Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
|---|---|
| Enthalten in: |
Nature immunology - 23(2022), 8 vom: 28. Aug., Seite 1256-1272 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 09.08.2022 Date Revised 02.09.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41590-022-01271-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM344223612 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM344223612 | ||
| 003 | DE-627 | ||
| 005 | 20231226022250.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41590-022-01271-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1147.xml |
| 035 | |a (DE-627)NLM344223612 | ||
| 035 | |a (NLM)35902638 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Csomos, Krisztian |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.08.2022 | ||
| 500 | |a Date Revised 02.09.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a RAG2 protein, human |2 NLM | |
| 650 | 7 | |a RAG-1 protein |2 NLM | |
| 650 | 7 | |a 128559-51-3 |2 NLM | |
| 700 | 1 | |a Ujhazi, Boglarka |e verfasserin |4 aut | |
| 700 | 1 | |a Blazso, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Herrera, Jose L |e verfasserin |4 aut | |
| 700 | 1 | |a Tipton, Christopher M |e verfasserin |4 aut | |
| 700 | 1 | |a Kawai, Tomoki |e verfasserin |4 aut | |
| 700 | 1 | |a Gordon, Sumai |e verfasserin |4 aut | |
| 700 | 1 | |a Ellison, Maryssa |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Stowell, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Haynes, Lauren |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Zakota, Bence |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Johnny |e verfasserin |4 aut | |
| 700 | 1 | |a Altrich, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Geier, Christoph B |e verfasserin |4 aut | |
| 700 | 1 | |a Sharapova, Svetlana |e verfasserin |4 aut | |
| 700 | 1 | |a Dasso, Joseph F |e verfasserin |4 aut | |
| 700 | 1 | |a Leiding, Jennifer W |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Grace |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Herz, Waleed |e verfasserin |4 aut | |
| 700 | 1 | |a de Barros Dorna, Mayra |e verfasserin |4 aut | |
| 700 | 1 | |a Fadugba, Olajumoke |e verfasserin |4 aut | |
| 700 | 1 | |a Fronkova, Eva |e verfasserin |4 aut | |
| 700 | 1 | |a Kanderova, Veronika |e verfasserin |4 aut | |
| 700 | 1 | |a Svaton, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Henrickson, Sarah E |e verfasserin |4 aut | |
| 700 | 1 | |a Hernandez, Joseph D |e verfasserin |4 aut | |
| 700 | 1 | |a Kuijpers, Taco |e verfasserin |4 aut | |
| 700 | 1 | |a Kandilarova, Snezhina Mihailova |e verfasserin |4 aut | |
| 700 | 1 | |a Naumova, Elizaveta |e verfasserin |4 aut | |
| 700 | 1 | |a Milota, Tomas |e verfasserin |4 aut | |
| 700 | 1 | |a Sediva, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Moshous, Despina |e verfasserin |4 aut | |
| 700 | 1 | |a Neven, Benedicte |e verfasserin |4 aut | |
| 700 | 1 | |a Saco, Tara |e verfasserin |4 aut | |
| 700 | 1 | |a Sargur, Ravishankar |e verfasserin |4 aut | |
| 700 | 1 | |a Savic, Sinisa |e verfasserin |4 aut | |
| 700 | 1 | |a Sleasman, John |e verfasserin |4 aut | |
| 700 | 1 | |a Sunkersett, Gauri |e verfasserin |4 aut | |
| 700 | 1 | |a Ward, Brant R |e verfasserin |4 aut | |
| 700 | 1 | |a Komatsu, Masanobu |e verfasserin |4 aut | |
| 700 | 1 | |a Pittaluga, Stefania |e verfasserin |4 aut | |
| 700 | 1 | |a Kumanovics, Attila |e verfasserin |4 aut | |
| 700 | 1 | |a Butte, Manish J |e verfasserin |4 aut | |
| 700 | 1 | |a Cancro, Michael P |e verfasserin |4 aut | |
| 700 | 1 | |a Pillai, Shiv |e verfasserin |4 aut | |
| 700 | 1 | |a Meffre, Eric |e verfasserin |4 aut | |
| 700 | 1 | |a Notarangelo, Luigi D |e verfasserin |4 aut | |
| 700 | 1 | |a Walter, Jolan E |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature immunology |d 2000 |g 23(2022), 8 vom: 28. Aug., Seite 1256-1272 |w (DE-627)NLM10805523X |x 1529-2916 |7 nnns |
| 773 | 1 | 8 | |g volume:23 |g year:2022 |g number:8 |g day:28 |g month:08 |g pages:1256-1272 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41590-022-01271-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 23 |j 2022 |e 8 |b 28 |c 08 |h 1256-1272 | ||