LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

被引：0

作者：

Ransmayr, Bernhard ^{[1
,2
,3
]}

Bal, Sevgi Koestel ^{[1
,2
,3
]}

Thian, Marini ^{[1
,2
,3
,33
]}

Svaton, Michael ^{[1
,2
]}

van de Wetering, Cheryl ^{[1
,2
]}

Hafemeister, Christoph ^{[1
]}

Segarra-Roca, Anna ^{[1
]}

Block, Jana ^{[1
,2
,3
]}

Frohne, Alexandra ^{[1
]}

Krolo, Ana ^{[2
,3
,34
]}

Altunbas, Melek Yorgun ^{[4
,5
,6
,7
]}

Bilgic-Eltan, Sevgi ^{[4
,5
,6
,7
]}

Kiykim, Ayca ^{[8
]}

Aydiner, Omer ^{[9
]}

Kesim, Selin ^{[10
]}

Inanir, Sabahat ^{[10
]}

Karakoc-Aydiner, Elif ^{[4
,5
,6
,7
]}

Ozen, Ahmet ^{[4
,5
,6
,7
]}

Aba, Uemran ^{[11
,12
]}

Comak, Aylin ^{[13
]}

Tugcu, Goekcen Dilsa ^{[14
]}

Pazdzior, Robert ^{[2
,35
]}

Huber, Bettina ^{[15
]}

Farlik, Matthias ^{[15
]}

Kubicek, Stefan ^{[2
]}

von Bernuth, Horst ^{[16
,17
,18
,19
,20
,21
,22
,23
]}

Simonitsch-Klupp, Ingrid ^{[24
]}

Rizzi, Marta ^{[25
,26
,27
,28
]}

Halbritter, Florian ^{[1
]}

Tumanov, Alexei V. ^{[29
]}

Kraakman, Michael J. ^{[1
,2
,3
]}

Metin, Ayse ^{[30
]}

Castanon, Irinka ^{[1
,2
]}

Erman, Baran ^{[11
,12
]}

Baris, Safa ^{[4
,5
,6
,7
]}

Boztug, Kaan ^{[1
,2
,3
,31
,32
]}

机构：

[1] St Anna Childrens Canc Res Inst, Vienna, Austria

[2] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[3] Ludwig Boltzmann Inst Rare & Undiag Dis, Vienna, Austria

[4] Marmara Univ, Dept Pediat, Div Allergy & Immunol, Sch Med, Istanbul, Turkiye

[5] Istanbul Jeffrey Modell Diag Ctr Primary Immunodef, Istanbul, Turkiye

[6] Marmara Univ, Isil Berat Barlan Ctr Translat Med, Istanbul, Turkiye

[7] Marmara Univ, Educ & Res Hosp, Istanbul, Turkiye

[8] Istanbul Univ, CerrahpaSa Fac Med, Dept Pediat Allergy & Immunol, Istanbul, Turkiye

[9] Kartal Dr Lutfi Kirdar City Hosp, Dept Pediat Neurol, Istanbul, Turkiye

[10] Marmara Univ, Fac Med, Dept Nucl Med, Istanbul, Turkiye

[11] Hacettepe Univ, Can Sucak Res Lab Translat Immunol, Ankara, Turkiye

[12] Hacettepe Univ, Inst Child Hlth, Ankara, Turkiye

[13] Ankara Bilkent City Hosp, Dept Nucl Med, Ankara, Turkiye

[14] Ankara Bilkent City Hosp, Childrens Hosp, Dept Pediat Neurol, Ankara, Turkiye

[15] Med Univ Vienna, Dept Dermatol, Vienna, Austria

[16] Charite, Dept Pediat Resp Med Immunol & Crit Care Med, Berlin, Germany

[17] Free Univ Berlin, Berlin, Germany

[18] Humboldt Univ, Berlin, Germany

[19] Berlin Inst Hlth, Berlin, Germany

[20] Lab Berlin Charite Vivantes, Dept Immunol, Berlin, Germany

[21] Charite Univ Med Berlin, Berlin Inst Int Hlth Global Hlth Ctr, D-13353 Berlin, Germany

[22] Charite Univ Med Berlin, Berlin, Germany

[23] Berlin Inst Hlth BIH, Berlin Brandenburg Ctr Regenerat Therapies BCRT, Berlin, Germany

[24] Med Univ Vienna, Dept Pathol, Vienna, Austria

[25] Univ Freiburg, Dept Rheumatol & Clin Immunol, Freiburg, Germany

[26] Univ Freiburg, Fac Med, Ctr Chron Immunodeficiency, Med Ctr, Freiburg, Germany

[27] Univ Freiburg, Ctr Integrat Biol Signalling Studies CIBSS, Freiburg, Germany

[28] Med Univ Vienna, Inst Immunol, Ctr Pathophysiol Infectiol & Immunol, Vienna, Austria

[29] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol Immunol & Mol Genet, San Antonio, TX USA

[30] Ankara Bilkent City Hosp, Dept Pediat Allergy Immunol, Ankara, Turkiye

[31] Med Univ Vienna, Dept Pediat & Adolescent Med, Vienna, Austria

[32] St Anna Childrens Hosp, Vienna, Austria

[33] Takeda Pharmaceut USA inc, Drug Safety Res & Evaluat, Cambridge, MA USA

[34] Boehringer Ingelheim GmbH & Co KG, Canc Pharmacol & Dis Positioning, Vienna, Austria

[35] Univ Konstanz, Dept Chem, Constance, Germany

来源：

SCIENCE IMMUNOLOGY | 2024年 / 9卷 / 101期

基金：

欧洲研究理事会;

关键词：

TUMOR-NECROSIS-FACTOR; LYMPHOTOXIN ALPHA/BETA; RECEPTOR; EXPRESSION; APOPTOSIS; LIGHT; IMMUNODEFICIENCY; PATHOGENICITY; AUTOIMMUNITY; HOMEOSTASIS;

D O I：

10.1126/sciimmunol.adq8796

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in LTBR, encoding the lymphotoxin beta receptor (LT beta R), primarily expressed on stromal cells. Patients with LT beta R deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LT beta R-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.

引用

页数：17