title: Separation of function between isotype switching and affinity maturation in vivo during acute immune responses and circulating autoantibodies in UNG-deficient mice.
abstract: Activation-induced deaminase converts deoxycytidine to deoxyuridine at the Ig loci. Complementary pathways, initiated by the uracil-DNA glycosylase (UNG) or the mismatch repair factor MSH2/MSH6, must process the deoxyuridine to initiate class-switch recombination (CSR) and somatic hypermutation. UNG deficiency most severely reduces CSR efficiency and only modestly affects the somatic hypermutation spectrum in vitro. This would predict isotype-switching deficiency but normal affinity maturation in Ung(-/-) mice in vivo, but this has not been tested. Moreover, puzzling differences in the amount of circulating Ig between UNG-deficient humans and mice make it unclear to what extent MSH2/MSH6 can complement for UNG in vivo. We find that Ab affinity maturation is indeed unaffected in Ung(-/-) mice, even allowing IgM responses with higher than normal affinity. Ung(-/-) mice display normal to only moderately reduced basal levels of most circulating Ig subclasses and gut-associated IgA, which are elicited in response to chronically available environmental Ag. In contrast, their ability to produce switched Ig in response to immunization or vesicular stomatitis virus infection is strongly impaired. Our results uncover a specific need for UNG in CSR for timely and efficient acute Ab responses in vivo. Furthermore, Ung(-/-) mice provide a novel model for separating isotype switching and affinity maturation during acute (but not chronic) Ab responses, which could be useful for dissecting their relative contribution to some infections. Interestingly, Ung(-/-) mice present with circulating autoantibodies, suggesting that UNG may impinge on tolerance.
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Astrid
authors.initials: A
authors.lastname: Zahn
authors.forename: Matthieu
authors.initials: M
authors.lastname: Daugan
authors.forename: Shiva
authors.initials: S
authors.lastname: Safavi
authors.forename: David
authors.initials: D
authors.lastname: Godin
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.forename: Alain
authors.initials: A
authors.lastname: Lamarre
authors.forename: Javier M
authors.initials: JM
authors.lastname: Di Noia
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051981:Uracil-DNA Glycosidase / Q000172:deficiency / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D051981:Uracil-DNA Glycosidase