c-Rel gain in B cells drives germinal center reactions and autoantibody production

被引：10

作者：

Kober-Hasslacher, Maike ^{[1
,2
,13
]}

Oh-Strauss, Hyunju ^{[1
,3
]}

Kumar, Dilip ^{[2
,14
]}

Soberon, Valeria ^{[1
,3
]}

Diehl, Carina ^{[1
,3
]}

Lech, Maciej ^{[4
]}

Engleitner, Thomas ^{[3
,5
,6
,7
]}

Katab, Eslam ^{[3
,8
]}

Fernandez-Saiz, Jvanesa ^{[3
,8
]}

Piontek, Guido ^{[9
]}

Li, Hongwei ^{[3
,10
]}

Menze, Bjorn ^{[3
,10
]}

Ziegenhain, Christoph ^{[11
]}

Enard, Wolfgang ^{[11
]}

Rad, Roland ^{[3
,5
,6
,7
]}

Boettcher, Jan P. ^{[12
]}

Anders, Hans-Joachim ^{[4
]}

Rudelius, Martina ^{[9
]}

Schmidt-Supprian, Marc ^{[1
,2
,3
,5
,6
]}

机构：

[1] Tech Univ Munich, Sch Med, Inst Expt Hematol, Ismaninger Str 22, D-81675 Munich, Germany

[2] Max Planck Inst Biochem, Martinsried, Germany

[3] Tech Univ Munich, Ctr Translat Canc Res TranslaTUM, Sch Med, Munich, Germany

[4] Klinikum Ludwig Maximilians Univ, Renal Div, Med Klin & Polildin 4, Munich, Germany

[5] German Canc Consortium DKTK, Heidelberg, Germany

[6] German Canc Res Ctr, Heidelberg, Germany

[7] Tech Univ Munich, Inst Mol Oncol & Funct Genom, Sch Med, Munich, Germany

[8] Tech Univ Munich, Dept Med 3, Sch Med, Munich, Germany

[9] Klinikum Ludwig Maximilians Univ, Inst Pathol, Munich, Germany

[10] Tech Univ Munich, Dept Informat, Munich, Germany

[11] Ludwig Maximilians Univ Munchen, Dept Biol 2, Anthropol & Human Genom, Martinsried, Germany

[12] Tech Univ Munich, Sch Med, Inst Mol Immunol & Expt Oncol, Munich, Germany

[13] Merck KGaA, Darmstadt, Germany

[14] Singapore Immunol Network SIgN, Singapore, Singapore

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 06期

基金：

欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; TRANSCRIPTION FACTOR; CYCLE PROGRESSION; MICE LACKING; GENE; EXPRESSION; DIFFERENTIATION; SUSCEPTIBILITY; DISEASE; PROLIFERATION;

D O I：

10.1172/JCI124382

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Single-nucleotide polymorphisms and locus amplification fink the NF-kappa B transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.

引用

页码：3270 / 3286

页数：17

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