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A Germline-Encoded Structural Arginine Trap Underlies the Anti-DNA Reactivity of a Murine V Gene Segment.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Apr 26; Vol. 22 (9). Date of Electronic Publication: 2021 Apr 26. - Publication Year :
- 2021
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Abstract
- Autoimmunity may have its origins of early repertoire selection in developmental B cells. Such a primary repertoire is probably shaped by selecting B cells that can efficiently perform productive signaling, stimulated by self-antigens in the bone marrow, such as DNA. In support of that idea, we previously found a V segment from V <subscript>H</subscript> 10 family that can form antibodies that bind to DNA independent of CDR3 usage. In this paper we designed four antibody fragments in a novel single-chain pre-BCR (scpre-BCR) format containing germinal V gene segments from families known to bind DNA (V <subscript>H</subscript> 10) or not (V <subscript>H</subscript> 4) connected to a murine surrogate light chain (SLC), lacking the highly charged unique region (UR), by a hydrophilic peptide linker. We also tested the influence of CDR2 on DNA reactivity by shuffling the CDR2 loop. The scpre-BCRs were expressed in bacteria. V <subscript>H</subscript> 10 bearing scpre-BCR could bind DNA, while scpre-BCR carrying the V <subscript>H</subscript> 4 segment did not. The CDR2 loop shuffling hampered V <subscript>H</subscript> 10 reactivity while displaying a gain-of-function in the nonbinding V <subscript>H</subscript> 4 germline. We modeled the binding sites demonstrating the conservation of a positivity charged pocket in the V <subscript>H</subscript> 10 CDR2 as the possible cross-reactive structural element. We presented evidence of DNA reactivity hardwired in a V gene, suggesting a structural mechanism for innate autoreactivity. Therefore, while autoreactivity to DNA can lead to autoimmunity, efficiently signaling for B cell development is likely a trade-off mechanism leading to the selection of potentially autoreactive repertoires.
- Subjects :
- Amino Acid Sequence genetics
Animals
Antibodies, Antinuclear genetics
Arginine genetics
Arginine metabolism
Autoantigens genetics
Autoimmunity immunology
Base Sequence genetics
DNA immunology
Germ Cells immunology
Humans
Immunoglobulin Heavy Chains genetics
Immunoglobulin Heavy Chains metabolism
Immunoglobulin Variable Region metabolism
Immunoglobulin Variable Region ultrastructure
Mice
Single-Domain Antibodies ultrastructure
Structure-Activity Relationship
Immunoglobulin Variable Region genetics
Single-Domain Antibodies genetics
Single-Domain Antibodies immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33926148
- Full Text :
- https://doi.org/10.3390/ijms22094541