVpp65)422–439 mimics an endogenous antigen and initiates lupus-like autoimmunity. Amino acid homology between HCMVpp65422-439 and TAF9134-144 (TATA-box binding protein associated factor 9, TAF9) was investigated using a similarity search in NCBI protein BLAST program (BLASTP). A murine model was used to confirm their antigenicity and ability to induce lupus-like symptoms. HCMVpp65422-439 induced immune responses with the presence of specific antibodies against HCMVpp65422-439 and TAF9134-144, as well as anti-nuclear and anti-double-stranded (ds)DNA antibodies that are characteristic of SLE. In addition, the majority of HCMVpp65422-439 and TAF9134-144 immunized mice developed proteinuria, and their renal pathology revealed glomerulonephritis with typical abnormalities, such as mesangial hypercellularity and immune complex deposition. Immunoglobulin eluted from the glomeruli of HCMVpp65422-439 immunized mice showed cross-reactivity with TAF9134-144 and dsDNA. Increased anti-TAF9 antibody activity was also observed in the sera from SLE patients compared with healthy people and disease controls. Molecular mimicry between HCMVpp65 peptide and host protein has the potential to drive lupus-like autoimmunity. This proof-of-concept study highlights the mechanisms underlying the link between HCMV infection and the induction of SLE.

Highlights

Human cytomegalovirus (HCMV) has been linked to the triggering of systemic lupus erythematosus (SLE)
Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disease characterized by the production of various antibodies against self-antigens, and tissue inflammatory responses that lead to severe organ damage
The authors postulated that cross-reactive antibodies produced in TATA-box binding protein associated factor 9 (TAF9)[134–144] or HCMVpp65422-439 immunized mice may lead to epitope spreading and contribute to the pathogenesis of glomerulonephritis

Summary

Introduction

Human cytomegalovirus (HCMV) has been linked to the triggering of systemic lupus erythematosus (SLE). Molecular mimicry between HCMVpp[65] peptide and host protein has the potential to drive lupus-like autoimmunity This proof-of-concept study highlights the mechanisms underlying the link between HCMV infection and the induction of SLE. The authors postulated that cross-reactive antibodies produced in TATA-box binding protein associated factor 9 (TAF9)[134–144] or HCMVpp65422-439 immunized mice may lead to epitope spreading and contribute to the pathogenesis of glomerulonephritis. To verify this hypothesis, a murine model was designed, which immunized mice with a peptide-C3d complex with a streptavidin (SA)-biotin backbone that was shown to hasten the immunogenicity of the peptides. The presence of antibodies against HCMVpp[65] and TAF9 proteins was examined in human subjects with SLE, those with other autoimmune diseases, and normal controls to confirm the findings in humans

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