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.
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 DHlocus (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 DHand 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.
a Department of Medicine , University of Alabama at Birmingham , Birmingham , AL , USA.|b Genetic Engineering and Biotechnology Division, National Research Center , Cairo , Egypt.
Mohamed
M
Khass
c Department of Pediatrics , University of Alabama at Birmingham , Birmingham , AL , USA.
Robert L
RL
Schelonka
a Department of Medicine , University of Alabama at Birmingham , Birmingham , AL , USA.
Cun Ren
CR
Liu
a Department of Medicine , University of Alabama at Birmingham , Birmingham , AL , USA.
Ada
A
Elgavish
d Department of Pathology , University of Florida , Gainesville , FL , USA , and.
Laurence
L
Morel
e Department of Microbiology , University of Alabama at Birmingham , Birmingham , AL , USA.
Peter D
PD
Burrows
a Department of Medicine , University of Alabama at Birmingham , Birmingham , AL , USA.|e Department of Microbiology , University of Alabama at Birmingham , Birmingham , AL , USA.
Harry W
HW
Schroeder
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000917:Antibody Formation; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D040641:Quantitative Trait Loci
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D007075:Immunoglobulin M
B-cell repertoire; CDR-H3 and diversity gene segments; DH; Sle; Systemic lupus erythematosus; third complementary determining region heavy chain