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Recognition of Amin...
Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis
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- Steen, Johanna (author)
- Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden.
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- Forsström, Björn (author)
- KTH,Systembiologi
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- Sahlström, Peter (author)
- Karolinska Institutet
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- Odowd, Victoria (author)
- UCB Pharma, Slough, Berks, England.
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- Israelsson, Lena (author)
- Karolinska Institutet
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- Krishnamurthy, Akilan (author)
- Karolinska Institutet
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- Badreh, Sara (author)
- Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden.
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- Mathsson Alm, Linda (author)
- Uppsala universitet,Klinisk immunologi,Thermo Fisher Sci, Uppsala, Sweden.;Uppsala Univ, Uppsala, Sweden.
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- Compson, Joanne (author)
- UCB Pharma, Slough, Berks, England.
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- Ramsköld, Daniel (author)
- Karolinska Institutet
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- Ndlovu, Welcome (author)
- UCB Pharma, Slough, Berks, England.
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- Rapecki, Stephen (author)
- UCB Pharma, Slough, Berks, England.
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- Hansson, Monika (author)
- Karolinska Institutet
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- Titcombe, Philip J. (author)
- Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden.;Univ Minnesota, Med Sch, Minneapolis, MN 55455 USA.
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- Bang, Holger (author)
- Orgentec Diagnost, Mainz, Germany.
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- Mueller, Daniel L. (author)
- Univ Minnesota, Med Sch, Minneapolis, MN 55455 USA.,UCB Pharma, Slough, Berks, England.
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- Catrina, Anca I. (author)
- Karolinska Institutet
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- Grönwall, Caroline (author)
- Karolinska Institutet
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- Skriner, Karl (author)
- Charite, Berlin, Germany.
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- Nilsson, Peter (author)
- KTH,Affinitets-proteomik
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- Lightwood, Daniel (author)
- UCB Pharma, Slough, Berks, England
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- Klareskog, Lars (author)
- Karolinska Institutet
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- Malmström, Vivianne (author)
- Karolinska Institutet
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Karolinska Inst, Karolinska Univ Hosp, Stockholm, Sweden Systembiologi (creator_code:org_t)
- 2019-01-29
- 2019
- English.
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In: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 196-209
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Abstract
Subject headings
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- Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity.Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated.Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay.Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Steen, Johanna
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Forsström, Björn
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Sahlström, Peter
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Odowd, Victoria
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Israelsson, Lena
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Krishnamurthy, A ...
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show more...
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Badreh, Sara
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Mathsson Alm, Li ...
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Compson, Joanne
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Ramsköld, Daniel
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Ndlovu, Welcome
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Rapecki, Stephen
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Hansson, Monika
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Titcombe, Philip ...
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Bang, Holger
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Mueller, Daniel ...
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Catrina, Anca I.
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Grönwall, Caroli ...
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Skriner, Karl
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Nilsson, Peter
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Lightwood, Danie ...
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Klareskog, Lars
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Malmström, Vivia ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
- Articles in the publication
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Arthritis & Rheu ...
- By the university
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Uppsala University
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Royal Institute of Technology
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Karolinska Institutet