Control of autoantibody affinity by selection against amino acid replacements in the complementarity-determining regions
| Autor: | Øystein Førre, I Randen, K M Thompson, M Børretzen, Jacob B. Natvig, E Zdárský |
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| Rok vydání: | 1994 |
| Předmět: |
Molecular Sequence Data
Antibody Affinity Immunoglobulin Variable Region Somatic hypermutation Complementarity determining region Arthritis Rheumatoid Affinity maturation Structure-Activity Relationship Antigen Rheumatoid Factor Humans Rheumatoid factor DNA Primers Hybridomas Multidisciplinary Base Sequence Genes Immunoglobulin biology Autoantibody Molecular biology Immunoglobulin M Mutation Immunology biology.protein Immunoglobulin heavy chain Female Antibody Immunoglobulin Heavy Chains Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences. 91:12917-12921 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.91.26.12917 |
| Popis: | Rheumatoid factor (RF) autoantibodies can be produced in healthy individuals after infections or immunizations and thus escape normal tolerization mechanisms. It has not been clear whether such autoantibodies can undergo somatic hypermutation and affinity maturation similar to antibodies to exogenous antigens. We have investigated how these autoantibodies are regulated in normal individuals by analyzing the sequences of monoclonal IgM RFs obtained as hybridomas from donors after immunization. The variable regions undergo extensive hypermutation, but in contrast to antibodies against exogenous antigens, there is a strong selection against mutations that result in replacement of amino acids in the hypervariable, or complementarity-determining, regions. Furthermore, we found no increase in affinity of these RFs with the accumulation of mutations. This suggests that high-affinity variants are tolerized during the hypermutation process and there is a peripheral mechanism operating on certain autoreactive B cells that, while not deleting or anergizing all autoreactive cells, prevents the generation of high-affinity autoantibodies. Comparison of RFs by using the VH1 DP-10 heavy chain variable region segment from both normal individuals and rheumatoid arthritis (RA) patients suggests that RF from RA patients may not be subject to such a controlling mechanism. |
| Databáze: | OpenAIRE |
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