Effect of a Genetic Deficiency of Terminal Deoxynucleotidyl Transferase on Autoantibody Production by C57BL6 Faslpr Mice

The neonatal Ab and TCR repertoires are much less diverse, and also very different from, the adult repertoires due to the delayed onset of terminal deoxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontemplated N nucleotides to the junctions of Igs and TCRs, and thus its absence removes one of the major components of junctional diversity in complementarity-determining region 3 (CDR3). We have generated TdT-deficient MRL/lpr, Fas-deficient (MRL-Faslpr) mice, and show that they have an increased lifespan, decreased incidence of skin lesions, and much lower serum levels of anti-dsDNA, anti-chromatin, and IgM rheumatoid factors. The generalized hypergammaglobulinemia characteristic of MRL-Faslpr mice is also greatly reduced, as is the percentage of CD4−CD8−B220+ (double-negative) T cells. IgG deposits in the kidney are significantly reduced, although evidence of renal disease is present in many mice at 6 mo. CDR3 regions of both IgH and TCR from peripheral lymphocytes of MRL-Faslpr mice are shorter in the absence of TdT, and there is a paucity of arginines in the IgH CDR3 regions of the MRL-Faslpr TdT−/− mice. Because the amelioration of symptoms is so widespread, it is likely that the absence of N regions has more of an affect than merely decreasing the precursor frequency of anti-dsDNA B cells. Hence, either the T or B cell repertoires, or more likely both, require N region diversity to produce the full spectrum of autoimmune lupus disease.

Section: Discussionmentioning

confidence: 79%

Terminal Deoxynucleotidyl Transferase Deficiency Decreases Autoimmune Disease in MRL-Fas lpr Mice

Feeney

Lawson

Kono

et al. 2001

“…It has also been suggested that TdT may play a role in both the production of anti-DNA Abs and Ig gene usage. TdT-mediated N nucleotide additions increase the length of the CDR3 thus increasing the potential to generate arginine residues in the Ag binding site (39). C57BL/6-Fas(lpr) mice deficient in TdT had significantly fewer arginines in their CDR3 and a lower frequency of anti-DNA Abs (39).…”

Section: Discussionmentioning

confidence: 99%

“…TdT-mediated N nucleotide additions increase the length of the CDR3 thus increasing the potential to generate arginine residues in the Ag binding site (39). C57BL/6-Fas(lpr) mice deficient in TdT had significantly fewer arginines in their CDR3 and a lower frequency of anti-DNA Abs (39). Further, Tuaillon and Capra (40) recently demonstrated that the presence or absence of TdT can modulate the choice of V H , D, and J H use independent of B cell Ag stimulation.…”

Section: Discussionmentioning

confidence: 99%

Heavy Chain Revision in MRL Mice: A Potential Mechanism for the Development of Autoreactive B Cell Precursors

Klonowski

Monestier

2000

Abs reactive to DNA and DNA/histone complexes are distinguished by the presence of positively charged amino acids, such as arginine, in the heavy chain complementarity-determining region 3. The presence of these amino acids partly results from atypical VH-D-JH rearrangements such as D-D fusions and D inversions. Previous results in our laboratory demonstrated that newborn autoimmune MRL/MpJ-+/+ mice undergo these unusual recombinations more frequently when compared with normal C3H/HeJ controls. In addition, the heavy chain junctions in newborn MRL mice demonstrated a preferred usage of VH-proximal D genes and distal JH genes suggestive of secondary gene rearrangements. In this study we explore the possibility that adult MRL B220+IgM− pre B cells, which have not yet undergone Ag selection, exhibit similar rearrangement patterns. Indeed, MRL pre-B cells possessed more atypical rearrangements (D-D fusions) than those of C3H/HeJ mice. However, the biased use of upstream D genes and downstream JH genes observed in the newborn MRL mice was not present in the pre-B cell library. These results suggest that the heavy chain rearrangement process persists later during B cell life in lupus-prone mice and lead us to propose a model of heavy chain receptor revision in the periphery of autoimmune mice.

“…B cell-deficient-MRL/lpr mice failed to develop glomerulonephritis (22)(23)(24). Also important is a diverse lymphocyte repertoire, because MRL/lpr mice lacking terminal deoxynucleotidyl transferase, an enzyme that adds nucleotides to the V(D)J segments during recombination, have decreased glomerular disease (25)(26)(27)(28)(29). However, how B cells contribute to lupus nephritis might be more complicated than previously appreciated.…”

Section: Rl-fasmentioning

confidence: 99%

Abrogation of Lupus Nephritis in Activation-Induced Deaminase-Deficient MRL/lpr Mice

Jiang

Foley²,

Clayton³

et al. 2007

We generated MRL/lpr mice deficient in activation-induced deaminase (AID). Because AID is required for Ig hypermutation and class switch recombination, these mice lack hypermutated IgG Abs. Unlike their AID wild-type littermates, AID-deficient MRL/lpr mice not only lacked autoreactive IgG Abs but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype in AID-deficient mice translated into a significant reduction in glomerulonephritis, minimal mononuclear cell infiltration in the kidney, and a dramatic increase in survival to levels comparable to those previously reported for MRL/lpr mice completely lacking B cells and well below those of mice lacking secreted Abs. Therefore, this study wherein littermates with either high levels of autoreactive IgM or autoreactive IgG were directly examined proves that autoreactive IgM Abs alone are not sufficient to promote kidney disease in MRL/lpr mice. In addition, the substantial decrease in mortality combined with a dramatic increase in autoreactive IgM Abs in AID-deficient MRL/lpr mice suggest that autoreactive IgM Abs might not only fail to promote nephritis but may also provide a protective role in MRL/lpr mice. This novel mouse model containing high levels of autoreactive, unmutated IgM Abs will help delineate the contribution of autoreactive IgM to autoimmunity.