Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells
Krisztián Csomós, Boglárka Ujházi, Péter Blazsó, José Luís Herrera, Christopher M. Tipton, Tomoki Kawai, Sumai Gordon, Maryssa Ellison, Kevin Y. Wu, Matthew Stowell, L.W. Haynes, Rachel Cruz, Bence Zakota, Johnny Nguyen, Michelle Altrich, Christoph B. Geier, Svetlana Sharapova, Joseph Dasso, Jennifer W. Leiding, Grace Smith, Waleed Al–Herz, Mayra de Barros Dorna, Olajumoke Fadugba, Eva Froňková, Veronika Kanderová, Michael Svatoň, Sarah E. Henrickson, Joseph D. Hernandez, Taco W. Kuijpers, Snezhina Mihailova Kandilarova, Е. А. Наумова, Tomáš Milota, Anna Šedivá, Despina Moshous, Bénédicte Neven, Tara Saco, Ravishankar Sargur, Sinisa Savic, John W. Sleasman, Gauri Sunkersett, Brant R. Ward, Masanobu Komatsu, Stefania Pittaluga, Attila Kumánovics, Manish J. Butte, Michael P. Cancro, Shiv Pillai, Eric Meffre, Luigi D. Notarangelo, Jolán E. Walter
Abstract
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.