Search tips
Search criteria 


Logo of f1000resSubmitAuthor GuidelinesAboutAdvisory PanelF1000ResearchView this article
Version 1. F1000Res. 2017; 6: 196.
Published online 2017 February 28. doi:  10.12688/f1000research.10595.1
PMCID: PMC5333609

Tertiary lymphoid organs in systemic autoimmune diseases:  pathogenic or protective?


Tertiary lymphoid organs are found at sites of chronic inflammation in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. These organized accumulations of T and B cells resemble secondary lymphoid organs and generate autoreactive effector cells. However, whether they contribute to disease pathogenesis or have protective functions is unclear. Here, we discuss how tertiary lymphoid organs can generate potentially pathogenic cells but may also limit the extent of the response and damage in autoimmune disease.

Keywords: Tertiary Lymphoid Organs, Lymph node, Autoimmune disease, Lupus, Rheumatoid Arthritis


Autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis are marked by chronic inflammation in end organs that can be associated with the development of tertiary lymphoid organs (TLOs) 16. TLOs are also known as tertiary lymphoid tissues, ectopic lymphoid follicles, or ectopic lymphoid structures and are accumulations of lymphocytes and stromal cells in an organized structure that occur outside of secondary lymphoid organs (SLOs). TLOs share many features with SLOs, such as the presence of T and B cell compartmentalization into T cell zones and B cell follicles, chemokines that mediate the compartmentalization, antigen-presenting cells, lymphatic sinuses, high endothelial venules, follicular dendritic cells, and fibroblastic reticular cells (FRCs) 711. In SLE, inflammation in the kidney interstitial tissue is associated with greater risk for kidney failure 12. Up to almost half of patients have well-circumscribed aggregates of B cells, plasma cells, and T cells and a small fraction can have well-organized germinal centers with follicular dendritic cells 1, 2. In rheumatoid arthritis, TLOs ranging from B and T cell aggregates to germinal centers are found in the inflamed synovium of about half of biopsied patients and are associated with more severe joint and systemic inflammation 36, 13. TLOs are also found in other organs in other autoimmune diseases or models, such as in the salivary and lacrimal glands in Sjögren’s syndrome 1416, the central nervous system in multiple sclerosis 7, 1722, the pancreas in diabetes 2325, the thymus in myasthenia gravis 26, 27, and the intestines in inflammatory bowel disease 28, 29. While findings in recent years have begun to delineate the mechanisms that regulate the formation of TLOs (recently reviewed in 711), it is unclear whether TLOs provide pathogenic or protective contributions to SLE, rheumatoid arthritis, and other autoimmune diseases. Here we will review evidence that TLOs may generate potentially pathogenic cells but that they may limit the extent of pathogenic cell activity.

Tertiary lymphoid organs can generate potentially pathogenic cells

In the setting of infections, TLOs have been generally considered to be protective, adopting SLO-like functions and acting as “outposts” of SLOs that are directly positioned at the site of inflammation. TLOs form in the lung of influenza-infected mice 3032 that can maintain and reactivate memory CD8+ T cells 33 and produce plasma cells and antiviral serum immunoglobulins 31. Remarkably, although there is a delay in anti-viral immunity development, TLOs are sufficient for protection when the hosts are deficient in SLOs 33, underscoring the idea that TLOs can generate effector cells that provide effective host defense. Innate lymphoid cells (ILCs) in the lung are induced after influenza infection and have been shown to maintain lung function, epithelial integrity, and airway remodeling 34. Although it is unknown whether TLOs play a role in maintaining or stimulating lung ILCs after influenza infection, ILCs have been shown to be associated with TLOs and have even been associated with decreased disease progression in lung cancer 3537. It is possible that influenza-induced lung TLOs also provide a suitable environment for ILCs to populate and function in a protective manner. Similar to influenza virus infection, TLOs form with pulmonary Mycobacterium tuberculosis (MTB) infection 3840. Latent tuberculosis is associated with more frequent, well-organized TLOs while TLOs are less frequent and less well-formed in active tuberculosis 40, suggesting a protective role for TLOs in controlling disease. The TLOs contribute to the formation of granulomas, which function to promote immunity and limit tissue damage 41. Additionally, CXCL13 expression that organizes the B cell follicles serves to recruit CXCR5-expressing T helper (Th) cells into granulomas to activate macrophages that are essential to infection control 38, 40. These studies on TLOs in infection models highlight the ability of TLOs to support immune responses that are capable of protecting the host.

Similar to immune responses generated in SLOs, immune responses targeted to self may be harmful to the host. The TLOs in SLE kidneys contain germinal centers that show clonal expansion and somatic hypermutation characteristic of germinal center responses in SLOs 2, demonstrating well-developed effector responses. The TLOs correlate strongly with the presence of immune complexes, suggesting that the locally generated antibodies are autoantibodies to renal antigens that can fix complement and thus cause tissue inflammation and damage 2. Similarly, the B cell responses associated with TLOs in the rheumatoid arthritis synovium 42, the salivary glands in Sjögren’s syndrome 43, and other target tissues show autoimmunity 10. SLE kidneys and rheumatoid synovium are also characterized by the accumulation of Th17 cells, which can have proinflammatory roles 4448. While IL-17-expressing cells could help to induce TLO formation, as has been shown in the central nervous system and in neonatal lung 20, 22, 49, the TLOs could potentially also help to support Th17 cell maintenance or acquisition of additional proinflammatory properties 20, 50, 51. Indeed, B cells are necessary for the accumulation of activated T cells, likely by presenting antigen to the T cells 5254, and B cells in TLOs may be pathogenic in part by stimulating autoreactive T cells, which then can contribute to the inflammatory milieu in the affected end organs. TLOs in autoimmune diseases, then, can be a source of potentially pathogenic lymphocytes.

Tertiary lymphoid organs can potentially limit pathogenic responses

Despite the generation of autoreactive and proinflammatory cells, TLOs could also have a protective role by sequestering pathogenic lymphocytes and preventing them from leaving the specific tissue or tissue compartment to cause further damage. For example, in SLE, glomerular damage is unrelated to the extent of interstitial inflammation 12, but failure to sequester lymphocytes within the interstitial tissue could potentially result in the migration of lymphocytes to the glomeruli and worsened glomerular damage. Alternatively, in the absence of TLOs, the lymphocytes could enter the circulation to home to and potentially damage additional organs outside the kidneys. That inflammatory cells are able to find alternative niches despite the absence of TLOs is seen in MTB infection, where antigen-specific T cells still accumulate, showing an altered, perivascular location, in the absence of TLOs 38, 40. Also, B cell selection in the pancreas is unaltered by follicular disruption of TLO in the pancreas of non-obese diabetic mice 25. Interestingly, TLOs within tumors but not at the tumor periphery are correlated with good outcomes in a study of pancreatic carcinoma patients 55, raising the possibility that the TLOs at the tumor periphery prevent potential anti-tumor lymphocytes from accessing the tumor parenchyma. The concept that TLOs might have a sequestration function is analogous to the sequestration of lymphocytes within SLOs with the S1P agonist fingolimod, which is used to treat multiple sclerosis 56. Fingolimod downregulates SIP receptor 1, preventing lymphocyte egress from the SLOs and subsequent migration to end organs 57. Sequestration of potentially pathogenic cells, then, may help limit the extent of disease.

TLOs can also be protective if they provide a microenvironment that generates regulatory or reparative cells that reduce the pathogenicity of inflammatory cells. In the apoE-/- model of atherosclerosis, TLOs that form on the outer aspects of the atherosclerotic vessel wall generate regulatory T cells (Tregs). These TLOs are dependent on lymphotoxin β receptor (LTβR) stimulation of presumably local vascular smooth muscle, and preventing TLO formation by deleting LTβR from smooth muscle cells resulted in more and enlarged plaques 58. These results suggested that the TLOs were protective, perhaps by the generation of the Tregs. Here, the TLO stroma may be critical for the generation of regulatory cells. Lymph node FRCs have been implicated in Treg generation by presenting self-antigen on MHCII and by guiding T cells into a tolerance-inducing environment 59, 60. FRCs, along with endothelial cells, can additionally promote tolerance by MHCI presentation of autoantigen 61, 62 and regulate the magnitude of T cell activation by expressing inducible nitric oxide synthase 6365. Tregs have also been shown to mediate tissue repair via amphiregulin in lung with influenza infection 66 and in muscle after injury 67, and thus TLO generation of Tregs can have protective effects independent of their immunosuppressive functions. Similarly, ILCs are another source of amphiregulin that is important for repair 34, and TLOs may potentially support their development 68. Interestingly, both SLE patients and lupus-prone mice possess decreased numbers and abnormal function of Tregs 6972 while exhibiting increased calcium/calmodulin-dependent protein kinase IV (CamK4) 73, 74, which is responsible for an imbalance in Th17 cells and Tregs with a shift towards more Th17 cells. Inhibition of CamK4 corrected this imbalance in lupus-prone mice, decreasing Th17 cells and increasing Tregs in the kidney in association with reduced organ damage 75. It is tempting to speculate that the TLOs (and perhaps the SLOs) in SLE do not function correctly to foster optimal Treg generation. TLOs, then, may not only sequester potentially pathogenic cells but also provide an environment that limits the magnitude or severity of the response.


In conclusion, in autoimmune diseases, TLOs can generate and harbor autoreactive and proinflammatory, potentially pathogenic lymphocytes but could potentially serve to limit pathogenic responses by sequestering these cells or by reducing the magnitude of the response. Therapeutically, targeting TLOs may offer opportunities to ameliorate disease, and more understanding of the potential pathogenic and protective functions is needed. For example, can we identify TLOs that generate more pathogenic cells versus those that have more regulatory functions? Do these different functions in part reflect the evolution of TLO development and maturation? What are the vascular, stromal, and hematopoietic elements that contribute to the different microenvironments, and can we modulate them to generate a more immunoregulatory environment? Furthermore, understanding how the affected tissue outside the TLOs may be similar or distinct in supporting the generation and maintenance of autoreactive lymphocytes would enrich our understanding of the distinct nature of TLOs and also allow us to prevent the lymphocytes from potentially accumulating elsewhere upon TLO disruption. Continued improved understanding of TLO biology will help us better understand how to treat autoimmune disease.


[version 1; referees: 2 approved]

Funding Statement

This work was supported by MSTP T32GM007739 from NIGMS/NIH to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program (WDS), Lupus Research Alliance (TTL), St. Giles Foundation (TTL), and an O’Neill Foundation grant from the Barbara Volcker Center for Women and Rheumatic Diseases (TTL).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • George Tsokos, Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    No competing interests were disclosed.
  • Troy D Randall, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA
    No competing interests were disclosed.


1. Steinmetz OM, Velden J, Kneissler U, et al. : Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int. 2008;74(4):448–57. 10.1038/ki.2008.191 [PubMed] [Cross Ref] F1000 Recommendation
2. Chang A, Henderson SG, Brandt D, et al. : In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol. 2011;186(3):1849–60. 10.4049/jimmunol.1001983 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
3. Humby F, Bombardieri M, Manzo A, et al. : Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 2009;6(1):e1. 10.1371/journal.pmed.0060001 [PubMed] [Cross Ref]
4. Wengner AM, Höpken UE, Petrow PK, et al. : CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 2007;56(10):3271–83. 10.1002/art.22939 [PubMed] [Cross Ref]
5. Shi K, Hayashida K, Kaneko M, et al. : Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol. 2001;166(1):650–5. 10.4049/jimmunol.166.1.650 [PubMed] [Cross Ref]
6. Takemura S, Braun A, Crowson C, et al. : Lymphoid neogenesis in rheumatoid synovitis. J Immunol. 2001;167(2):1072–80. 10.4049/jimmunol.167.2.1072 [PubMed] [Cross Ref] F1000 Recommendation
7. Pikor NB, Prat A, Bar-Or A, et al. : Meningeal Tertiary Lymphoid Tissues and Multiple Sclerosis: A Gathering Place for Diverse Types of Immune Cells during CNS Autoimmunity. Front Immunol. 2015;6:657. 10.3389/fimmu.2015.00657 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
8. Barone F, Gardner DH, Nayar S, et al. : Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation. Front Immunol. 2016;7:477. 10.3389/fimmu.2016.00477 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
9. Buckley CD, Barone F, Nayar S, et al. : Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annu Rev Immunol. 2015;33:715–45. 10.1146/annurev-immunol-032713-120252 [PubMed] [Cross Ref] F1000 Recommendation
10. Corsiero E, Nerviani A, Bombardieri M, et al. : Ectopic Lymphoid Structures: Powerhouse of Autoimmunity. Front Immunol. 2016;7:430. 10.3389/fimmu.2016.00430 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
11. Ruddle NH.: High Endothelial Venules and Lymphatic Vessels in Tertiary Lymphoid Organs: Characteristics, Functions, and Regulation. Front Immunol. 2016;7:491. 10.3389/fimmu.2016.00491 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
12. Hsieh C, Chang A, Brandt D, et al. : Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken). 2011;63(6):865–74. 10.1002/acr.20441 [PMC free article] [PubMed] [Cross Ref]
13. Thurlings RM, Wijbrandts CA, Mebius RE, et al. : Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype. Arthritis Rheum. 2008;58(6):1582–9. 10.1002/art.23505 [PubMed] [Cross Ref]
14. Fava RA, Kennedy SM, Wood SG, et al. : Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome. Arthritis Res Ther. 2011;13(6):R182. 10.1186/ar3507 [PMC free article] [PubMed] [Cross Ref]
15. Bombardieri M, Barone F, Lucchesi D, et al. : Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice. J Immunol. 2012;189(7):3767–76. 10.4049/jimmunol.1201216 [PMC free article] [PubMed] [Cross Ref]
16. Holdgate N, St Clair EW.: Recent advances in primary Sjogren's syndrome [version 1; referees: 3 approved]. F1000Res. 2016;5: pii: F1000 Faculty Rev-1412. 10.12688/f1000research.8352.1 [PMC free article] [PubMed] [Cross Ref]
17. Columba-Cabezas S, Griguoli M, Rosicarelli B, et al. : Suppression of established experimental autoimmune encephalomyelitis and formation of meningeal lymphoid follicles by lymphotoxin beta receptor-Ig fusion protein. J Neuroimmunol. 2006;179(1–2):76–86. 10.1016/j.jneuroim.2006.06.015 [PubMed] [Cross Ref]
18. Magliozzi R, Columba-Cabezas S, Serafini B, et al. : Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148(1–2):11–23. 10.1016/j.jneuroim.2003.10.056 [PubMed] [Cross Ref]
19. Mitsdoerffer M, Peters A.: Tertiary Lymphoid Organs in Central Nervous System Autoimmunity. Front Immunol. 2016;7:451. 10.3389/fimmu.2016.00451 [PMC free article] [PubMed] [Cross Ref]
20. Peters A, Pitcher LA, Sullivan JM, et al. : Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 2011;35(6):986–96. 10.1016/j.immuni.2011.10.015 [PMC free article] [PubMed] [Cross Ref]
21. Serafini B, Rosicarelli B, Magliozzi R, et al. : Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14(2):164–74. 10.1111/j.1750-3639.2004.tb00049.x [PubMed] [Cross Ref]
22. Pikor NB, Astarita JL, Summers-Deluca L, et al. : Integration of Th17- and Lymphotoxin-Derived Signals Initiates Meningeal-Resident Stromal Cell Remodeling to Propagate Neuroinflammation. Immunity. 2015;43(6):1160–73. 10.1016/j.immuni.2015.11.010 [PubMed] [Cross Ref]
23. Astorri E, Bombardieri M, Gabba S, et al. : Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets. J Immunol. 2010;185(6):3359–68. 10.4049/jimmunol.1001836 [PubMed] [Cross Ref]
24. Ludewig B, Odermatt B, Landmann S, et al. : Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J Exp Med. 1998;188(8):1493–501. 10.1084/jem.188.8.1493 [PMC free article] [PubMed] [Cross Ref]
25. Henry RA, Kendall PL.: CXCL13 blockade disrupts B lymphocyte organization in tertiary lymphoid structures without altering B cell receptor bias or preventing diabetes in nonobese diabetic mice. J Immunol. 2010;185(3):1460–5. 10.4049/jimmunol.0903710 [PMC free article] [PubMed] [Cross Ref]
26. Hill ME, Shiono H, Newsom-Davis J, et al. : The myasthenia gravis thymus: a rare source of human autoantibody-secreting plasma cells for testing potential therapeutics. J Neuroimmunol. 2008;201–202:50–6. 10.1016/j.jneuroim.2008.06.027 [PubMed] [Cross Ref]
27. Zhang X, Liu S, Chang T, et al. : Intrathymic Tfh/B Cells Interaction Leads to Ectopic GCs Formation and Anti-AChR Antibody Production: Central Role in Triggering MG Occurrence. Mol Neurobiol. 2016;53(1):120–31. 10.1007/s12035-014-8985-1 [PubMed] [Cross Ref]
28. Buettner M, Lochner M.: Development and Function of Secondary and Tertiary Lymphoid Organs in the Small Intestine and the Colon. Front Immunol. 2016;7:342. 10.3389/fimmu.2016.00342 [PMC free article] [PubMed] [Cross Ref]
29. Olivier BJ, Cailotto C, van der Vliet J, et al. : Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis. Eur J Immunol. 2016;46(10):2467–80. 10.1002/eji.201646370 [PubMed] [Cross Ref]
30. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, et al. : Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med. 2004;10(9):927–34. 10.1038/nm1091 [PubMed] [Cross Ref]
31. GeurtsvanKessel CH, Willart MA, Bergen IM, et al. : Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med. 2009;206(11):2339–49. 10.1084/jem.20090410 [PMC free article] [PubMed] [Cross Ref]
32. Halle S, Dujardin HC, Bakocevic N, et al. : Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells. J Exp Med. 2009;206(12):2593–601. 10.1084/jem.20091472 [PMC free article] [PubMed] [Cross Ref]
33. Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, et al. : Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity. 2006;25(4):643–54. 10.1016/j.immuni.2006.08.022 [PubMed] [Cross Ref]
34. Monticelli LA, Sonnenberg GF, Abt MC, et al. : Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011;12(11):1045–54. [PMC free article] [PubMed]
35. Carrega P, Loiacono F, Di Carlo E, et al. : NCR +ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat Commun. 2015;6:8280. 10.1038/ncomms9280 [PubMed] [Cross Ref]
36. Meier D, Bornmann C, Chappaz S, et al. : Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity. 2007;26(5):643–54. 10.1016/j.immuni.2007.04.009 [PubMed] [Cross Ref]
37. Schmutz S, Bosco N, Chappaz S, et al. : Cutting edge: IL-7 regulates the peripheral pool of adult ROR gamma + lymphoid tissue inducer cells. J Immunol. 2009;183(4):2217–21. 10.4049/jimmunol.0802911 [PubMed] [Cross Ref]
38. Khader SA, Rangel-Moreno J, Fountain JJ, et al. : In a murine tuberculosis model, the absence of homeostatic chemokines delays granuloma formation and protective immunity. J Immunol. 2009;183(12):8004–14. 10.4049/jimmunol.0901937 [PMC free article] [PubMed] [Cross Ref]
39. Ulrichs T, Kosmiadi GA, Trusov V, et al. : Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol. 2004;204(2):217–28. 10.1002/path.1628 [PubMed] [Cross Ref]
40. Slight SR, Rangel-Moreno J, Gopal R, et al. : CXCR5 + T helper cells mediate protective immunity against tuberculosis. J Clin Invest. 2013;123(2):712–26. 10.1172/JCI65728 [PMC free article] [PubMed] [Cross Ref]
41. Bean AG, Roach DR, Briscoe H, et al. : Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol. 1999;162(6):3504–11. [PubMed]
42. Corsiero E, Bombardieri M, Carlotti E, et al. : Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs. Ann Rheum Dis. 2016;75(10):1866–75. 10.1136/annrheumdis-2015-208356 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
43. Salomonsson S, Jonsson MV, Skarstein K, et al. : Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome. Arthritis Rheum. 2003;48(11):3187–201. 10.1002/art.11311 [PubMed] [Cross Ref]
44. Pisitkun P, Ha HL, Wang H, et al. : Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis. Immunity. 2012;37(6):1104–15. 10.1016/j.immuni.2012.08.014 [PMC free article] [PubMed] [Cross Ref]
45. Zhang Z, Kyttaris VC, Tsokos GC.: The role of IL-23/IL-17 axis in lupus nephritis. J Immunol. 2009;183(5):3160–9. 10.4049/jimmunol.0900385 [PMC free article] [PubMed] [Cross Ref]
46. Crispín JC, Oukka M, Bayliss G, et al. : Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol. 2008;181(12):8761–6. 10.4049/jimmunol.181.12.8761 [PMC free article] [PubMed] [Cross Ref]
47. Genovese MC, Durez P, Richards HB, et al. : One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol. 2014;41(3):414–21. 10.3899/jrheum.130637 [PubMed] [Cross Ref] F1000 Recommendation
48. Hirota K, Yoshitomi H, Hashimoto M, et al. : Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med. 2007;204(12):2803–12. 10.1084/jem.20071397 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
49. Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, et al. : The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol. 2011;12(7):639–46. 10.1038/ni.2053 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
50. Nistala K, Adams S, Cambrook H, et al. : Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci U S A. 2010;107(33):14751–6. 10.1073/pnas.1003852107 [PubMed] [Cross Ref] F1000 Recommendation
51. Harbour SN, Maynard CL, Zindl CL, et al. : Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015;112(22):7061–6. 10.1073/pnas.1415675112 [PubMed] [Cross Ref] F1000 Recommendation
52. Chan OT, Madaio MP, Shlomchik MJ.: B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity. J Immunol. 1999;163(7):3592–6. [PubMed]
53. Chan OT, Hannum LG, Haberman AM, et al. : A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med. 1999;189(10):1639–48. 10.1084/jem.189.10.1639 [PMC free article] [PubMed] [Cross Ref]
54. Weyand CM, Goronzy JJ, Takemura S, et al. : Cell-cell interactions in synovitis. Interactions between T cells and B cells in rheumatoid arthritis. Arthritis Res. 2000;2(6):457–63. 10.1186/ar128 [PMC free article] [PubMed] [Cross Ref]
55. Hiraoka N, Ino Y, Yamazaki-Itoh R, et al. : Intratumoral tertiary lymphoid organ is a favourable prognosticator in patients with pancreatic cancer. Br J Cancer. 2015;112(11):1782–90. 10.1038/bjc.2015.145 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
56. Brinkmann V, Billich A, Baumruker T, et al. : Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9(11):883–97. 10.1038/nrd3248 [PubMed] [Cross Ref]
57. Matloubian M, Lo CG, Cinamon G, et al. : Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427(6972):355–60. 10.1038/nature02284 [PubMed] [Cross Ref]
58. Hu D, Mohanta SK, Yin C, et al. : Artery Tertiary Lymphoid Organs Control Aorta Immunity and Protect against Atherosclerosis via Vascular Smooth Muscle Cell Lymphotoxin β Receptors. Immunity. 2015;42(6):1100–15. 10.1016/j.immuni.2015.05.015 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
59. Baptista AP, Roozendaal R, Reijmers RM, et al. : Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. eLife. 2014;3:e04433. 10.7554/eLife.04433 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
60. Warren KJ, Iwami D, Harris DG, et al. : Laminins affect T cell trafficking and allograft fate. J Clin Invest. 2014;124(5):2204–18. 10.1172/JCI73683 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
61. Fletcher AL, Lukacs-Kornek V, Reynoso ED, et al. : Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207(4):689–97. 10.1084/jem.20092642 [PMC free article] [PubMed] [Cross Ref]
62. Cohen JN, Guidi CJ, Tewalt EF, et al. : Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med. 2010;207(4):681–8. 10.1084/jem.20092465 [PMC free article] [PubMed] [Cross Ref]
63. Lukacs-Kornek V, Malhotra D, Fletcher AL, et al. : Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol. 2011;12(11):1096–104. 10.1038/ni.2112 [PMC free article] [PubMed] [Cross Ref]
64. Siegert S, Huang HY, Yang CY, et al. : Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide. PLoS One. 2011;6(11):e27618. 10.1371/journal.pone.0027618 [PMC free article] [PubMed] [Cross Ref]
65. Khan O, Headley M, Gerard A, et al. : Regulation of T cell priming by lymphoid stroma. PLoS One. 2011;6(11):e26138. 10.1371/journal.pone.0026138 [PMC free article] [PubMed] [Cross Ref]
66. Arpaia N, Green JA, Moltedo B, et al. : A Distinct Function of Regulatory T Cells in Tissue Protection. Cell. 2015;162(5):1078–89. 10.1016/j.cell.2015.08.021 [PMC free article] [PubMed] [Cross Ref]
67. Burzyn D, Kuswanto W, Kolodin D, et al. : A special population of regulatory T cells potentiates muscle repair. Cell. 2013;155(6):1282–95. 10.1016/j.cell.2013.10.054 [PMC free article] [PubMed] [Cross Ref]
68. Barone F, Nayar S, Campos J, et al. : IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc Natl Acad Sci U S A. 2015;112(35):11024–9. 10.1073/pnas.1503315112 [PubMed] [Cross Ref]
69. Valencia X, Yarboro C, Illei G, et al. : Deficient CD4 +CD25 high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579–88. 10.4049/jimmunol.178.4.2579 [PubMed] [Cross Ref]
70. Hsu W, Suen J, Chiang B.: The role of CD4 +CD25 + T cells in autoantibody production in murine lupus. Clin Exp Immunol. 2006;145(3):513–9. 10.1111/j.1365-2249.2006.03173.x [PubMed] [Cross Ref]
71. Scalapino KJ, Tang Q, Bluestone JA, et al. : Suppression of disease in New Zealand Black/New Zealand White lupus-prone mice by adoptive transfer of ex vivo expanded regulatory T cells. J Immunol. 2006;177(3):1451–9. 10.4049/jimmunol.177.3.1451 [PubMed] [Cross Ref]
72. Liu MF, Wang CR, Fung LL, et al. : Decreased CD4 +CD25 + T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol. 2004;59(2):198–202. 10.1111/j.0300-9475.2004.01370.x [PubMed] [Cross Ref]
73. Juang YT, Wang Y, Solomou EE, et al. : Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J Clin Invest. 2005;115(4):996–1005. 10.1172/JCI22854 [PMC free article] [PubMed] [Cross Ref]
74. Koga T, Ichinose K, Mizui M, et al. : Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J Immunol. 2012;189(7):3490–6. 10.4049/jimmunol.1201785 [PMC free article] [PubMed] [Cross Ref]
75. Koga T, Mizui M, Yoshida N, et al. : KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3 + regulatory T cells in MRL/ lpr mice. Autoimmunity. 2014;47(7):445–50. 10.3109/08916934.2014.915954 [PMC free article] [PubMed] [Cross Ref]

Articles from F1000Research are provided here courtesy of F1000 Research Ltd