Adult lupus-prone MRL/MpJ2+ mice express a primary antibody repertoire that differs in CDR-H3 length distribution and hydrophobicity from that expressed in the C3H parental strain.
Anti-dsDNA antibodies tend to be enriched for heavy chain complementarity determining region 3 (CDR-H3) intervals of above average length that contain an increased frequency of charged amino acids. It is unclear whether these types of CDR-H3s are more common in the primary B-cell repertoire of auto-immune prone strains or whether their increased prevalence in affected individuals reflects positive selection and expansion of atypical CDR-H3s in the pathogenic response to self-antigen. Here, we present evidence that when compared to C3H, a MRL/MpJ(2+) parental strain, CDR-H3 intervals from pre-B cells of adult lupus-prone MRL/MpJ(2+) mice are longer on average and are enriched for charged amino acids. The predicted prevalence of deformed loops per Shirai H3 criteria is also higher. In contrast, the frequency of charge, the distribution of length, and the pattern of predicted deformed loop structures did not differ in sequences obtained from neonates of the same two strains. These observations suggest that the mechanisms that serve to shape the initial CDR-H3 repertoire in adults, but not neonates, are being regulated differently in C3H versus MRL/MpJ(2+). Dysregulation of the adult pre-B CDR-H3 antibody repertoire could be a contributing factor for the development of florid auto-immune disease in MRL/MpJ(2+) mice.
Zemlin
Michael
M
Clinic for Neonatology and Neuropediatrics, Philipps Universität Marburg, Deutschhausstr. 12, 35037 Marburg, Germany.
Ippolito
Gregory C
GC
Zemlin
Cosima
C
Link
Jason
J
Monestier
Marc
M
Schroeder
Harry W
HW
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000276:immunology; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000276:immunology; D018507:Gene Expression Regulation, Developmental; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D008099:Liver / Q000276:immunology; D008177:Lupus Vulgaris / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D004247:DNA