Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.

Validation of a murine proteome-wide phage display library for identification of autoantibody specificities.
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DOI:
10.1172/jci.insight.174976
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发表时间:
2023-12-08
期刊:
影响因子:
8
通讯作者:
Derisi, Joseph L.
Derisi, Joseph L.
中科院分区:
医学1区
文献类型:
--
作者:
Rackaityte, Elze;Proekt, Irina;Miller, Haleigh S.;Ramesh, Akshaya;Brooks, Jeremy F.;Kung, Andrew F.;Mandel-Brehm, Caleigh;Yu, David;Zamecnik, Colin R.;Bair, Rebecca;Vazquez, Sara E.;Sunshine, Sara;Abram, Clare L.;Lowell, Clifford A.;Rizzuto, Gabrielle;Wilson, Michael R.;Zikherman, Julie;Anderson, Mark S.;Derisi, Joseph L.

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Autoimmunity is characterized by loss of tolerance to tissue-specific as well as systemic antigens, resulting in complex autoantibody landscapes. Here, we introduce and extensively validate the performance characteristics of a murine proteome-wide library for phage display immunoprecipitation and sequencing (PhIP-seq) in profiling mouse autoantibodies. This library was validated using 7 genetically distinct mouse lines across a spectrum of autoreactivity. Mice deficient in antibody production (Rag2–/– and μMT) were used to model nonspecific peptide enrichments, while cross-reactivity was evaluated using anti-ovalbumin B cell receptor–restricted OB1 mice as a proof of principle. The PhIP-seq approach was then utilized to interrogate 3 distinct autoimmune disease models. First, serum from Lyn–/– IgD+/– mice with lupus-like disease was used to identify nuclear and apoptotic bleb reactivities. Second, serum from nonobese diabetic (NOD) mice, a polygenic model of pancreas-specific autoimmunity, was enriched in peptides derived from both insulin and predicted pancreatic proteins. Lastly, Aire–/– mouse sera were used to identify numerous autoantigens, many of which were also observed in previous studies of humans with autoimmune polyendocrinopathy syndrome type 1 carrying recessive mutations in AIRE. These experiments support the use of murine proteome-wide PhIP-seq for antigenic profiling and autoantibody discovery, which may be employed to study a range of immune perturbations in mouse models of autoimmunity profiling.
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