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Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts

Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts
Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts
The question of whether immunoglobulin (Ig)M rheumatoid factors (RF) arise as the result of an abnormal expansion of already existing clones producing natural autoantibodies or emerge as new clones that are somatically mutated owing to an antigen driven immune response has never been conclusively answered. In this study, an inhibition ELISA was utilized to measure the affinities of recombinant antibodies using VH segments reverted back to their closest germline counterparts (germline revertants). In all cases, the somatically mutated parental RFs had a decreased affinity for immunoglobulin (Ig)G Fc compared to the germline revertant, indicating that the antibodies in the germline configuration had the higher affinities. This demonstrates that somatic mutation is not a prerequisite to generate disease associated antibodies. The presence of mutations in the parental IgM RFS suggests that these cells had been involved in a germinal centre reaction. As the germinal centre is the conventional site of the acquisition of mutations during an antigen driven response, these data suggest a role for germinal centres in the generation of the antibody diversity in addition to the selection of higher affinity antibodies. Assuming that only antigen selected cells survive deletion, these data support the hypothesis that IgM RFS can be derived from the natural autoantibody repertoire and result from an antigen driven response. Mechanisms controlling the survival of B cells based on the affinity/avidity of the immunoglobulin receptor are shown to be functional in patients with rheumatoid arthritis.
0300-9475
327-36
Carayannopoulos, M.O.
b8429e07-1150-4e76-8cda-833ca1d9875a
Potter, K. N.
86a99047-494b-405b-a3f7-650c1dcd5838
Li, Yong
0817e950-114f-47f3-aefe-74bf9ec0e2a3
Natvig, J. B.
e5153f77-0bee-4663-a10d-b29d825aabbe
Capra, J. D.
395e1a31-454a-4616-aa16-e48a96c3ab6a
Carayannopoulos, M.O.
b8429e07-1150-4e76-8cda-833ca1d9875a
Potter, K. N.
86a99047-494b-405b-a3f7-650c1dcd5838
Li, Yong
0817e950-114f-47f3-aefe-74bf9ec0e2a3
Natvig, J. B.
e5153f77-0bee-4663-a10d-b29d825aabbe
Capra, J. D.
395e1a31-454a-4616-aa16-e48a96c3ab6a

Carayannopoulos, M.O., Potter, K. N., Li, Yong, Natvig, J. B. and Capra, J. D. (2000) Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural autoantibody pool and undergo an antigen driven immune response in which somatically mutated rheumatoid factors have lower affinities for immunoglobulin G Fc than their germline counterparts. Scandinavian Journal of Immunology, 51 (4), 327-36.

Record type: Article

Abstract

The question of whether immunoglobulin (Ig)M rheumatoid factors (RF) arise as the result of an abnormal expansion of already existing clones producing natural autoantibodies or emerge as new clones that are somatically mutated owing to an antigen driven immune response has never been conclusively answered. In this study, an inhibition ELISA was utilized to measure the affinities of recombinant antibodies using VH segments reverted back to their closest germline counterparts (germline revertants). In all cases, the somatically mutated parental RFs had a decreased affinity for immunoglobulin (Ig)G Fc compared to the germline revertant, indicating that the antibodies in the germline configuration had the higher affinities. This demonstrates that somatic mutation is not a prerequisite to generate disease associated antibodies. The presence of mutations in the parental IgM RFS suggests that these cells had been involved in a germinal centre reaction. As the germinal centre is the conventional site of the acquisition of mutations during an antigen driven response, these data suggest a role for germinal centres in the generation of the antibody diversity in addition to the selection of higher affinity antibodies. Assuming that only antigen selected cells survive deletion, these data support the hypothesis that IgM RFS can be derived from the natural autoantibody repertoire and result from an antigen driven response. Mechanisms controlling the survival of B cells based on the affinity/avidity of the immunoglobulin receptor are shown to be functional in patients with rheumatoid arthritis.

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Published date: April 2000

Identifiers

Local EPrints ID: 157785
URI: http://eprints.soton.ac.uk/id/eprint/157785
ISSN: 0300-9475
PURE UUID: 40518378-ef98-47d6-be9d-bb71e32890db

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Date deposited: 06 Jul 2010 13:53
Last modified: 16 Jul 2019 23:56

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Contributors

Author: M.O. Carayannopoulos
Author: K. N. Potter
Author: Yong Li
Author: J. B. Natvig
Author: J. D. Capra

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