Integration of Th17-and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation

被引：167

作者：

Pikor, Natalia B. ^{[1
]}

Astarita, Jillian L. ^{[2
,3
,4
,5
]}

Summers-Deluca, Leslie ^{[1
]}

Galicia, Georgina ^{[1
]}

Qu, Joy ^{[1
]}

Ward, Lesley A. ^{[1
]}

Armstrong, Susan ^{[1
]}

Dominguez, Claudia X. ^{[5
]}

Malhotra, Deepali ^{[2
,3
,4
]}

Heiden, Brendan ^{[2
,3
,4
]}

Kay, Robert ^{[1
]}

Castanov, Valera ^{[1
]}

Touil, Hanane ^{[6
]}

Boon, Louis ^{[7
]}

O'Connor, Paul ^{[8
,9
]}

Bar-Or, Amit ^{[6
]}

Prat, Alexandre ^{[10
]}

Ramaglia, Valeria ^{[12
]}

Ludwin, Samuel ^{[11
]}

Turley, Shannon J. ^{[2
,3
,4
,5
]}

Gommerman, Jennifer L. ^{[1
]}

机构：

[1] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada

[2] Dana Farber Canc Inst, Dept Canc Immunol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, AIDS, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Div Med Sci, Boston, MA 02115 USA

[5] Genentech Inc, Dept Canc Immunol, San Francisco, CA 94080 USA

[6] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada

[7] EPIRUS Biopharmaceut Netherlands, NL-3584 CM Utrecht, Netherlands

[8] Univ Toronto, Dept Med, Toronto, ON M5B 1W8, Canada

[9] St Michaels Hosp, Toronto, ON M5B 1W8, Canada

[10] CHU Montreal, Ctr Rech, Neuroimmunol Res Lab, Montreal, PQ H2L 4M1, Canada

[11] Queens Univ, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada

[12] Acad Med Ctr, Dept Genome Anal, NL-1105 AZ Noord Holland, Netherlands

来源：

IMMUNITY | 2015年 / 43卷 / 06期

基金：

加拿大健康研究院; 美国国家科学基金会;

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; FIBROBLASTIC RETICULAR CELLS; MULTIPLE-SCLEROSIS; LYMPHOID FOLLICLES; DENDRITIC CELLS; B-CELLS; BETA; DISEASE; SYSTEM; DEMYELINATION;

D O I：

10.1016/j.immuni.2015.11.010

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin ab (LT alpha beta) on Th17 cells and LT beta R on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTbR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.

引用

页码：1160 / 1173

页数：14

共 29 条

[1] Lymphoid neogenesis in chronic inflammatory diseases [J].

Aloisi, F ;

Pujol-Borrell, R .

NATURE REVIEWS IMMUNOLOGY, 2006, 6 (03) :205-217

[2] Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions [J].

Bartholomaeus, Ingo ;

Kawakami, Naoto ;

Odoardi, Francesca ;

Schlaeger, Christian ;

Miljkovic, Djordje ;

Ellwart, Joachim W. ;

Klinkert, Wolfgang E. F. ;

Fluegel-Koch, Cassandra ;

Issekutz, Thomas B. ;

Wekerle, Hartmut ;

Fluegel, Alexander .

NATURE, 2009, 462 (7269) :94-U104

[3] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis [J].

Beecham, Ashley H. ;

Patsopoulos, Nikolaos A. ;

Xifara, Dionysia K. ;

Davis, Mary F. ;

Kemppinen, Anu ;

Cotsapas, Chris ;

Shah, Tejas S. ;

Spencer, Chris ;

Booth, David ;

Goris, An ;

Oturai, Annette ;

Saarela, Janna ;

Fontaine, Bertrand ;

Hemmer, Bernhard ;

Martin, Claes ;

Zipp, Frauke ;

D'Alfonso, Sandra ;

Martinelli-Boneschi, Filippo ;

Taylor, Bruce ;

Harbo, Hanne F. ;

Kockum, Ingrid ;

Hillert, Jan ;

Olsson, Tomas ;

Ban, Maria ;

Oksenberg, Jorge R. ;

Hintzen, Rogier ;

Barcellos, Lisa F. ;

Agliardi, Cristina ;

Alfredsson, Lars ;

Alizadeh, Mehdi ;

Anderson, Carl ;

Andrews, Robert ;

Sondergaard, Helle Bach ;

Baker, Amie ;

Band, Gavin ;

Baranzini, Sergio E. ;

Barizzone, Nadia ;

Barrett, Jeffrey ;

Bellenguez, Celine ;

Bergamaschi, Laura ;

Bernardinelli, Luisa ;

Berthele, Achim ;

Biberacher, Viola ;

Binder, Thomas M. C. ;

Blackburn, Hannah ;

Bomfim, Izaura L. ;

Brambilla, Paola ;

Broadley, Simon ;

Brochet, Bruno ;

Brundin, Lou .

NATURE GENETICS, 2013, 45 (11) :1353-+

[4] Maturation of Lymph Node Fibroblastic Reticular Cells from Myofibroblastic Precursors Is Critical for Antiviral Immunity [J].

Chai, Qian ;

Onder, Lucas ;

Scandella, Elke ;

Gil-Cruz, Cristina ;

Perez-Shibayama, Christian ;

Cupovic, Jovana ;

Danuser, Renzo ;

Sparwasser, Tim ;

Luther, Sanjiv A. ;

Thiel, Volker ;

Ruelicke, Thomas ;

Stein, Jens V. ;

Hehlgans, Thomas ;

Ludewig, Burkhard .

IMMUNITY, 2013, 38 (05) :1013-1024

[5] Targeted depletion of lymphotoxin-α-expressing TH1 and TH17 cells inhibits autoimmune disease [J].

Chiang, Eugene Y. ;

Kolumam, Ganesh A. ;

Yu, Xin ;

Francesco, Michelle ;

Ivelja, Sinisa ;

Peng, Ivan ;

Gribling, Peter ;

Shu, Jean ;

Lee, Wyne P. ;

Refino, Canio J. ;

Balazs, Mercedesz ;

Paler-Martinez, Andres ;

Nguyen, Allen ;

Young, Judy ;

Barck, Kai H. ;

Carano, Richard A. D. ;

Ferrando, Ron ;

Diehl, Lauri ;

Chatterjea, Devavani ;

Grogan, Jane L. .

NATURE MEDICINE, 2009, 15 (07) :766-U10

[6] Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin β receptor-Ig fusion protein [J].

Columba-Cabezas, Sandra ;

Griguoli, Marilena ;

Rosicarelli, Barbara ;

Magliozzi, Roberta ;

Ria, Francesco ;

Serafini, Barbara ;

Aloisi, Francesca .

JOURNAL OF NEUROIMMUNOLOGY, 2006, 179 (1-2) :76-86

[7] B cell homeostasis and follicle confines are governed by fibroblastic reticular cells [J].

Cremasco, Viviana ;

Woodruff, Matthew C. ;

Onder, Lucas ;

Cupovic, Jovana ;

Nieves-Bonilla, Janice M. ;

Schildberg, Frank A. ;

Chang, Jonathan ;

Cremasco, Floriana ;

Harvey, Christopher J. ;

Wucherpfennig, Kai ;

Ludewig, Burkhard ;

Carroll, Michael C. ;

Turley, Shannon J. .

NATURE IMMUNOLOGY, 2014, 15 (10) :973-U222

[8] Substrain Differences Reveal Novel Disease-Modifying Gene Candidates That Alter the Clinical Course of a Rodent Model of Multiple Sclerosis [J].

deLuca, Leslie E. Summers ;

Pikor, Natalia B. ;

O'Leary, Jennifer ;

Galicia-Rosas, Georgina ;

Ward, Lesley A. ;

Defreitas, Dustin ;

Finlay, Trisha M. ;

Ousman, Shalina S. ;

Osborne, Lucy R. ;

Gommerman, Jennifer L. .

JOURNAL OF IMMUNOLOGY, 2010, 184 (06) :3174-3185

[9] Fine-tuning of dendritic cell biology by the TNF superfamily [J].

deLuca, Leslie Summers ;

Gommerman, Jennifer L. .

NATURE REVIEWS IMMUNOLOGY, 2012, 12 (05) :339-351

[10] Ectopic LTαβ directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase [J].

Drayton, DL ;

Ying, XY ;

Lee, J ;

Lesslauer, W ;

Ruddle, NH .

JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (09) :1153-1163

← 1 2 3 →