Habenicht, Andreas J.R.

Maffia, Pasquale

Mohanta, Sarajo

Yin, Changjun

Frontiers in Immunology

English

PubMed

Changjun Yin

Sarajo Mohanta

Pasquale Maffia

Andreas J. R. Habenicht

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Editorial: Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity

The immune system employs TLOs to elicit highly localized and forceful responses to unresolvable peripheral tissue inflammation. Current data indicate that TLOs are protective but they may also lead to collateral tissue injury and serve as nesting places to generate autoreactive lymphocytes. A better comprehension of these powerhouses of disease immunity will likely facilitate development to unprecedented and specific therapies to fight chronic inflammatory diseases

Andreas J.R. Habenicht

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Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity

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MAFFIA, PASQUALE

Habenicht, Andreas J. R.

Archivio della ricerca - Università degli studi di Napoli Federico II

March 2017 | Volume 8 | Article 2281Editorialpublished: 06 March 2017doi: 10.3389/fimmu.2017.00228Frontiers in Immunology | www.frontiersin.orgEdited and Reviewed by: Pietro Ghezzi, Brighton and Sussex Medical School, UK*Correspondence:Changjun Yin  changjun.yin@med.uni-muenchen.de†These authors have contributed equally to this work.Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in ImmunologyReceived: 13 January 2017Accepted: 17 February 2017Published: 06 March 2017Citation: Yin C, Mohanta S, Maffia P and Habenicht AJR (2017) Editorial: Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity. Front. Immunol. 8:228. doi: 10.3389/fimmu.2017.00228Editorial: tertiary lymphoid organs (tlos): Powerhouses of disease immunityChangjun Yin1,2*†, Sarajo Mohanta1†, Pasquale Maffia3,4,5 and Andreas J. R. Habenicht11 Institute for Cardiovascular Prevention, Ludwig Maximilians University of Munich, Munich, Germany, 2 German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany, 3 Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK, 4 BHF Centre for Excellence in Vascular Science and Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK, 5 Department of Pharmacy, University of Naples Federico II, Naples, ItalyKeywords: tertiary lymphoid organs, disease immunity, antigen, autoimmunity, autoinflammation, immune tolerance, non-resolving peripheral tissue inflammation, dichotomies of immune responsesEditorial on the Research TopicTertiary Lymphoid Organs (TLOs): Powerhouses of Disease ImmunityTertiary lymphoid organs (TLOs) arise in peripheral tissues (1) of adult organisms in response to non-resolving inflammation (2) including chronic infection, allograft rejection, cancer, autoimmune diseases, and a large number of other pathologies. One denominator of many—but certainly not all—of these conditions may be the presence of (auto)antigens that are recognized by the immune system as non-self. This notion—though unproven—is consistent with what we would like to call the antigen-driven TLO hypothesis. However, for many TLO-associated diseases, the presence of antigen-triggered immune responses—let alone antigen-triggered disease-causing immunity—has not been demonstrated (3). We therefore consider an alternative sequence of events, i.e., that TLOs arise in response to an inflammatory environment in the absence of antigen(s). The latter school of thought may be recapitulated as inflammation-driven TLO hypothesis. It is conceivable that chronic inflammation may be initiated by any form of unspecific, antigen-independent tissue injury, lead-ing, in the second phase, to protracted inflammatory tissue reaction that may ultimately unmask previously cryptic epitopes. However, it is not known at which stage of chronic inflammation TLOs are triggered. During the third stage, when breakdown of peripheral tolerance reaches a critical level, autoreactive T- and/or B-cells may be generated to cause clinically overt organ destruction. Of course, any of these scenarios generate proinflammatory and immunosuppressive T- and B-cells yielding complex dichotomically acting lymphocyte subsets that may initially coexist for long periods of time without tissue damage. Cytokines associated with inflammation may be sufficient in many instances to initiate and later to shape TLO phenotypes. Again, critical checkpoints in the immune system leading to T/B lymphocyte clusters remain to be identified, although the forma-tion of lymphorganogenic chemokines has been identified as drivers of both secondary lymphoid organs during embryogenesis and TLO neogenesis in adult organisms. The presence of antigen, however, is apparent in infectious diseases, allogeneic transplant rejection, some forms of cancers, and bona fide autoimmune diseases such as Myasthenia Gravis and Basedow’s Disease. Thus, the search for and identification of antigen(s) as the potential driving forces of TLO-dependent autoim-munity continue. New approaches and technologies including single-cell transcriptome analyses (4), next-generation sequencing of the T- and B-cell receptor repertoires (5), improved large-scale autoantigen detection technologies (6), tissue clearing methods (7), and translational research from experimental systems into human diseases will all be important to make progress.Tertiary lymphoid organs are striking illustrations of the amazing degree of plasticity of the immune system in response to non-resolving peripheral tissue inflammation. Recent research has 2Yin et al. Powerhouses of Disease ImmunityFrontiers in Immunology | www.frontiersin.org March 2017 | Volume 8 | Article 228uncovered key common features between secondary lymphoid organogenesis and TLO formation. However, the various types of TLOs also reveal some disease-specific features, which may ultimately determine whether the associated immune responses are harmful or protective. Such disease-specific characteristics may arise through one of several mechanisms including organ specificity and the nature of tissue damage. A major challenge for future research is to identify both the common and the specific features of individual TLO-associated diseases, with a view to develop new selective immune-based therapies. In an ideal case scenario, such therapeutics should interfere with TLO immunity (promotion or suppression) without compromising the systemic immune response and the integrity of the surrounding tissue. While identification of shared mechanisms has made major advances in recent years, disease-specific alterations of TLO immunity are less well understood. Studies on the peripheral plasticity of TLO characteristics should focus on CD4+ T cells (8); microglia cells in the central nervous system (9); the biology of epithelia and tissue environment in cancer (10); immunoglobulin-like receptors (11); innate immune cells (12); immune tolerance mechanisms (13); B-cell subtype plasticity in autoimmunity (14); identification of transcriptional and epigenetic circuits in dendritic cells, other immune cells, and the mesenchyme (15); identification of special phenotypes of tissue-specific monocytes/macrophages (16); meningeal Th-17 cell (17); intestinal microbiota (18); the various forms of lymphoid tissue organizer cells (19), and lymphoid tis-sue inducer cells (20). Advances in these areas are likely to yield new insight into the pathogenesis of chronic inflammation and may pave the way for the design of novel tissue- and/or disease-specific therapeutic approaches.The recent surge of interest in the TLO microcosm of disease immunity is remarkable as very little is known about the impact of these lymphocyte aggregates on disease progression: How and when TLOs are triggered? What distinct tasks do they have—located so close to diseased tissues when compared to the more distant secondary lymphoid organs? Are they critically important for disease progression and—if they are—what are the underly-ing mechanisms? How do they connect to the tissue-draining lymph nodes and lymphatics? Are they beneficial, injurious, or both, depending on the context and stage of disease, anatomical location, and other factors? Can they be exploited or even arti-ficially constructed for therapeutic purposes? Are there ways to disrupt them or enhance their activity without interfering with the systemic immune response? These are only a few of the ques-tions that are being addressed in various disciplines. Until these fundamental issues will have been resolved, the interest in TLOs will most likely intensify. Hence, this research topic assembles scientists who agree on the premise that it is time to study these enigmatic lymphocyte aggregates over a broad range of angles.This research topic is organized into two major sections as follows.Section 1 covers the structures and cellular composition of TLOs and their development and function. It is introduced by Nancy Ruddle (Yale University) who provides an overview on functional and regulatory features of high endothelial venules (HEVs) and the lymphatic system in TLOs; Nancy emphasizes the impor-tance of HEVs in the recruitment of naïve and central memory lymphocytes and of lymph vessels to transport antigen and serve as an entry site for antigen-presenting cells and lymphocytes. Ann Ager (Cardiff University) also discusses blood vessels and HEVs as critical regulators of lymphoid organ development and function. In particular, this review focuses on the role of vascular addressins in the regulation of lymphocyte trafficking and stresses the role of CD11c+ dendritic cells to regulate addres-sin expression in HEVs. Francesca Barone et  al. (University of Birmingham and University of Lausanne) discuss the complex issue of stromal fibroblasts in shaping TLOs; Francesca proposes that these cells may represent a novel therapeutic target in chronic inflammation. Jan Kranich (Ludwig-Maximilians-University Munich) and Nike Julia Krautler (ETH Zurich) cover the area of follicular dendritic cells in shaping the B-cell antigenome. Jan and Nike highlight the origin and role of follicular dendritic cells in the capture and retention of antigen, thereby allowing B cells to undergo affinity maturation in germinal centers. Catherine Hughes et  al. (University of Glasgow) assess the area of TLO antigen presentation and antigen-presenting cells. Gareth Wyn Jones et al. (Cardiff University) evaluate and discuss the complex interaction of immune cells as drivers in TLO development. James A. Butler et al. (University of York) provide an overview on their unconventional approach of model-driven experimentation to understand TLO neogenesis and function. Finally, Katrijn Neyt et al. (Ghent University) complement this section by providing original data on the role of interleukin 1 in TLO neogenesis.Section 2 covers prototypical examples of an expanding number of clinically significant diseases in which TLOs have been observed. Alice Koenig and Olivier Thaunat (University of Lyon) discuss TLOs in chronic transplant rejection; Alice and Olivier challenge the traditional view that TLOs may contribute to transplant rejection by pointing out the recent finding that TLOs have been described in stably accepted organ grafts. Elisa Corsiero et al. (Queen Mary University of London) review ectopic lym-phoid structures as powerhouses of autoimmunity, and Meike Mitsdoerffer and Anneli Peters (Technical University of Munich and Max Planck Institute of Neurobiology Munich) focus atten-tion on central nervous system autoimmunity. Changjun Yin et  al. (Ludwig-Maximilians-University Munich) discuss the structures and possible impacts of artery TLOs in atheroscle-rosis. Manuela Buettner and Matthias Lochner (University of Hannover) summarize the special features, development, and function of TLOs in the small intestine and colon; Nobuyoshi Hiraoka et al. (National Cancer Center Institute Tokyo) cover the expanding area of TLOs in cancer tissues. Eoin Neil McNamee and Jesus Rivera-Nieves (University of Colorado and University of California San Diego) discuss the roles of TLOs in inflamma-tory bowel disease as potentially protective or disease-promoting immune cell aggregates. Aliyah M. Weinstein and Walter J. Storkus (University of Pittsburg) summarize what is currently known on the biosynthesis and functional significance of peripheral node addressin in cancer-associated TLOs. Ji Young Hwang et  al. (University of Alabama at Birmingham) point out the unique features of inducible bronchus-associated lymphoid tissue as pro-tective immune aggregates in the lung. Jorge Caamaño and Sara Cruz-Migoni (University of Birmingham) summarize the recent discovery of fat-associated lymphoid clusters and their potential 3Yin et al. Powerhouses of Disease ImmunityFrontiers in Immunology | www.frontiersin.org March 2017 | Volume 8 | Article 228role in bridging metabolism and inflammation in adipose tissue. Marc Clement et al. (University of Paris Diderot) provide origi-nal observations on TLOs in Takayasu Arteritis. The section on TLOs in diseases is complemented by Catherine Sautes-Fridman et al. (Cordeliers Research Center Paris) on the epidemiology of tertiary lymphoid structures in cancers. The research topic ends with an original contribution by Yuka Kobayashi and Takeshi Watanabe (Tazuke-Kofukai Medical Research Institute Osaka) on their work on the in vivo generation of artificially constructed TLOs and their function in attempts to exploit TLOs for future therapeutic purposes.We hope that this research topic and E-book will help to start spreading the news on TLOs to accelerate information on and interest in the important issue of the functional impacts of these still largely enigmatic disease-restricted lymphocyte aggregates.aUtHor CoNtriBUtioNSAll authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.aCKNoWlEdGMENtSWe thank all authors who contributed to this research topic and E-book. This work was funded by Deutsche Forschungsgemeinschaft: YI 133/2-1 to CY; HA 1083/15-4 to AH; MO 3054/1-1 to SM; the British Heart Foundation grants PG/06/083/21198, PG/12/81/29897, and RE/13/5/30177, the Medical Research Scotland grant 276 FRG-L-0806, and the European Commission Marie Skłodowska-Curie Individual Fellowships 661369 to PM.rEFErENCES1. Leslie M. Immunity goes local. Science (2016) 352:21–3. doi:10.1126/science.352.6281.21 2. Nathan C, Ding A. Nonresolving inflammation. Cell (2010) 140:871–82. doi:10.1016/j.cell.2010.02.029 3. Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, et  al. Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res (2014) 114:1772–87. doi:10.1161/CIRCRESAHA.114.301137 4. Klein AM, Mazutis L, Akartuna I, Tallapragada N, Veres A, et  al. Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells. Cell (2015) 161:1187–201. doi:10.1016/j.cell.2015.04.044 5. Georgiou G, Ippolito GC, Beausang J, Busse CE, Wardemann H, Quake SR. The promise and challenge of high-throughput sequencing of the antibody repertoire. Nat Biotechnol (2014) 32:158–68. doi:10.1038/nbt.2782 6. Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. Antigen microarrays identify CNS-produced autoantibodies in RRMS. Neurology (2012) 78(8):532–9. doi:10.1212/WNL.0b013e318247f9f3 7. Richardson DS, Lichtman JW. Clarifying tissue clearing. Cell (2015) 162:246–57. doi:10.1016/j.cell.2015.06.067 8. DuPage M, Bluestone JA. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat Rev Immunol (2016) 16:149–63. doi:10.1038/nri.2015.18 9. Shemer A, Erny D, Jung S, Prinz M. Microglia plasticity during health and disease: an immunological perspective. Trends Immunol (2015) 36:614–24. doi:10.1016/j.it.2015.08.003 10. Aparicio LA, Blanco M, Castosa R, Concha Á, Valladares M, Calvo L, et al. Clinical implications of epithelial cell plasticity in cancer progression. Cancer Lett (2015) 366:1–10. doi:10.1016/j.canlet.2015.06.007 11. Hirayasu K, Arase H. Functional and genetic diversity of leukocyte immu-noglobulin-like receptor and implication for disease associations. J Hum Genet (2015) 60:703–8. doi:10.1038/jhg.2015.64 12. Soumelis V, Pattarini L, Michea P, Cappuccio A. Systems approaches to unravel innate immune cell diversity, environmental plasticity and func-tional specialization. Curr Opin Immunol (2015) 32:42–7. doi:10.1016/j.coi.2014.12.007 13. Schwartz M, Baruch K. Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: boosting autoimmunity to fight-off chronic neuroinflammation. J Autoimmun (2014) 54:8–14. doi:10.1016/j.jaut.2014.08.002 14. Perez-Shibayama C, Gil-Cruz C, Ludewig B. Plasticity and complexity of B cell responses against persisting pathogens. Immunol Lett (2014) 162:53–8. doi:10.1016/j.imlet.2014.07.003 15. Paul F, Amit I. Plasticity in the transcriptional and epigenetic circuits regu-lating dendritic cell lineage specification and function. Curr Opin Immunol (2014) 30:1–8. doi:10.1016/j.coi.2014.04.004 16. Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol (2014) 14:81–93. doi:10.1038/nri3600 17. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz B, et  al. Th17  cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity (2011) 35:986–96. doi:10.1016/j.immuni.2011.10.015 18. Lochner M, Ohnmacht C, Presley L, Bruhns P, Si-Tahar M, Sawa S, et  al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J Exp Med (2011) 208:125–34. doi:10.1084/jem.20100052 19. Hu D, Mohanta SK, Yin C, Peng L, Ma Z, et  al. Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell lymphotoxin β receptors. Immunity (2015) 42:1100–15. doi:10.1016/j.immuni.2015.05.015 20. van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol (2010) 10:664–74. doi:10.1038/nri2832 Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2017 Yin, Mohanta, Maffia and Habenicht. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, pro-vided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Enlighten: Publications

Editorial: tertiary lymphoid organs (TLOs): powerhouses of disease immunity

March 2017 | Volume 8 | Article 2281
Editorial
published: 06 March 2017
doi: 10.3389/fimmu.2017.00228
Frontiers in Immunology | www.frontiersin.org
Edited and Reviewed by: 
Pietro Ghezzi, 
Brighton and Sussex 
Medical School, UK
*Correspondence:
Changjun Yin  
changjun.yin@med.uni-muenchen.de
†These authors have contributed 
equally to this work.
Specialty section: 
This article was submitted to 
Inflammation, 
a section of the journal 
Frontiers in Immunology
Received: 13 January 2017
Accepted: 17 February 2017
Published: 06 March 2017
Citation: 
Yin C, Mohanta S, Maffia P and 
Habenicht AJR (2017) Editorial: 
Tertiary Lymphoid Organs (TLOs): 
Powerhouses of Disease Immunity. 
Front. Immunol. 8:228. 
doi: 10.3389/fimmu.2017.00228
Editorial: tertiary lymphoid organs 
(tlos): Powerhouses of disease 
immunity
Changjun Yin1,2*†, Sarajo Mohanta1†, Pasquale Maffia3,4,5 and Andreas J. R. Habenicht1
1 Institute for Cardiovascular Prevention, Ludwig Maximilians University of Munich, Munich, Germany, 2 German Centre for 
Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany, 3 Centre for Immunobiology, Institute of Infection, 
Immunity and Inflammation, University of Glasgow, Glasgow, UK, 4 BHF Centre for Excellence in Vascular Science and 
Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK, 5 Department of Pharmacy, 
University of Naples Federico II, Naples, Italy
Keywords: tertiary lymphoid organs, disease immunity, antigen, autoimmunity, autoinflammation, immune 
tolerance, non-resolving peripheral tissue inflammation, dichotomies of immune responses
Editorial on the Research Topic
Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity
Tertiary lymphoid organs (TLOs) arise in peripheral tissues (1) of adult organisms in response to 
non-resolving inflammation (2) including chronic infection, allograft rejection, cancer, autoimmune 
diseases, and a large number of other pathologies. One denominator of many—but certainly not 
all—of these conditions may be the presence of (auto)antigens that are recognized by the immune 
system as non-self. This notion—though unproven—is consistent with what we would like to call 
the antigen-driven TLO hypothesis. However, for many TLO-associated diseases, the presence of 
antigen-triggered immune responses—let alone antigen-triggered disease-causing immunity—has 
not been demonstrated (3). We therefore consider an alternative sequence of events, i.e., that TLOs 
arise in response to an inflammatory environment in the absence of antigen(s). The latter school of 
thought may be recapitulated as inflammation-driven TLO hypothesis. It is conceivable that chronic 
inflammation may be initiated by any form of unspecific, antigen-independent tissue injury, lead-
ing, in the second phase, to protracted inflammatory tissue reaction that may ultimately unmask 
previously cryptic epitopes. However, it is not known at which stage of chronic inflammation TLOs 
are triggered. During the third stage, when breakdown of peripheral tolerance reaches a critical 
level, autoreactive T- and/or B-cells may be generated to cause clinically overt organ destruction. 
Of course, any of these scenarios generate proinflammatory and immunosuppressive T- and B-cells 
yielding complex dichotomically acting lymphocyte subsets that may initially coexist for long 
periods of time without tissue damage. Cytokines associated with inflammation may be sufficient 
in many instances to initiate and later to shape TLO phenotypes. Again, critical checkpoints in the 
immune system leading to T/B lymphocyte clusters remain to be identified, although the forma-
tion of lymphorganogenic chemokines has been identified as drivers of both secondary lymphoid 
organs during embryogenesis and TLO neogenesis in adult organisms. The presence of antigen, 
however, is apparent in infectious diseases, allogeneic transplant rejection, some forms of cancers, 
and bona fide autoimmune diseases such as Myasthenia Gravis and Basedow’s Disease. Thus, the 
search for and identification of antigen(s) as the potential driving forces of TLO-dependent autoim-
munity continue. New approaches and technologies including single-cell transcriptome analyses 
(4), next-generation sequencing of the T- and B-cell receptor repertoires (5), improved large-scale 
autoantigen detection technologies (6), tissue clearing methods (7), and translational research from 
experimental systems into human diseases will all be important to make progress.
Tertiary lymphoid organs are striking illustrations of the amazing degree of plasticity of the 
immune system in response to non-resolving peripheral tissue inflammation. Recent research has 
2Yin et al. Powerhouses of Disease Immunity
Frontiers in Immunology | www.frontiersin.org March 2017 | Volume 8 | Article 228
uncovered key common features between secondary lymphoid 
organogenesis and TLO formation. However, the various types 
of TLOs also reveal some disease-specific features, which may 
ultimately determine whether the associated immune responses 
are harmful or protective. Such disease-specific characteristics 
may arise through one of several mechanisms including organ 
specificity and the nature of tissue damage. A major challenge for 
future research is to identify both the common and the specific 
features of individual TLO-associated diseases, with a view to 
develop new selective immune-based therapies. In an ideal case 
scenario, such therapeutics should interfere with TLO immunity 
(promotion or suppression) without compromising the systemic 
immune response and the integrity of the surrounding tissue. While 
identification of shared mechanisms has made major advances 
in recent years, disease-specific alterations of TLO immunity are 
less well understood. Studies on the peripheral plasticity of TLO 
characteristics should focus on CD4+ T cells (8); microglia cells in 
the central nervous system (9); the biology of epithelia and tissue 
environment in cancer (10); immunoglobulin-like receptors (11); 
innate immune cells (12); immune tolerance mechanisms (13); 
B-cell subtype plasticity in autoimmunity (14); identification of 
transcriptional and epigenetic circuits in dendritic cells, other 
immune cells, and the mesenchyme (15); identification of special 
phenotypes of tissue-specific monocytes/macrophages (16); 
meningeal Th-17 cell (17); intestinal microbiota (18); the various 
forms of lymphoid tissue organizer cells (19), and lymphoid tis-
sue inducer cells (20). Advances in these areas are likely to yield 
new insight into the pathogenesis of chronic inflammation and 
may pave the way for the design of novel tissue- and/or disease-
specific therapeutic approaches.
The recent surge of interest in the TLO microcosm of disease 
immunity is remarkable as very little is known about the impact 
of these lymphocyte aggregates on disease progression: How and 
when TLOs are triggered? What distinct tasks do they have—
located so close to diseased tissues when compared to the more 
distant secondary lymphoid organs? Are they critically important 
for disease progression and—if they are—what are the underly-
ing mechanisms? How do they connect to the tissue-draining 
lymph nodes and lymphatics? Are they beneficial, injurious, or 
both, depending on the context and stage of disease, anatomical 
location, and other factors? Can they be exploited or even arti-
ficially constructed for therapeutic purposes? Are there ways to 
disrupt them or enhance their activity without interfering with 
the systemic immune response? These are only a few of the ques-
tions that are being addressed in various disciplines. Until these 
fundamental issues will have been resolved, the interest in TLOs 
will most likely intensify. Hence, this research topic assembles 
scientists who agree on the premise that it is time to study these 
enigmatic lymphocyte aggregates over a broad range of angles.
This research topic is organized into two major sections as 
follows.
Section 1 covers the structures and cellular composition of TLOs 
and their development and function. It is introduced by Nancy 
Ruddle (Yale University) who provides an overview on functional 
and regulatory features of high endothelial venules (HEVs) and 
the lymphatic system in TLOs; Nancy emphasizes the impor-
tance of HEVs in the recruitment of naïve and central memory 
lymphocytes and of lymph vessels to transport antigen and serve 
as an entry site for antigen-presenting cells and lymphocytes. 
Ann Ager (Cardiff University) also discusses blood vessels and 
HEVs as critical regulators of lymphoid organ development 
and function. In particular, this review focuses on the role of 
vascular addressins in the regulation of lymphocyte trafficking 
and stresses the role of CD11c+ dendritic cells to regulate addres-
sin expression in HEVs. Francesca Barone et  al. (University of 
Birmingham and University of Lausanne) discuss the complex 
issue of stromal fibroblasts in shaping TLOs; Francesca proposes 
that these cells may represent a novel therapeutic target in chronic 
inflammation. Jan Kranich (Ludwig-Maximilians-University 
Munich) and Nike Julia Krautler (ETH Zurich) cover the area 
of follicular dendritic cells in shaping the B-cell antigenome. Jan 
and Nike highlight the origin and role of follicular dendritic cells 
in the capture and retention of antigen, thereby allowing B cells 
to undergo affinity maturation in germinal centers. Catherine 
Hughes et  al. (University of Glasgow) assess the area of TLO 
antigen presentation and antigen-presenting cells. Gareth Wyn 
Jones et al. (Cardiff University) evaluate and discuss the complex 
interaction of immune cells as drivers in TLO development. James 
A. Butler et al. (University of York) provide an overview on their 
unconventional approach of model-driven experimentation to 
understand TLO neogenesis and function. Finally, Katrijn Neyt 
et al. (Ghent University) complement this section by providing 
original data on the role of interleukin 1 in TLO neogenesis.
Section 2 covers prototypical examples of an expanding number 
of clinically significant diseases in which TLOs have been observed. 
Alice Koenig and Olivier Thaunat (University of Lyon) discuss 
TLOs in chronic transplant rejection; Alice and Olivier challenge 
the traditional view that TLOs may contribute to transplant 
rejection by pointing out the recent finding that TLOs have 
been described in stably accepted organ grafts. Elisa Corsiero 
et al. (Queen Mary University of London) review ectopic lym-
phoid structures as powerhouses of autoimmunity, and Meike 
Mitsdoerffer and Anneli Peters (Technical University of Munich 
and Max Planck Institute of Neurobiology Munich) focus atten-
tion on central nervous system autoimmunity. Changjun Yin 
et  al. (Ludwig-Maximilians-University Munich) discuss the 
structures and possible impacts of artery TLOs in atheroscle-
rosis. Manuela Buettner and Matthias Lochner (University of 
Hannover) summarize the special features, development, and 
function of TLOs in the small intestine and colon; Nobuyoshi 
Hiraoka et al. (National Cancer Center Institute Tokyo) cover the 
expanding area of TLOs in cancer tissues. Eoin Neil McNamee 
and Jesus Rivera-Nieves (University of Colorado and University 
of California San Diego) discuss the roles of TLOs in inflamma-
tory bowel disease as potentially protective or disease-promoting 
immune cell aggregates. Aliyah M. Weinstein and Walter J. Storkus 
(University of Pittsburg) summarize what is currently known on 
the biosynthesis and functional significance of peripheral node 
addressin in cancer-associated TLOs. Ji Young Hwang et  al. 
(University of Alabama at Birmingham) point out the unique 
features of inducible bronchus-associated lymphoid tissue as pro-
tective immune aggregates in the lung. Jorge Caamaño and Sara 
Cruz-Migoni (University of Birmingham) summarize the recent 
discovery of fat-associated lymphoid clusters and their potential 
3Yin et al. Powerhouses of Disease Immunity
Frontiers in Immunology | www.frontiersin.org March 2017 | Volume 8 | Article 228
role in bridging metabolism and inflammation in adipose tissue. 
Marc Clement et al. (University of Paris Diderot) provide origi-
nal observations on TLOs in Takayasu Arteritis. The section on 
TLOs in diseases is complemented by Catherine Sautes-Fridman 
et al. (Cordeliers Research Center Paris) on the epidemiology of 
tertiary lymphoid structures in cancers. The research topic ends 
with an original contribution by Yuka Kobayashi and Takeshi 
Watanabe (Tazuke-Kofukai Medical Research Institute Osaka) 
on their work on the in vivo generation of artificially constructed 
TLOs and their function in attempts to exploit TLOs for future 
therapeutic purposes.
We hope that this research topic and E-book will help to start 
spreading the news on TLOs to accelerate information on and 
interest in the important issue of the functional impacts of these 
still largely enigmatic disease-restricted lymphocyte aggregates.
aUtHor CoNtriBUtioNS
All authors listed have made substantial, direct, and intellectual 
contribution to the work and approved it for publication.
aCKNoWlEdGMENtS
We thank all authors who contributed to this research 
topic and E-book. This work was funded by Deutsche 
Forschungsgemeinschaft: YI 133/2-1 to CY; HA 1083/15-4 to 
AH; MO 3054/1-1 to SM; the British Heart Foundation grants 
PG/06/083/21198, PG/12/81/29897, and RE/13/5/30177, the 
Medical Research Scotland grant 276 FRG-L-0806, and the 
European Commission Marie Skłodowska-Curie Individual 
Fellowships 661369 to PM.
rEFErENCES
1. Leslie M. Immunity goes local. Science (2016) 352:21–3. doi:10.1126/
science.352.6281.21 
2. Nathan C, Ding A. Nonresolving inflammation. Cell (2010) 140:871–82. 
doi:10.1016/j.cell.2010.02.029 
3. Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, et  al. Artery 
tertiary lymphoid organs contribute to innate and adaptive immune 
responses in advanced mouse atherosclerosis. Circ Res (2014) 114:1772–87. 
doi:10.1161/CIRCRESAHA.114.301137 
4. Klein AM, Mazutis L, Akartuna I, Tallapragada N, Veres A, et  al. Droplet 
barcoding for single-cell transcriptomics applied to embryonic stem cells. 
Cell (2015) 161:1187–201. doi:10.1016/j.cell.2015.04.044 
5. Georgiou G, Ippolito GC, Beausang J, Busse CE, Wardemann H, Quake SR. 
The promise and challenge of high-throughput sequencing of the antibody 
repertoire. Nat Biotechnol (2014) 32:158–68. doi:10.1038/nbt.2782 
6. Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. Antigen 
microarrays identify CNS-produced autoantibodies in RRMS. Neurology 
(2012) 78(8):532–9. doi:10.1212/WNL.0b013e318247f9f3 
7. Richardson DS, Lichtman JW. Clarifying tissue clearing. Cell (2015) 
162:246–57. doi:10.1016/j.cell.2015.06.067 
8. DuPage M, Bluestone JA. Harnessing the plasticity of CD4+ T cells to treat 
immune-mediated disease. Nat Rev Immunol (2016) 16:149–63. doi:10.1038/
nri.2015.18 
9. Shemer A, Erny D, Jung S, Prinz M. Microglia plasticity during health and 
disease: an immunological perspective. Trends Immunol (2015) 36:614–24. 
doi:10.1016/j.it.2015.08.003 
10. Aparicio LA, Blanco M, Castosa R, Concha Á, Valladares M, Calvo L, et al. 
Clinical implications of epithelial cell plasticity in cancer progression. Cancer 
Lett (2015) 366:1–10. doi:10.1016/j.canlet.2015.06.007 
11. Hirayasu K, Arase H. Functional and genetic diversity of leukocyte immu-
noglobulin-like receptor and implication for disease associations. J Hum 
Genet (2015) 60:703–8. doi:10.1038/jhg.2015.64 
12. Soumelis V, Pattarini L, Michea P, Cappuccio A. Systems approaches to 
unravel innate immune cell diversity, environmental plasticity and func-
tional specialization. Curr Opin Immunol (2015) 32:42–7. doi:10.1016/j.
coi.2014.12.007 
13. Schwartz M, Baruch K. Breaking peripheral immune tolerance to CNS 
antigens in neurodegenerative diseases: boosting autoimmunity to fight-off 
chronic neuroinflammation. J Autoimmun (2014) 54:8–14. doi:10.1016/j.
jaut.2014.08.002 
14. Perez-Shibayama C, Gil-Cruz C, Ludewig B. Plasticity and complexity of 
B cell responses against persisting pathogens. Immunol Lett (2014) 162:53–8. 
doi:10.1016/j.imlet.2014.07.003 
15. Paul F, Amit I. Plasticity in the transcriptional and epigenetic circuits regu-
lating dendritic cell lineage specification and function. Curr Opin Immunol 
(2014) 30:1–8. doi:10.1016/j.coi.2014.04.004 
16. Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissue-specific 
context. Nat Rev Immunol (2014) 14:81–93. doi:10.1038/nri3600 
17. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz 
B, et  al. Th17  cells induce ectopic lymphoid follicles in central nervous 
system tissue inflammation. Immunity (2011) 35:986–96. doi:10.1016/j.
immuni.2011.10.015 
18. Lochner M, Ohnmacht C, Presley L, Bruhns P, Si-Tahar M, Sawa S, et  al. 
Microbiota-induced tertiary lymphoid tissues aggravate inflammatory 
disease in the absence of RORgamma t and LTi cells. J Exp Med (2011) 
208:125–34. doi:10.1084/jem.20100052 
19. Hu D, Mohanta SK, Yin C, Peng L, Ma Z, et  al. Artery tertiary lymphoid 
organs control aorta immunity and protect against atherosclerosis via 
vascular smooth muscle cell lymphotoxin β receptors. Immunity (2015) 
42:1100–15. doi:10.1016/j.immuni.2015.05.015 
20. van de Pavert SA, Mebius RE. New insights into the development of lymphoid 
tissues. Nat Rev Immunol (2010) 10:664–74. doi:10.1038/nri2832 
Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.
Copyright © 2017 Yin, Mohanta, Maffia and Habenicht. This is an open-access 
article distributed under the terms of the Creative Commons Attribution License 
(CC BY). The use, distribution or reproduction in other forums is permitted, pro-
vided the original author(s) or licensor are credited and that the original publication 
in this journal is cited, in accordance with accepted academic practice. No use, 
distribution or reproduction is permitted which does not comply with these terms.


Universität München: Elektronischen Publikationen

March 2017 | Volume 8 | Article 2281
Editorial
published: 06 March 2017
doi: 10.3389/fimmu.2017.00228
Frontiers in Immunology | www.frontiersin.org
Edited and Reviewed by: 
Pietro Ghezzi, 
Brighton and Sussex 
Medical School, UK
*Correspondence:
Changjun Yin  
changjun.yin@med.uni-muenchen.de
†These authors have contributed 
equally to this work.
Specialty section: 
This article was submitted to 
Inflammation, 
a section of the journal 
Frontiers in Immunology
Received: 13 January 2017
Accepted: 17 February 2017
Published: 06 March 2017
Citation: 
Yin C, Mohanta S, Maffia P and 
Habenicht AJR (2017) Editorial: 
Tertiary Lymphoid Organs (TLOs): 
Powerhouses of Disease Immunity. 
Front. Immunol. 8:228. 
doi: 10.3389/fimmu.2017.00228
Editorial: tertiary lymphoid organs 
(tlos): Powerhouses of disease 
immunity
Changjun Yin1,2*†, Sarajo Mohanta1†, Pasquale Maffia3,4,5 and Andreas J. R. Habenicht1
1 Institute for Cardiovascular Prevention, Ludwig Maximilians University of Munich, Munich, Germany, 2 German Centre for 
Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany, 3 Centre for Immunobiology, Institute of Infection, 
Immunity and Inflammation, University of Glasgow, Glasgow, UK, 4 BHF Centre for Excellence in Vascular Science and 
Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK, 5 Department of Pharmacy, 
University of Naples Federico II, Naples, Italy
Keywords: tertiary lymphoid organs, disease immunity, antigen, autoimmunity, autoinflammation, immune 
tolerance, non-resolving peripheral tissue inflammation, dichotomies of immune responses
Editorial on the Research Topic
Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity
Tertiary lymphoid organs (TLOs) arise in peripheral tissues (1) of adult organisms in response to 
non-resolving inflammation (2) including chronic infection, allograft rejection, cancer, autoimmune 
diseases, and a large number of other pathologies. One denominator of many—but certainly not 
all—of these conditions may be the presence of (auto)antigens that are recognized by the immune 
system as non-self. This notion—though unproven—is consistent with what we would like to call 
the antigen-driven TLO hypothesis. However, for many TLO-associated diseases, the presence of 
antigen-triggered immune responses—let alone antigen-triggered disease-causing immunity—has 
not been demonstrated (3). We therefore consider an alternative sequence of events, i.e., that TLOs 
arise in response to an inflammatory environment in the absence of antigen(s). The latter school of 
thought may be recapitulated as inflammation-driven TLO hypothesis. It is conceivable that chronic 
inflammation may be initiated by any form of unspecific, antigen-independent tissue injury, lead-
ing, in the second phase, to protracted inflammatory tissue reaction that may ultimately unmask 
previously cryptic epitopes. However, it is not known at which stage of chronic inflammation TLOs 
are triggered. During the third stage, when breakdown of peripheral tolerance reaches a critical 
level, autoreactive T- and/or B-cells may be generated to cause clinically overt organ destruction. 
Of course, any of these scenarios generate proinflammatory and immunosuppressive T- and B-cells 
yielding complex dichotomically acting lymphocyte subsets that may initially coexist for long 
periods of time without tissue damage. Cytokines associated with inflammation may be sufficient 
in many instances to initiate and later to shape TLO phenotypes. Again, critical checkpoints in the 
immune system leading to T/B lymphocyte clusters remain to be identified, although the forma-
tion of lymphorganogenic chemokines has been identified as drivers of both secondary lymphoid 
organs during embryogenesis and TLO neogenesis in adult organisms. The presence of antigen, 
however, is apparent in infectious diseases, allogeneic transplant rejection, some forms of cancers, 
and bona fide autoimmune diseases such as Myasthenia Gravis and Basedow’s Disease. Thus, the 
search for and identification of antigen(s) as the potential driving forces of TLO-dependent autoim-
munity continue. New approaches and technologies including single-cell transcriptome analyses 
(4), next-generation sequencing of the T- and B-cell receptor repertoires (5), improved large-scale 
autoantigen detection technologies (6), tissue clearing methods (7), and translational research from 
experimental systems into human diseases will all be important to make progress.
Tertiary lymphoid organs are striking illustrations of the amazing degree of plasticity of the 
immune system in response to non-resolving peripheral tissue inflammation. Recent research has 
2
Yin et al. Powerhouses of Disease Immunity
Frontiers in Immunology | www.frontiersin.org March 2017 | Volume 8 | Article 228
uncovered key common features between secondary lymphoid 
organogenesis and TLO formation. However, the various types 
of TLOs also reveal some disease-specific features, which may 
ultimately determine whether the associated immune responses 
are harmful or protective. Such disease-specific characteristics 
may arise through one of several mechanisms including organ 
specificity and the nature of tissue damage. A major challenge for 
future research is to identify both the common and the specific 
features of individual TLO-associated diseases, with a view to 
develop new selective immune-based therapies. In an ideal case 
scenario, such therapeutics should interfere with TLO immunity 
(promotion or suppression) without compromising the systemic 
immune response and the integrity of the surrounding tissue. While 
identification of shared mechanisms has made major advances 
in recent years, disease-specific alterations of TLO immunity are 
less well understood. Studies on the peripheral plasticity of TLO 
characteristics should focus on CD4+ T cells (8); microglia cells in 
the central nervous system (9); the biology of epithelia and tissue 
environment in cancer (10); immunoglobulin-like receptors (11); 
innate immune cells (12); immune tolerance mechanisms (13); 
B-cell subtype plasticity in autoimmunity (14); identification of 
transcriptional and epigenetic circuits in dendritic cells, other 
immune cells, and the mesenchyme (15); identification of special 
phenotypes of tissue-specific monocytes/macrophages (16); 
meningeal Th-17 cell (17); intestinal microbiota (18); the various 
forms of lymphoid tissue organizer cells (19), and lymphoid tis-
sue inducer cells (20). Advances in these areas are likely to yield 
new insight into the pathogenesis of chronic inflammation and 
may pave the way for the design of novel tissue- and/or disease-
specific therapeutic approaches.
The recent surge of interest in the TLO microcosm of disease 
immunity is remarkable as very little is known about the impact 
of these lymphocyte aggregates on disease progression: How and 
when TLOs are triggered? What distinct tasks do they have—
located so close to diseased tissues when compared to the more 
distant secondary lymphoid organs? Are they critically important 
for disease progression and—if they are—what are the underly-
ing mechanisms? How do they connect to the tissue-draining 
lymph nodes and lymphatics? Are they beneficial, injurious, or 
both, depending on the context and stage of disease, anatomical 
location, and other factors? Can they be exploited or even arti-
ficially constructed for therapeutic purposes? Are there ways to 
disrupt them or enhance their activity without interfering with 
the systemic immune response? These are only a few of the ques-
tions that are being addressed in various disciplines. Until these 
fundamental issues will have been resolved, the interest in TLOs 
will most likely intensify. Hence, this research topic assembles 
scientists who agree on the premise that it is time to study these 
enigmatic lymphocyte aggregates over a broad range of angles.
This research topic is organized into two major sections as 
follows.
Section 1 covers the structures and cellular composition of TLOs 
and their development and function. It is introduced by Nancy 
Ruddle (Yale University) who provides an overview on functional 
and regulatory features of high endothelial venules (HEVs) and 
the lymphatic system in TLOs; Nancy emphasizes the impor-
tance of HEVs in the recruitment of naïve and central memory 
lymphocytes and of lymph vessels to transport antigen and serve 
as an entry site for antigen-presenting cells and lymphocytes. 
Ann Ager (Cardiff University) also discusses blood vessels and 
HEVs as critical regulators of lymphoid organ development 
and function. In particular, this review focuses on the role of 
vascular addressins in the regulation of lymphocyte trafficking 
and stresses the role of CD11c+ dendritic cells to regulate addres-
sin expression in HEVs. Francesca Barone et  al. (University of 
Birmingham and University of Lausanne) discuss the complex 
issue of stromal fibroblasts in shaping TLOs; Francesca proposes 
that these cells may represent a novel therapeutic target in chronic 
inflammation. Jan Kranich (Ludwig-Maximilians-University 
Munich) and Nike Julia Krautler (ETH Zurich) cover the area 
of follicular dendritic cells in shaping the B-cell antigenome. Jan 
and Nike highlight the origin and role of follicular dendritic cells 
in the capture and retention of antigen, thereby allowing B cells 
to undergo affinity maturation in germinal centers. Catherine 
Hughes et  al. (University of Glasgow) assess the area of TLO 
antigen presentation and antigen-presenting cells. Gareth Wyn 
Jones et al. (Cardiff University) evaluate and discuss the complex 
interaction of immune cells as drivers in TLO development. James 
A. Butler et al. (University of York) provide an overview on their 
unconventional approach of model-driven experimentation to 
understand TLO neogenesis and function. Finally, Katrijn Neyt 
et al. (Ghent University) complement this section by providing 
original data on the role of interleukin 1 in TLO neogenesis.
Section 2 covers prototypical examples of an expanding number 
of clinically significant diseases in which TLOs have been observed. 
Alice Koenig and Olivier Thaunat (University of Lyon) discuss 
TLOs in chronic transplant rejection; Alice and Olivier challenge 
the traditional view that TLOs may contribute to transplant 
rejection by pointing out the recent finding that TLOs have 
been described in stably accepted organ grafts. Elisa Corsiero 
et al. (Queen Mary University of London) review ectopic lym-
phoid structures as powerhouses of autoimmunity, and Meike 
Mitsdoerffer and Anneli Peters (Technical University of Munich 
and Max Planck Institute of Neurobiology Munich) focus atten-
tion on central nervous system autoimmunity. Changjun Yin 
et  al. (Ludwig-Maximilians-University Munich) discuss the 
structures and possible impacts of artery TLOs in atheroscle-
rosis. Manuela Buettner and Matthias Lochner (University of 
Hannover) summarize the special features, development, and 
function of TLOs in the small intestine and colon; Nobuyoshi 
Hiraoka et al. (National Cancer Center Institute Tokyo) cover the 
expanding area of TLOs in cancer tissues. Eoin Neil McNamee 
and Jesus Rivera-Nieves (University of Colorado and University 
of California San Diego) discuss the roles of TLOs in inflamma-
tory bowel disease as potentially protective or disease-promoting 
immune cell aggregates. Aliyah M. Weinstein and Walter J. Storkus 
(University of Pittsburg) summarize what is currently known on 
the biosynthesis and functional significance of peripheral node 
addressin in cancer-associated TLOs. Ji Young Hwang et  al. 
(University of Alabama at Birmingham) point out the unique 
features of inducible bronchus-associated lymphoid tissue as pro-
tective immune aggregates in the lung. Jorge Caamaño and Sara 
Cruz-Migoni (University of Birmingham) summarize the recent 
discovery of fat-associated lymphoid clusters and their potential 
3
Yin et al. Powerhouses of Disease Immunity
Frontiers in Immunology | www.frontiersin.org March 2017 | Volume 8 | Article 228
role in bridging metabolism and inflammation in adipose tissue. 
Marc Clement et al. (University of Paris Diderot) provide origi-
nal observations on TLOs in Takayasu Arteritis. The section on 
TLOs in diseases is complemented by Catherine Sautes-Fridman 
et al. (Cordeliers Research Center Paris) on the epidemiology of 
tertiary lymphoid structures in cancers. The research topic ends 
with an original contribution by Yuka Kobayashi and Takeshi 
Watanabe (Tazuke-Kofukai Medical Research Institute Osaka) 
on their work on the in vivo generation of artificially constructed 
TLOs and their function in attempts to exploit TLOs for future 
therapeutic purposes.
We hope that this research topic and E-book will help to start 
spreading the news on TLOs to accelerate information on and 
interest in the important issue of the functional impacts of these 
still largely enigmatic disease-restricted lymphocyte aggregates.
aUtHor CoNtriBUtioNS
All authors listed have made substantial, direct, and intellectual 
contribution to the work and approved it for publication.
aCKNoWlEdGMENtS
We thank all authors who contributed to this research 
topic and E-book. This work was funded by Deutsche 
Forschungsgemeinschaft: YI 133/2-1 to CY; HA 1083/15-4 to 
AH; MO 3054/1-1 to SM; the British Heart Foundation grants 
PG/06/083/21198, PG/12/81/29897, and RE/13/5/30177, the 
Medical Research Scotland grant 276 FRG-L-0806, and the 
European Commission Marie Skłodowska-Curie Individual 
Fellowships 661369 to PM.
rEFErENCES
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science.352.6281.21 
2. Nathan C, Ding A. Nonresolving inflammation. Cell (2010) 140:871–82. 
doi:10.1016/j.cell.2010.02.029 
3. Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, et  al. Artery 
tertiary lymphoid organs contribute to innate and adaptive immune 
responses in advanced mouse atherosclerosis. Circ Res (2014) 114:1772–87. 
doi:10.1161/CIRCRESAHA.114.301137 
4. Klein AM, Mazutis L, Akartuna I, Tallapragada N, Veres A, et  al. Droplet 
barcoding for single-cell transcriptomics applied to embryonic stem cells. 
Cell (2015) 161:1187–201. doi:10.1016/j.cell.2015.04.044 
5. Georgiou G, Ippolito GC, Beausang J, Busse CE, Wardemann H, Quake SR. 
The promise and challenge of high-throughput sequencing of the antibody 
repertoire. Nat Biotechnol (2014) 32:158–68. doi:10.1038/nbt.2782 
6. Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL. Antigen 
microarrays identify CNS-produced autoantibodies in RRMS. Neurology 
(2012) 78(8):532–9. doi:10.1212/WNL.0b013e318247f9f3 
7. Richardson DS, Lichtman JW. Clarifying tissue clearing. Cell (2015) 
162:246–57. doi:10.1016/j.cell.2015.06.067 
8. DuPage M, Bluestone JA. Harnessing the plasticity of CD4+ T cells to treat 
immune-mediated disease. Nat Rev Immunol (2016) 16:149–63. doi:10.1038/
nri.2015.18 
9. Shemer A, Erny D, Jung S, Prinz M. Microglia plasticity during health and 
disease: an immunological perspective. Trends Immunol (2015) 36:614–24. 
doi:10.1016/j.it.2015.08.003 
10. Aparicio LA, Blanco M, Castosa R, Concha Á, Valladares M, Calvo L, et al. 
Clinical implications of epithelial cell plasticity in cancer progression. Cancer 
Lett (2015) 366:1–10. doi:10.1016/j.canlet.2015.06.007 
11. Hirayasu K, Arase H. Functional and genetic diversity of leukocyte immu-
noglobulin-like receptor and implication for disease associations. J Hum 
Genet (2015) 60:703–8. doi:10.1038/jhg.2015.64 
12. Soumelis V, Pattarini L, Michea P, Cappuccio A. Systems approaches to 
unravel innate immune cell diversity, environmental plasticity and func-
tional specialization. Curr Opin Immunol (2015) 32:42–7. doi:10.1016/j.
coi.2014.12.007 
13. Schwartz M, Baruch K. Breaking peripheral immune tolerance to CNS 
antigens in neurodegenerative diseases: boosting autoimmunity to fight-off 
chronic neuroinflammation. J Autoimmun (2014) 54:8–14. doi:10.1016/j.
jaut.2014.08.002 
14. Perez-Shibayama C, Gil-Cruz C, Ludewig B. Plasticity and complexity of 
B cell responses against persisting pathogens. Immunol Lett (2014) 162:53–8. 
doi:10.1016/j.imlet.2014.07.003 
15. Paul F, Amit I. Plasticity in the transcriptional and epigenetic circuits regu-
lating dendritic cell lineage specification and function. Curr Opin Immunol 
(2014) 30:1–8. doi:10.1016/j.coi.2014.04.004 
16. Hussell T, Bell TJ. Alveolar macrophages: plasticity in a tissue-specific 
context. Nat Rev Immunol (2014) 14:81–93. doi:10.1038/nri3600 
17. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, Franz 
B, et  al. Th17  cells induce ectopic lymphoid follicles in central nervous 
system tissue inflammation. Immunity (2011) 35:986–96. doi:10.1016/j.
immuni.2011.10.015 
18. Lochner M, Ohnmacht C, Presley L, Bruhns P, Si-Tahar M, Sawa S, et  al. 
Microbiota-induced tertiary lymphoid tissues aggravate inflammatory 
disease in the absence of RORgamma t and LTi cells. J Exp Med (2011) 
208:125–34. doi:10.1084/jem.20100052 
19. Hu D, Mohanta SK, Yin C, Peng L, Ma Z, et  al. Artery tertiary lymphoid 
organs control aorta immunity and protect against atherosclerosis via 
vascular smooth muscle cell lymphotoxin β receptors. Immunity (2015) 
42:1100–15. doi:10.1016/j.immuni.2015.05.015 
20. van de Pavert SA, Mebius RE. New insights into the development of lymphoid 
tissues. Nat Rev Immunol (2010) 10:664–74. doi:10.1038/nri2832 
Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.
Copyright © 2017 Yin, Mohanta, Maffia and Habenicht. This is an open-access 
article distributed under the terms of the Creative Commons Attribution License 
(CC BY). The use, distribution or reproduction in other forums is permitted, pro-
vided the original author(s) or licensor are credited and that the original publication 
in this journal is cited, in accordance with accepted academic practice. No use, 
distribution or reproduction is permitted which does not comply with these terms.


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