Anti-nuclear antibody reactivity in lupus may be partly hard-wired into the primary B-cell repertoire

Sooghee Chang, Liu Yang, Young Mee Moon, Young Gyu Cho, So Youn Min, Tae Joo Kim, Young Joo Kim, Wilson Patrick, Ho Youn Kim, Chandra Mohan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

When monoclonal ANAs and non-ANAs generated from a genetically simplified mouse model of lupus, B6.Sle1, were recently compared, the ANAs exhibited three sequence motifs in their immunoglobulin heavy chains, including increased cationicity in CDR3 ("motif A"), reduced anionicity in CDR2 ("motif B") and increased aspartate at H50 ("motif C"). The present study was designed to elucidate the extent to which these ANA-associated sequence motifs might be hard-wired into the primary B-cell repertoire in lupus. The immunoglobulin heavy chain sequence of total splenic B-cells, follicular B-cells and marginal zone B-cells from B6.Sle1 congenic mice and C57BL/6 controls were amplified by single-cell PCR and compared. Analysis of the primary immunoglobulin heavy chain repertoire indicated that the first two sequence motifs "A" and "B" were already encoded in the naïve repertoire of B6.Sle1z mice, whereas the third motif "C" was introduced in part by somatic mutation. Site-directed mutagenesis confirmed that non-anionic CDR2 and cationic CDR3 residues in the immunoglobulin heavy chain facilitated nuclear antigen binding in concert, whereas aspartate at H50 strongly vetoed DNA-binding, while preserving nucleosome reactivity. Hence, anti-nuclear antibodies appear to arise as a consequence of two distinct processes-genetically programmed selection of specific CDR charge motifs into the primary immunoglobulin repertoire, with secondary contribution from somatic mutation. Polymorphisms in the lupus susceptibility gene Ly108 that impair central B-cell tolerance may be mechanistically responsible for these early repertoire differences in lupus.

Original languageEnglish (US)
Pages (from-to)3420-3426
Number of pages7
JournalMolecular Immunology
Volume46
Issue number16
DOIs
StatePublished - Oct 2009

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Immunoglobulin Heavy Chains
Anti-Idiotypic Antibodies
B-Lymphocytes
Aspartic Acid
Congenic Mice
Nuclear Antigens
Mutation
Nucleosomes
Site-Directed Mutagenesis
Immunoglobulins
Polymerase Chain Reaction
DNA
Genes

Keywords

  • Autoantibodies
  • Autoimmunity
  • B-cells
  • Genetics
  • Immunoglobulin repertoire

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

Anti-nuclear antibody reactivity in lupus may be partly hard-wired into the primary B-cell repertoire. / Chang, Sooghee; Yang, Liu; Moon, Young Mee; Cho, Young Gyu; Min, So Youn; Kim, Tae Joo; Kim, Young Joo; Patrick, Wilson; Kim, Ho Youn; Mohan, Chandra.

In: Molecular Immunology, Vol. 46, No. 16, 10.2009, p. 3420-3426.

Research output: Contribution to journalArticle

Chang, S, Yang, L, Moon, YM, Cho, YG, Min, SY, Kim, TJ, Kim, YJ, Patrick, W, Kim, HY & Mohan, C 2009, 'Anti-nuclear antibody reactivity in lupus may be partly hard-wired into the primary B-cell repertoire', Molecular Immunology, vol. 46, no. 16, pp. 3420-3426. https://doi.org/10.1016/j.molimm.2009.07.014
Chang, Sooghee ; Yang, Liu ; Moon, Young Mee ; Cho, Young Gyu ; Min, So Youn ; Kim, Tae Joo ; Kim, Young Joo ; Patrick, Wilson ; Kim, Ho Youn ; Mohan, Chandra. / Anti-nuclear antibody reactivity in lupus may be partly hard-wired into the primary B-cell repertoire. In: Molecular Immunology. 2009 ; Vol. 46, No. 16. pp. 3420-3426.
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AU - Chang, Sooghee

AU - Yang, Liu

AU - Moon, Young Mee

AU - Cho, Young Gyu

AU - Min, So Youn

AU - Kim, Tae Joo

AU - Kim, Young Joo

AU - Patrick, Wilson

AU - Kim, Ho Youn

AU - Mohan, Chandra

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N2 - When monoclonal ANAs and non-ANAs generated from a genetically simplified mouse model of lupus, B6.Sle1, were recently compared, the ANAs exhibited three sequence motifs in their immunoglobulin heavy chains, including increased cationicity in CDR3 ("motif A"), reduced anionicity in CDR2 ("motif B") and increased aspartate at H50 ("motif C"). The present study was designed to elucidate the extent to which these ANA-associated sequence motifs might be hard-wired into the primary B-cell repertoire in lupus. The immunoglobulin heavy chain sequence of total splenic B-cells, follicular B-cells and marginal zone B-cells from B6.Sle1 congenic mice and C57BL/6 controls were amplified by single-cell PCR and compared. Analysis of the primary immunoglobulin heavy chain repertoire indicated that the first two sequence motifs "A" and "B" were already encoded in the naïve repertoire of B6.Sle1z mice, whereas the third motif "C" was introduced in part by somatic mutation. Site-directed mutagenesis confirmed that non-anionic CDR2 and cationic CDR3 residues in the immunoglobulin heavy chain facilitated nuclear antigen binding in concert, whereas aspartate at H50 strongly vetoed DNA-binding, while preserving nucleosome reactivity. Hence, anti-nuclear antibodies appear to arise as a consequence of two distinct processes-genetically programmed selection of specific CDR charge motifs into the primary immunoglobulin repertoire, with secondary contribution from somatic mutation. Polymorphisms in the lupus susceptibility gene Ly108 that impair central B-cell tolerance may be mechanistically responsible for these early repertoire differences in lupus.

AB - When monoclonal ANAs and non-ANAs generated from a genetically simplified mouse model of lupus, B6.Sle1, were recently compared, the ANAs exhibited three sequence motifs in their immunoglobulin heavy chains, including increased cationicity in CDR3 ("motif A"), reduced anionicity in CDR2 ("motif B") and increased aspartate at H50 ("motif C"). The present study was designed to elucidate the extent to which these ANA-associated sequence motifs might be hard-wired into the primary B-cell repertoire in lupus. The immunoglobulin heavy chain sequence of total splenic B-cells, follicular B-cells and marginal zone B-cells from B6.Sle1 congenic mice and C57BL/6 controls were amplified by single-cell PCR and compared. Analysis of the primary immunoglobulin heavy chain repertoire indicated that the first two sequence motifs "A" and "B" were already encoded in the naïve repertoire of B6.Sle1z mice, whereas the third motif "C" was introduced in part by somatic mutation. Site-directed mutagenesis confirmed that non-anionic CDR2 and cationic CDR3 residues in the immunoglobulin heavy chain facilitated nuclear antigen binding in concert, whereas aspartate at H50 strongly vetoed DNA-binding, while preserving nucleosome reactivity. Hence, anti-nuclear antibodies appear to arise as a consequence of two distinct processes-genetically programmed selection of specific CDR charge motifs into the primary immunoglobulin repertoire, with secondary contribution from somatic mutation. Polymorphisms in the lupus susceptibility gene Ly108 that impair central B-cell tolerance may be mechanistically responsible for these early repertoire differences in lupus.

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