Antibody Epitope Specificity for dsDNA Phosphate Backbone Is an Intrinsic Property of the Heavy Chain Variable Germline Gene Segment Used.

Tatjana Srdic-Rajic,Vladimir Jurisic,Radmila Metlas,Heinz Kohler

doi:10.3389/fimmu.2018.02378

Tatjana Srdic-Rajic, Vladimir Jurisic + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2018.02378

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Abstract

Analysis of protein sequences by the informational spectrum method (ISM) enables characterization of their specificity according to encoded information represented with defined frequency (F). Our previous data showed that F(0.367) is characteristic for variable heavy chain (VH) domains (a combination of variable (V), diversity (D) and joining (J) gene segments) of the anti-phosphocholine (PC) T15 antibodies and mostly dependent on the CDR2 region, a site for PC phosphate group binding. Because the T15 dsDNA-reactive U4 mutant also encodes F(0.367), we hypothesized that the same frequency may also be characteristic for anti-DNA antibodies. Data obtained from an analysis of 60 spontaneously produced anti-DNA antibody VH domain sequences supported our hypothesis only for antibodies, which use V gene segment in germline configuration, such as S57(VH31), MRL-DNA22, and VH11, members of the VH1 (J558) and VH7 (S107) gene families. The important finding is that out of seven V gene segments used by spontaneous anti-DNA antibodies, F(0.367) is only expressed by the germline configuration of these three V gene segments. The data suggest that antibody specificity for the phosphate group moiety delineated as F(0.367) is the intrinsic property of the V germline gene segments used, whereas paratope/epitope interaction with antigens bearing this epitope, such as PC or dsDNA, requires corresponding antibody VH conformation that is susceptible to somatic mutation(s).

Highlights

Natural autoantibodies, mainly IgM whose heavy chains are encoded by unmutated VDJ genes, play a role in immune system homeostasis, provide the first line of defense against infections, and may play a role in autoimmune disease as somatically mutated IgG autoantibodies [1, 2]
The highly diverse CDR3 loops are assumed as the key determinant of specificity in antigen recognition, but in nonsomatically mutated antibodies, binding sites may consist of germline-encoded CDR1 and CDR2 sequences dominating in a number of contacts, whereas light chains play a subsidiary role to heavy chains [3, 4]
Using informational spectrum method (ISM) for protein sequence analysis [37], we showed that antibody variable heavy chain (VH) domains of T15 PC binding antibody and U4 dsDNA binding antibody encode information determining sequence specificity represented with characteristic frequency F(0.367), in short F(0.37) [36]

Summary

Introduction

Mainly IgM whose heavy chains are encoded by unmutated VDJ genes, play a role in immune system homeostasis, provide the first line of defense against infections, and may play a role in autoimmune disease as somatically mutated IgG autoantibodies [1, 2]. The highly diverse CDR3 loops are assumed as the key determinant of specificity in antigen recognition, but in nonsomatically mutated antibodies, binding sites may consist of germline-encoded CDR1 and CDR2 sequences dominating in a number of contacts, whereas light chains play a subsidiary role to heavy chains [3, 4]. It was suggested that in contrast to antigen specificity determined by CDR3 [5], Intrinsic Specificity of the Germline Gene germline-encoded CDR1 and CDR2 sequences accommodate binding to a number of different unrelated antigens [6]. An important finding is that the heavy chains of T15 and other PC binding proteins bearing M603 and M167 idiotypic determinants are derived from a single germline T15(V1) gene segment and three light chains, i.e., T15 (VK22), M603 (VK8), and M167 (VK24) [13, 16, 17]

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