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

Nadezhda Todorova,Ivanka Tsacheva,Daniela Dimitrova,Anna Yordanova,Safa Mohedin,Vanya Bogoeva,Ginka Nikolova,Miroslav Rangelov,Hristo Georgiev,Vishnya Stoyanova,Katerina Stoyanova

doi:10.3390/ijms22158288

Abstract

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.

Highlights

Introduction published maps and institutional affilC1q, the recognition molecule of the classical complement pathway, appears as an autoantigen in several human autoimmune disorders, most notably in systemic lupus erythematosus (SLE) [1,2,3,4]
We have found that lupus nephritis (LN) sera were positive for anti-C1q antibodies that recognized different combinations of C1q domains and their smaller fragments, e.g., collagen-like region (CLR) and the globular fragments of A, B and C chains comprising gC1q—ghA, ghB and ghC, along with the intact molecule
Based on our previous study of the epitope specificity of the polyclonal autoantibodies to C1q from LN sera [15], we classified the analysed sera into six groups according to their positivity for the used test-antigens: intact C1q, CLR and ghA, ghB and ghC as representatives of gC1q

Summary

Introduction

C1q, the recognition molecule of the classical complement pathway, appears as an autoantigen in several human autoimmune disorders, most notably in systemic lupus erythematosus (SLE) [1,2,3,4]. 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. Anti-C1q autoantibodies are associated with lupus nephritis (LN), a clinical condition in more than 30% of SLE patients [11]. LN follows a course of exacerbations and remissions iations

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Conclusion