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2015 ; 58
(ä): 67-77
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Predominant role for activation-induced cytidine deaminase in generating IgG
anti-nucleosomal antibodies of murine SLE
#MMPMID25634361
Detanico T
; Guo W
; Wysocki LJ
J Autoimmun
2015[Apr]; 58
(ä): 67-77
PMID25634361
show ga
Serum IgG anti-nuclear antibodies (ANA) directed to complexes of DNA and histones
are a hallmark of systemic lupus erythematosus (SLE) and reflect a failure in
lymphocyte self-tolerance. A prior study utilizing spontaneously autoimmune
B6.Nba2 mice deficient in terminal deoxynucleotidyl transferase (TdT) and with
heterozygous deficiencies in Jh and Igk loci underscored the importance of
somatic hypermutation (SHM) as a major generator of SLE-associated ANA. This
interpretation had to be qualified because of severely limited opportunities for
receptor editing and restricted VHCDR3 diversity. Therefore, we performed the
converse study using mice that carried functional Tdt genes and wild type Jh and
Igk loci but that could not undergo SHM. Analyses of ANA and ANA-producing
hybridomas from B6.Nba2 Aicda(-/-) mice revealed that few animals produced high
titers of the prototypical ANA directed to complexes of histones and DNA, that
this response was delayed and that those cells that did produce such antibody
exhibited limited clonal expansion, unusual Jk use and only infrequent dual
receptor expression. This, together with the additional finding of an intrinsic
propensity for SHM to generate Arg codons selectively in CDRs, reinforce the view
that most IgG autoimmune clones producing prototypical anti-nucleosome antibodies
in wild type mice are created by SHM.