Alterations in B cell development, CDR-H3 repertoire and dsDNA-binding antibody production among C57BL/6 ΔD−iD mice congenic for the lupus susceptibility loci sle1, sle2 or sle3

• Published in: Autoimmunity (Chur, Switzerland) Vol. 50; no. 1; pp. 42 - 51
• Main Authors: Khass, Mohamed, Schelonka, Robert L., Liu, Cun Ren, Elgavish, Ada, Morel, Laurence, Burrows, Peter D., Schroeder, Harry W.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.02.2017; Taylor & Francis Group
• Subjects: Alleles; Amino Acid Sequence; Animals; Antibodies, Antinuclear - immunology; Antibody Formation; Autoantibodies - immunology; B-cell repertoire; B-Lymphocytes - cytology; B-Lymphocytes - physiology; CDR-H3 and diversity gene segments; Cell Differentiation - genetics; Cell Differentiation - immunology; Complementarity Determining Regions - chemistry; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Disease Models, Animal; Disease Susceptibility; Immunoglobulin G - immunology; Immunoglobulin M - immunology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation; Lymphocyte Count; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Knockout; Quantitative Trait Loci; Sle; Systemic lupus erythematosus; third complementary determining region heavy chain; CDR-H3 and diversity gene segments; Systemic lupus erythematosus; DH; third complementary determining region heavy chain; Sle; B-cell repertoire
• ISSN: 0891-6934; 1607-842X
• DOI: 10.1080/08916934.2016.1272597

Systemic lupus erythematosus (SLE) is an autoimmune disease that reflects a failure to block the production of self-reactive antibodies, especially those that bind double-stranded DNA (dsDNA). Backcrossing the lupus-prone NZM2410 genome onto C57BL/6 led to the identification of three genomic intervals, termed sle1, sle2 and sle3, which are associated with lupus susceptibility. We previously generated a C57BL/6 strain congenic for an immunoglobulin D H locus (ΔD-iD) that enriches for arginine at dsDNA-binding positions. We individually introduced the ΔD-iD allele into the three sle strains to test whether one or more of these susceptibility loci could affect the developmental fate of B cells bearing arginine-enriched CDR-H3s, the CDR-H3 repertoire created by the D H and the prevalence of dsDNA-binding antibodies. We found that the combination of the ΔD-iD allele and the sle1 locus led to a decrease in mature, recirculating B cell numbers and an increase in marginal zone cell numbers while maintaining a highly charged CDR-H3 repertoire. ΔD-iD and sle2 had no effect on peripheral B cell numbers, but the CDR-H3 repertoire was partially normalized. ΔD-iD and sle3 led to an increase in marginal zone B cell numbers, with some normalization of hydrophobicity. Mice with ΔD-iD combined with either sle1 or sle3 had increased production of dsDNA-binding IgM and IgG by 12 months of age. These findings indicate that the peripheral CDR-H3 repertoire can be categorically manipulated by the effects of nonimmunoglobulin genes.