A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans

被引:18
作者
Hagelkruys, Astrid [1 ]
Wirnsberger, Gerald [1 ,2 ]
Stadlmann, Johannes [1 ,3 ]
Wohner, Miriam [4 ]
Horrer, Marion [1 ]
Vilagos, Bojan [5 ]
Jonsson, Gustav [1 ]
Kogler, Melanie [1 ]
Tortola, Luigi [1 ,6 ]
Novatchkova, Maria [4 ]
Bonelt, Peter [4 ]
Hoffmann, David [1 ]
Koglgruber, Rubina [1 ]
Steffen, Ulrike [7 ,8 ]
Schett, Georg [7 ,8 ]
Busslinger, Meinrad [4 ]
Bergthaler, Andreas [5 ]
Klein, Christoph [9 ]
Penninger, Josef M. [1 ,10 ]
机构
[1] Austrian Acad Sci, Inst Mol Biotechnol, Vienna, Austria
[2] Apeiron Biol AG, Vienna, Austria
[3] Univ Nat Resource & Life Sci, Inst Biochem, Vienna, Austria
[4] Vienna Bioctr, Res Inst Mol Pathol, Vienna, Austria
[5] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria
[6] Swiss Fed Inst Technol, Inst Mol Hlth Sci, Zurich, Switzerland
[7] Friedrich Alexander Univ Erlangen Nurnberg, Dept Internal Med 3, Rheumatol & Immunol, Erlangen, Germany
[8] Univ Klinikum Erlangen, Erlangen, Germany
[9] Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany
[10] Univ British Columbia, Life Sci Inst, Dept Med Genet, Vancouver, BC, Canada
关键词
UNFOLDED PROTEIN RESPONSE; FC-GAMMA-RIII; CENTER B-CELL; ENDOPLASMIC-RETICULUM; HUMAN-IGG; EFFECTOR FUNCTIONS; IMMUNOGLOBULIN-G; PLASMA-CELLS; BONE-MARROW; STRESS;
D O I
10.1084/jem.20200559
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.
引用
收藏
页数:24
相关论文
共 68 条
[1]   Natural variation in Fc glycosylation of HIV-specific antibodies impacts antiviral activity [J].
Ackerman, Margaret E. ;
Crispin, Max ;
Yu, Xiaojie ;
Baruah, Kavitha ;
Boesch, Austin W. ;
Harvey, David J. ;
Dugast, Anne-Sophie ;
Heizen, Erin L. ;
Ercan, Altan ;
Choi, Ickwon ;
Streeck, Hendrik ;
Nigrovic, Peter A. ;
Bailey-Kellogg, Chris ;
Scanlan, Chris ;
Alter, Galit .
JOURNAL OF CLINICAL INVESTIGATION, 2013, 123 (05) :2183-2192
[2]   The impact of glycosylation on the biological function and structure of human immunoglobulins [J].
Arnold, James N. ;
Wormald, Mark R. ;
Sim, Robert B. ;
Rudd, Pauline M. ;
Dwek, Raymond A. .
ANNUAL REVIEW OF IMMUNOLOGY, 2007, 25 :21-50
[3]   JAGN1 Deficient Severe Congenital Neutropenia: Two Cases from the Same Family [J].
Baris, S. ;
Karakoc-Aydiner, E. ;
Ozen, A. ;
Delil, K. ;
Kiykim, A. ;
Ogulur, I. ;
Baris, I. ;
Barlan, I. B. .
JOURNAL OF CLINICAL IMMUNOLOGY, 2015, 35 (04) :339-343
[4]  
BENNER R, 1981, CLIN EXP IMMUNOL, V46, P1
[5]   The transcription factor XBP1 is selectively required for eosinophil differentiation [J].
Bettigole, Sarah E. ;
Lis, Raphael ;
Adoro, Stanley ;
Lee, Ann-Hwee ;
Spencer, Lisa A. ;
Weller, Peter F. ;
Glimcher, Laurie H. .
NATURE IMMUNOLOGY, 2015, 16 (08) :829-+
[6]   Association between Galactosylation of Immunoglobulin G and Improvement of Rheumatoid Arthritis during Pregnancy Is Independent of Sialylation [J].
Bondt, Albert ;
Selman, Maurice H. J. ;
Deelder, Andre M. ;
Hazes, Johanna M. W. ;
Willemsen, Sten P. ;
Wuhrer, Manfred ;
Dolhain, Radboud J. E. M. .
JOURNAL OF PROTEOME RESEARCH, 2013, 12 (10) :4522-4531
[7]   JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia [J].
Boztug, Kaan ;
Jaervinen, Paeivi M. ;
Salzer, Elisabeth ;
Racek, Tomas ;
Moench, Sebastian ;
Garncarz, Wojciech ;
Gertz, E. Michael ;
Schaeffer, Alejandro A. ;
Antonopoulos, Aristotelis ;
Haslam, Stuart M. ;
Schieck, Lena ;
Puchalka, Jacek ;
Diestelhorst, Jana ;
Appaswamy, Giridharan ;
Lescoeur, Brigitte ;
Giambruno, Roberto ;
Bigenzahn, Johannes W. ;
Elling, Ulrich ;
Pfeifer, Dietmar ;
Conde, Cecilia Dominguez ;
Albert, Michael H. ;
Welte, Karl ;
Brandes, Gudrun ;
Sherkat, Roya ;
ten Bosch, Jutte van der Werff ;
Rezaei, Nima ;
Etzioni, Amos ;
Bellanne-Chantelot, Christine ;
Superti-Furga, Giulio ;
Penninger, Josef M. ;
Bennett, Keiryn L. ;
von Blume, Julia ;
Dell, Anne ;
Donadieu, Jean ;
Klein, Christoph .
NATURE GENETICS, 2014, 46 (09) :1021-+
[8]   Mammalian unfolded protein response inhibits cyclin D1 translation and cell-cycle progression [J].
Brewer, JW ;
Hendershot, LM ;
Sherr, CJ ;
Diehl, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (15) :8505-8510
[9]   The sarco/endoplasmic reticulum calcium-ATPase 2b is an endoplasmic reticulum stress-inducible protein [J].
Caspersen, C ;
Pedersen, PS ;
Treiman, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (29) :22363-22372
[10]   Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases [J].
Chen, Rong ;
Shi, Lisong ;
Hakenberg, Joerg ;
Naughton, Brian ;
Sklar, Pamela ;
Zhang, Jianguo ;
Zhou, Hanlin ;
Tian, Lifeng ;
Prakash, Om ;
Lemire, Mathieu ;
Sleiman, Patrick ;
Cheng, Wei-yi ;
Chen, Wanting ;
Shah, Hardik ;
Shen, Yulan ;
Fromer, Menachem ;
Omberg, Larsson ;
Deardorff, Matthew A. ;
Zackai, Elaine ;
Bobe, Jason R. ;
Levin, Elissa ;
Hudson, Thomas J. ;
Groop, Leif ;
Wang, Jun ;
Hakonarson, Hakon ;
Wojcicki, Anne ;
Diaz, George A. ;
Edelmann, Lisa ;
Schadt, Eric E. ;
Friend, Stephen H. .
NATURE BIOTECHNOLOGY, 2016, 34 (05) :531-538