Terminal deoxynucleotidyl transferase deficiency reduces the incidence of autoimmune nephritis in (New Zealand Black x New Zealand White)F1 mice.
Terminal deoxynucleotidyl transferase (TdT) enzyme activity in lymphocytes generates diversity in the Ag receptor repertoires by adding template-independent N nucleotides and disrupting homology-directed rearrangements. The importance of this diversity in vivo and the significance of the suppression of TdT during fetal life remain uncertain. Previous studies have shown that in TdT knockout mice (TdT(0)) 1) the T cell repertoire is less peptide oriented; and 2) natural autoantibody, particularly anti-DNA autoantibodies, are less polyreactive, and their mean affinities are reduced. Consequently, the suppression of TdT during early T/B cell ontogeny may participate in controlling autoimmunity. To study the impact of TdT suppression in autoimmune-prone mice, we introduced the TdT null mutation into the (NZB x NZW)F1 (B/W) mouse strain. We show that TdT deficiency significantly reduces the incidence of autoimmune nephritis and prolongs survival compared with those in control mice. Surprisingly, the long-term survivor TdT(0) mice produced amounts of anti-ADN and anti-histone autoantibodies similar to those of their TdT+ littermates. However, these TdT(0) mice showed no evidence of renal inflammation, and the immune deposits were restricted to the mesangium, whereas basal membrane deposits were clearly correlated with overt renal disease. The present study supports the idea that the absence of TdT enzyme activity in lymphocytes protects mice against autoimmunity and could offer a therapeutic approach to autoimmune diseases. Moreover, our results may help to unravel the mechanisms of lupus nephritis.
Conde
C
C
Laboratory of Immunopathology, Institute of Immuno-Hematology, Central Hospital, Strasbourg, France.
Weller
S
S
Gilfillan
S
S
Marcellin
L
L
Martin
T
T
Pasquali
J L
JL
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003433:Crosses, Genetic; D004253:DNA Nucleotidylexotransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D005920:Glomerular Mesangium / Q000473:pathology; D006942:Hypergammaglobulinemia / Q000235:genetics; D008181:Lupus Nephritis / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D004253:DNA Nucleotidylexotransferase