Autoantigenicity of human C1q is associated with increased hydrophobicity due to conformational transitions in the globular heads

Stoyanova, Vishnya; Bogoeva, Vanya; Petrova, Lidiya; Tchorbadjieva, M.; Petrova, Svetla; Georgieva, Ventsislava; Georgiev, Georgi V.; Deliyska, Boriana; Vasilev, Vasil; Tsacheva, Ivanka

doi:10.1039/c5mb00021a

Cited by 3 publications

(4 citation statements)

References 27 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we have found that conformational disturbance within ghB affected the degree of autoantigenicity of the whole C1q molecule [ 9 ]. If our hypothesis is supported by further analysis, it would mean that anti-gC1q autoantibodies are the first to appear in the autoimmune setting involving C1q as autoantigen.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-dsDNA autoantibodies, the hallmark of SLE, are hypothesized as a result of defective removal of apoptotic material, eventually resulting in an immune response to these normally sequestered autoantigens [ 5 ]. The anti-C1q autoantibodies, which closely follow the appearance of anti-dsDNA, are hypothesized as a result of conformational changes in C1q due to immobilization and exposure of neo-epitopes [ 6 , 7 , 8 ], underlain by increased hydrophobicity [ 9 ] or/and as a result of post-translational modifications [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-Idiotype scFv Localizes an Autoepitope in the Globular Domain of C1q

Todorova

Rangelov

Bogoeva

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

We addressed the issue of C1q autoantigenicity by studying the structural features of the autoepitopes recognized by the polyclonal anti-C1q antibodies present in Lupus Nephritis (LN) sera. We used six fractions of anti-C1q as antigens and selected anti-idiotypic scFv antibodies from the phage library “Griffin.1”. The monoclonal scFv A1 was the most potent inhibitor of the recognition of C1q and its fragments ghA, ghB and ghC, comprising the globular domain gC1q, by the lupus autoantibodies. It was sequenced and in silico folded by molecular dynamics into a 3D structure. The generated 3D model of A1 elucidated CDR similarity to the apical region of gC1q, thus mapping indirectly for the first time a globular autoepitope of C1q. The VH CDR2 of A1 mimicked the ghA sequence GSEAD suggested as a cross-epitope between anti-DNA and anti-C1q antibodies. Other potential inhibitors of the recognition of C1q by the LN autoantibodies among the selected recombinant antibodies were the monoclonal scFv F6, F9 and A12.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-Idiotype scFv Localizes an Autoepitope in the Globular Domain of C1q

Todorova

Rangelov

Bogoeva

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Control peptides derived from pathogens or human molecules, with the same core region as A08, were not recognized. This might be due to charge distribution, hydrophobic residue distribution, a combination of these and /or other factors that might affect the correct epitope conformation (42–44).…”

Section: Discussionmentioning

confidence: 99%

Anti-C1q Antibodies as Occurring in Systemic Lupus Erythematosus Could Be Induced by an Epstein-Barr Virus-Derived Antigenic Site

et al. 2019

View full text Add to dashboard Cite

Previous infection with Epstein-Barr virus (EBV) is believed to trigger autoimmunity and to drive autoantibody generation as occurring in patients with systemic lupus erythematosus (SLE). Complement C1q and autoantibodies targeting it (anti-C1q) are also considered to be involved in the pathogenesis of SLE, independently of the impact of environmental insults. Still, the circumstances under which these autoantibodies arise remain elusive. By studying a major antigenic site of C1q targeted by anti-C1q (A08), we aimed to determine environmental factors and possible mechanisms leading to the development of anti-C1q. First, we determined antigenic residues of A08 that were critical for the binding of anti-C1q; importantly, we found the binding to depend on amino-acid-identity. Anti-C1q of SLE patients targeting these critical antigenic residues specifically cross-reacted with the EBV-related EBNA-1 (Epstein-Barr virus nuclear antigen 1)-derived peptide EBNA348. In a cohort of 180 SLE patients we confirmed that patients that were seropositive for EBV and recognized the EBNA348 peptide had increased levels of anti-A08 and anti-C1q, respectively. The correlation of anti-EBNA348 with anti-A08 levels was stronger in SLE patients than in matched healthy controls. Finally, EBNA348 peptide-immunization of C1q−/− mice induced the generation of cross-reactive antibodies which recognized both the A08 epitope of C1q and intact C1q. These findings suggest that anti-C1q in SLE patients could be induced by an EBV-derived epitope through molecular mimicry, thereby further supporting the pathogenic role of EBV in the development of SLE. Considering the role of C1q and anti-C1q, modifying the anti-EBV response might be a promising strategy to improve the course of the disease.

show abstract

Section: Discussionmentioning

confidence: 99%