@article{1d0a5bd592084880aa86cbb4f2a1ad3e,
title = "Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients",
abstract = "Pemphigus vulgaris (PV) is a potentially fatal blistering disease caused by autoantibodies (autoAbs) against desmoglein 3 (Dsg3). Here, we clone anti-Dsg3 antibodies (Abs) from four PV patients and identify pathogenic VH1-46 autoAbs from all four patients. Unexpectedly, VH1-46 autoAbs had relatively few replacement mutations. We reverted antibody somatic mutations to their germline sequences to determine the requirement of mutations for autoreactivity. Three of five VH1-46 germline-reverted Abs maintain Dsg3 binding, compared with zero of five non-VH1-46 germline-reverted Abs. Site-directed mutagenesis of VH1-46 Abs demonstrates that acidic amino-acid residues introduced by somatic mutation or heavy chain VDJ recombination are necessary and sufficient for Dsg3 binding. Our data suggest that VH1-46 autoantibody gene usage is commonly found in PV because VH1-46 Abs require few to no mutations to acquire Dsg3 autoreactivity, which may favour their early selection. Common VH gene usage indicates common humoral immune responses, even among unrelated patients.",
author = "Cho, {Michael Jeffrey} and Lo, {Agnes S.Y.} and Xuming Mao and Nagler, {Arielle R.} and Ellebrecht, {Christoph T.} and Mukherjee, {Eric M.} and Hammers, {Christoph M.} and Choi, {Eun Jung} and Sharma, {Preety M.} and Mohamed Uduman and Hong Li and Rux, {Ann H.} and Farber, {Sara A.} and Rubin, {Courtney B.} and Kleinstein, {Steven H.} and Sachais, {Bruce S.} and Posner, {Marshall R.} and Cavacini, {Lisa A.} and Payne, {Aimee S.}",
note = "Funding Information: We thank John Stanley, Don Siegel and Steve Kacir for helpful scientific discussions and reagents. We thank Razzaque Ahmed for identifying PV patients 3 and 4 for this study. This project was supported in part by grants AR053505, AR057001 and P30-AR057217 from NIAMS/NIH (A.S.P.); Dermatology Foundation (X.M.); HA6736/1-1 (C.M.H.) and EL711/1-1 (C.T.E.) from Deutsche Forschungsgemeinschaft; T32-AR007465 (A.R.R, E.M.M., S.A.F, C.B.R.); T15-LM07056 from NIH/NLM (M.U.); R03AI092379 from NIH/ NIAID (S.H.K.); HL078726-S1 from NHLBI/NIH (B.S.S.); Dana-Farber Cancer Institute Friends Head and Neck Cancer Research Award (L.A.C.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAMS or NIH.",
year = "2014",
month = jun,
day = "19",
doi = "10.1038/ncomms5167",
language = "English",
volume = "5",
journal = "Nature Communications",
issn = "1751-8628",
}
