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Peptide Scanning-assisted Identification of a Monoclonal Antibody-recognized Linear B-cell Epitope
Published on: March 24, 2017
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Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms.
Bruno Raposo1, Doreen Dobritzsch, Changrong Ge
1Section for Medical Inflammation Research and 2 Section for Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
The Journal of Experimental Medicine
|February 19, 2014
Summary
Genetic variations in the variable heavy chain (VH) influence autoantibody responses to type II collagen (CII), a key factor in rheumatoid arthritis (RA) pathogenesis. This highlights the role of germline-encoded antibodies in autoimmune diseases.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Autoantibody formation is critical in autoimmune diseases like rheumatoid arthritis (RA).
- Anti-type II collagen (CII) antibodies are implicated in RA pathogenesis and cartilage damage.
- Autoreactivity to CII is conserved across species and targets multiple epitopes.
Purpose of the Study:
- To investigate the genetic basis of autoantibody responses to specific CII epitopes.
- To identify structural requirements for antibody recognition of CII epitopes.
- To understand the role of germline-encoded antibodies in autoimmune disease development.
Main Methods:
- Mapping antibody responses to CII in mice and associating them with the IgH locus.
- Gene sequencing to identify polymorphisms in variable heavy chain (VH) alleles.
- X-ray crystallography and site-directed mutagenesis to analyze antibody-epitope interactions.
Main Results:
- Polymorphisms at S31R and W33T in VH alleles were identified and linked to CII epitope recognition.
- Structural analysis confirmed the critical role of these variants in antigen binding.
- Back mutation to germline sequences indicated pre-existing recognition of the J1 epitope.
Conclusions:
- Epitope-specific autoantibody responses are genetically associated with specific VH alleles.
- Germline-encoded antibodies play a significant role in the pathogenesis of antibody-mediated autoimmune diseases.
- Understanding these genetic and structural factors can inform therapeutic strategies for RA.
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