Stromal cells in chronic inflammation and tertiary lymphoid organ formation.

Inflammation is an unstable state. It either resolves or persists. Why inflammation persists and the factors that define tissue tropism remain obscure. Increasing evidence suggests that tissue-resident stromal cells not only provide positional memory but also actively regulate the differential accumulation of inflammatory cells within inflamed tissues. Furthermore, at many sites of chronic inflammation, structures that mimic secondary lymphoid tissues are observed, suggesting that chronic inflammation and lymphoid tissue formation share common activation programs. Similarly, blood and lymphatic endothelial cells contribute to tissue homeostasis and disease persistence in chronic inflammation. This review highlights our increasing understanding of the role of stromal cells in inflammation and summarizes the novel immunological role that stromal cells exert in the persistence of inflammatory diseases.

[1]  S. Watson,et al.  Platelets in lymph vessel development and integrity. , 2014, Advances in anatomy, embryology, and cell biology.

[2]  Sakae Tanaka,et al.  Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in TRAF6‐deficient mice , 1999, Genes to cells : devoted to molecular & cellular mechanisms.

[3]  K. Alitalo,et al.  The lymphatic vasculature in disease , 2011, Nature Medicine.

[4]  M. Burdick,et al.  Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. , 2004, The Journal of clinical investigation.

[5]  M. Salmon,et al.  Fibroblasts as novel therapeutic targets in chronic inflammation , 2008, British journal of pharmacology.

[6]  S. Werner,et al.  An important role of lymphatic vessel activation in limiting acute inflammation. , 2011, Blood.

[7]  T. O’Toole,et al.  Lymph Node Stromal Cells Support Dendritic Cell-Induced Gut-Homing of T Cells1 , 2009, The Journal of Immunology.

[8]  F. Falciani,et al.  Global gene expression profiles in fibroblasts from synovial, skin and lymphoid tissue reveals distinct cytokine and chemokine expression patterns , 2003, Thrombosis and Haemostasis.

[9]  J. Lord,et al.  Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. , 2006, Arthritis and rheumatism.

[10]  P. Petrow,et al.  CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. , 2007, Arthritis and rheumatism.

[11]  J. Austyn,et al.  Principles of Cellular and Molecular Immunology , 1994 .

[12]  N. Perkins,et al.  Lymphotoxin a-dependent and -independent signals regulate stromal organizer cell homeostasis during lymph node organogenesis. , 2007, Blood.

[13]  Andrew Filer,et al.  Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells , 2009, European journal of immunology.

[14]  J. Pober,et al.  Memory T Cells and Their Costimulators in Human Allograft Injury1 , 2005, The Journal of Immunology.

[15]  R. Romieu-Mourez,et al.  Cytokine Modulation of TLR Expression and Activation in Mesenchymal Stromal Cells Leads to a Proinflammatory Phenotype1 , 2009, The Journal of Immunology.

[16]  S. Akira,et al.  Id2-, RORγt-, and LTβR-independent initiation of lymphoid organogenesis in ocular immunity , 2009, The Journal of experimental medicine.

[17]  M. Salmon,et al.  Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjögren's syndrome. , 2001, Arthritis and rheumatism.

[18]  R. Terkeltaub,et al.  Cartilage and joint inflammation. Regulation of IL-8 expression by human articular chondrocytes. , 1992, Journal of immunology.

[19]  Limin Liu,et al.  Regulation of T Cell Priming by Lymphoid Stroma , 2011, PloS one.

[20]  A. Filer,et al.  A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. , 2005, Arthritis and rheumatism.

[21]  D. Patel,et al.  CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. , 2001, Clinical immunology.

[22]  Burkhard Ludewig,et al.  B cell homeostasis and follicle confines are governed by fibroblastic reticular cells , 2014, Nature Immunology.

[23]  G. Kollias,et al.  TNFα-dependent development of lymphoid tissue in the absence of RORγt+ Lymphoid Tissue Inducer cells , 2013, Mucosal Immunology.

[24]  K. Maruyama,et al.  Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. , 2005, The Journal of clinical investigation.

[25]  Steffen Jung,et al.  Regulation of Peripheral Lymph Node Genesis by the Tumor Necrosis Factor Family Member Trance , 2000, The Journal of experimental medicine.

[26]  T. Springer,et al.  High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. , 1995, Immunology today.

[27]  A. Campos-Neto,et al.  Chronic inflammation caused by lymphotoxin is lymphoid neogenesis , 1996, The Journal of experimental medicine.

[28]  M. Si-Tahar,et al.  Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells , 2011, The Journal of experimental medicine.

[29]  D. Jackson,et al.  Presumptive Lymph Node Organizers are Differentially Represented in Developing Mesenteric and Peripheral Nodes1 , 2004, The Journal of Immunology.

[30]  D. Link,et al.  CXCL12 Production by Early Mesenchymal Progenitors is Required for Hematopoietic Stem Cell Maintenance , 2012, Nature.

[31]  S. Turley,et al.  Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions , 2010, The Journal of experimental medicine.

[32]  T. Hara,et al.  Lymph Node Fibroblastic Reticular Cells Construct the Stromal Reticulum via Contact with Lymphocytes , 2004, The Journal of experimental medicine.

[33]  M. Salmon,et al.  Defining a role for fibroblasts in the persistence of chronic inflammatory joint disease , 2004, Annals of the rheumatic diseases.

[34]  J. Cyster,et al.  Differing Activities of Homeostatic Chemokines CCL19, CCL21, and CXCL12 in Lymphocyte and Dendritic Cell Recruitment and Lymphoid Neogenesis1 , 2002, The Journal of Immunology.

[35]  H. Hammad,et al.  Tertiary lymphoid organs in infection and autoimmunity , 2012, Trends in Immunology.

[36]  A. Desmoulière,et al.  Normal and Pathologic Soft Tissue Remodeling: Role of the Myofibroblast, with Special Emphasis on Liver and Kidney Fibrosis , 2003, Laboratory Investigation.

[37]  D. Bates,et al.  Chemokine-mediated migration of melanoma cells towards lymphatics – a mechanism contributing to metastasis , 2007, Oncogene.

[38]  J. Pober,et al.  Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations. , 2007, The Journal of investigative dermatology.

[39]  G. Firestein Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? , 1996, Arthritis and rheumatism.

[40]  G. Getz,et al.  Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE−/− mice , 2009, The Journal of experimental medicine.

[41]  R. Gay,et al.  Expression of osteoclast differentiation factor in rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[42]  J. Cyster,et al.  Follicular stromal cells and lymphocyte homing to follicles , 2000, Immunological reviews.

[43]  P. Klimiuk,et al.  Circulating tumour necrosis factor α and soluble tumour necrosis factor receptors in patients with different patterns of rheumatoid synovitis , 2003, Annals of the rheumatic diseases.

[44]  David Botstein,et al.  Diversity, topographic differentiation, and positional memory in human fibroblasts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Y. Shoenfeld,et al.  Mosaic of anti-endothelial antibodies , 1995, Lupus.

[46]  C. Ware,et al.  Lymphotoxin-β receptor signaling through NF-κB2-RelB pathway reprograms adipocyte precursors as lymph node stromal cells. , 2012, Immunity.

[47]  P. Kyzas,et al.  Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma , 2005, The Journal of pathology.

[48]  J. Kriegsmann,et al.  Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. , 1996, The American journal of pathology.

[49]  Pilhan Kim,et al.  Podoplanin-Expressing Cells Derived From Bone Marrow Play a Crucial Role in Postnatal Lymphatic Neovascularization , 2010, Circulation.

[50]  C. Kunder,et al.  Mast cell modulation of the vascular and lymphatic endothelium. , 2011, Blood.

[51]  G. Valesini,et al.  Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome. , 2005, Arthritis and rheumatism.

[52]  J. Girard,et al.  Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules , 2011, Nature.

[53]  J. Becker,et al.  Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. , 2001, Immunity.

[54]  O. Thaunat,et al.  Is defective lymphatic drainage a trigger for lymphoid neogenesis? , 2006, Trends in immunology.

[55]  S. Sierakowski,et al.  Serum cytokines in different histological variants of rheumatoid arthritis. , 2001, The Journal of rheumatology.

[56]  A. Campos-Neto,et al.  Lymphotoxin: from chronic inflammation to lymphoid organs. , 1995, Journal of Inflammation.

[57]  R. Caporali,et al.  Involvement of subchondral bone marrow in rheumatoid arthritis: lymphoid neogenesis and in situ relationship to subchondral bone marrow osteoclast recruitment. , 2005, Arthritis and rheumatism.

[58]  Ying Xu,et al.  Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning , 2009, The Journal of experimental medicine.

[59]  B. Ludewig,et al.  Endothelial cell–specific lymphotoxin-β receptor signaling is critical for lymph node and high endothelial venule formation , 2013, The Journal of experimental medicine.

[60]  T. Kipps,et al.  Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. , 2001, The Journal of clinical investigation.

[61]  M. Burdick,et al.  Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. , 1994, The Journal of clinical investigation.

[62]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[63]  M. Salmon,et al.  The role of chemokines in leucocyte-stromal interactions in rheumatoid arthritis. , 2008, Frontiers in bioscience : a journal and virtual library.

[64]  M. Bajénoff,et al.  Identification of a New Stromal Cell Type Involved in the Regulation of Inflamed B Cell Follicles , 2013, PLoS biology.

[65]  S. Wienert,et al.  Fate mapping reveals origin and dynamics of lymph node follicular dendritic cells , 2014, The Journal of experimental medicine.

[66]  P. Bowness,et al.  Mediation of the proinflammatory cytokine response in rheumatoid arthritis and spondylarthritis by interactions between fibroblast-like synoviocytes and natural killer cells. , 2008, Arthritis and rheumatism.

[67]  M. Skobe,et al.  Inflamed Lymphatic Endothelium Suppresses Dendritic Cell Maturation and Function via Mac-1/ICAM-1-Dependent Mechanism1 , 2009, The Journal of Immunology.

[68]  C. Buckley,et al.  The role of non-hematopoietic stromal cells in the persistence of inflammation , 2013, Front. Immun..

[69]  T. Cupedo,et al.  Induction of secondary and tertiary lymphoid structures in the skin. , 2004, Immunity.

[70]  M. Gaxiola,et al.  Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. , 2006, The Journal of clinical investigation.

[71]  M. Matho,et al.  Unique Lamina Propria Stromal Cells Imprint the Functional Phenotype of Mucosal Dendritic Cells , 2014, Mucosal Immunology.

[72]  Kutlu G. Elpek,et al.  Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes , 2011, Nature Immunology.

[73]  D. Green,et al.  The Lymphotoxin-β Receptor Induces Different Patterns of Gene Expression via Two NF-κB Pathways , 2002 .

[74]  Raghu Kalluri,et al.  Fibroblasts in cancer , 2006, Nature Reviews Cancer.

[75]  Scott N. Mueller,et al.  Stromal cell contributions to the homeostasis and functionality of the immune system , 2009, Nature Reviews Immunology.

[76]  Michael Sixt,et al.  The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. , 2005, Immunity.

[77]  S. Liao,et al.  Synchrony of High Endothelial Venules and Lymphatic Vessels Revealed by Immunization1 , 2006, The Journal of Immunology.

[78]  Adrian L Harris,et al.  Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. , 2002, Cancer research.

[79]  S. Fukuyama,et al.  Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(-)CD4(+)CD45(+) cells. , 2002, Immunity.

[80]  M. Takeichi,et al.  Cadherin-11 in Synovial Lining Formation and Pathology in Arthritis , 2007, Science.

[81]  Peter C Taylor,et al.  Hypoxia and angiogenesis in rheumatoid arthritis , 2005, Current opinion in rheumatology.

[82]  A. Pitsillides,et al.  Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). , 1992, Arthritis and rheumatism.

[83]  Raquel Soares,et al.  Angiogenesis and chronic inflammation: cause or consequence? , 2007, Angiogenesis.

[84]  F. Tacchini-Cottier,et al.  Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes , 2013, Proceedings of the National Academy of Sciences.

[85]  N. Miyasaka,et al.  Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. , 2005, Arthritis and rheumatism.

[86]  M. Kapoor,et al.  Fibrosis—a lethal component of systemic sclerosis , 2014, Nature Reviews Rheumatology.

[87]  F. Weih,et al.  Mouse Aorta Smooth Muscle Cells Differentiate Into Lymphoid Tissue Organizer-Like Cells on Combined Tumor Necrosis Factor Receptor-1/Lymphotoxin &bgr;-Receptor NF-&kgr;B Signaling , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[88]  H. Augustin,et al.  Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. , 2000, Cancer research.

[89]  Seppo Ylä-Herttuala,et al.  Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. , 2005, The Journal of clinical investigation.

[90]  D. Cheresh,et al.  The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. , 1999, The Journal of clinical investigation.

[91]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[92]  Takeshi Watanabe,et al.  Generation of a synthetic lymphoid tissue–like organoid in mice , 2004, Nature Biotechnology.

[93]  S. Gay,et al.  A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells , 2011, Annals of the rheumatic diseases.

[94]  D. Fearon,et al.  Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells , 2014, Proceedings of the National Academy of Sciences.

[95]  Gary R. Grotendorst,et al.  Desmoplastic breast carcinoma as a source of human myofibroblasts. , 1984, The American journal of pathology.

[96]  G. Valesini,et al.  CXCL13, CCL21, and CXCL12 Expression in Salivary Glands of Patients with Sjögren’s Syndrome and MALT Lymphoma: Association with Reactive and Malignant Areas of Lymphoid Organization1 , 2008, The Journal of Immunology.

[97]  Yongwon Choi,et al.  An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells , 2004, Nature Immunology.

[98]  R. Germain,et al.  B-cell follicle development remodels the conduit system and allows soluble antigen delivery to follicular dendritic cells. , 2009, Blood.

[99]  Y. Yatomi,et al.  Platelet Activation Receptor CLEC-2 Regulates Blood/Lymphatic Vessel Separation by Inhibiting Proliferation, Migration, and Tube Formation of Lymphatic Endothelial Cells* , 2012, The Journal of Biological Chemistry.

[100]  D. Hanahan,et al.  BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. , 2000, Immunity.

[101]  J. Cyster,et al.  Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[102]  P. Laakkonen,et al.  Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. , 2004, Journal of the American Society of Nephrology : JASN.

[103]  S. Turley,et al.  Lymph node stroma broaden the peripheral tolerance paradigm. , 2011, Trends in immunology.

[104]  T. Luther,et al.  Advanced Glycation End Product-Induced Activation of NF-κB is Suppressed by α-Lipoic Acid in Cultured Endothelial Cells , 1997, Diabetes.

[105]  J. Kolls,et al.  The development of inducible Bronchus Associated Lymphoid Tissue (iBALT) is dependent on IL-17 , 2011, Nature Immunology.

[106]  A. Cumano,et al.  Inflammation Recapitulates the Ontogeny of Lymphoid Stromal Cells1 , 2009, The Journal of Immunology.

[107]  M. Dorf,et al.  Cutting Edge: Ectopic Expression of the Chemokine TCA4/SLC Is Sufficient to Trigger Lymphoid Neogenesis1 , 2000, The Journal of Immunology.

[108]  M. Detmar,et al.  An important role of lymphatic vessels in the control of UVB-induced edema formation and inflammation. , 2006, The Journal of investigative dermatology.

[109]  M. Dana,et al.  Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. , 2003, The American journal of pathology.

[110]  C. Buckley,et al.  Michael Mason prize essay 2003. Why do leucocytes accumulate within chronically inflamed joints? , 2003, Rheumatology.

[111]  Tatiana V. Petrova,et al.  Lymphangiogenesis in development and human disease , 2005, Nature.

[112]  Thomas Rülicke,et al.  Maturation of Lymph Node Fibroblastic Reticular Cells from Myofibroblastic Precursors Is Critical for Antiviral Immunity , 2013, Immunity.

[113]  D. van Schaardenburg,et al.  Features of the Synovium of Individuals at Risk of Developing Rheumatoid Arthritis , 2014, Arthritis & rheumatology.

[114]  C. Prati,et al.  Endothelial dysfunction in joint disease. , 2014, Joint, bone, spine : revue du rhumatisme.

[115]  T. C. Diss,et al.  Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori , 1993, The Lancet.

[116]  Kim L Kusser,et al.  Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity , 2004, Nature Medicine.

[117]  D. Littman,et al.  Cutting Edge: Organogenesis of Nasal-Associated Lymphoid Tissue (NALT) Occurs Independently of Lymphotoxin-α (LTα) and Retinoic Acid Receptor-Related Orphan Receptor-γ, but the Organization of NALT Is LTα Dependent1 , 2002, The Journal of Immunology.

[118]  M. Wahren-Herlenius,et al.  Expression of the B Cell‐Attracting Chemokine CXCL13 in the Target Organ and Autoantibody Production in Ectopic Lymphoid Tissue in the Chronic Inflammatory Disease Sjögren's Syndrome , 2002, Scandinavian journal of immunology.

[119]  P. Nelson,et al.  Fibroblastic Reticular Cells From Lymph Nodes Attenuate T Cell Expansion by Producing Nitric Oxide , 2011, PloS one.

[120]  Rakesh K. Jain,et al.  Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation , 1997, Nature Medicine.

[121]  G. Sutter,et al.  IL-17–induced CXCL12 recruits B cells and induces follicle formation in BALT in the absence of differentiated FDCs , 2014, The Journal of experimental medicine.

[122]  M. Auer,et al.  Transcytosis and Surface Presentation of IL-8 by Venular Endothelial Cells , 1997, Cell.

[123]  Ahmed Mansouri,et al.  Development of peripheral lymphoid organs and natural killer cells depends on the helix–loop–helix inhibitor Id2 , 1999, Nature.

[124]  D. Kerjaschki,et al.  Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants , 2006, Nature Medicine.

[125]  D. Adams,et al.  Leucocyte-endothelial interactions and regulation of leucocyte migration , 1994, The Lancet.

[126]  E. Kremmer,et al.  Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo , 2008, The Journal of experimental medicine.

[127]  M. Karkkainen,et al.  Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. , 2001, Cancer research.

[128]  M. Skobe,et al.  Lymphotoxin β receptor signaling is required for inflammatory lymphangiogenesis in the thyroid , 2007, Proceedings of the National Academy of Sciences.

[129]  R. Golan-Gerstl,et al.  Evasion of myofibroblasts from immune surveillance: A mechanism for tissue fibrosis , 2007, Proceedings of the National Academy of Sciences.

[130]  C. Ware,et al.  Ontogeny of Stromal Organizer Cells during Lymph Node Development , 2010, The Journal of Immunology.

[131]  William W. Agace,et al.  CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation , 2009, Nature Immunology.

[132]  M. Burdick,et al.  Macrophage Inflammatory Protein-Iβ: A C-C Chemokine in Osteoarthritis , 1995 .

[133]  Burkhard Ludewig,et al.  Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence , 2008, Nature Reviews Immunology.

[134]  C. Weyand,et al.  Ectopic Germinal Center Formation in Rheumatoid Synovitis , 2003, Annals of the New York Academy of Sciences.

[135]  U. V. von Andrian,et al.  Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. , 2009, Immunity.

[136]  B. Bresnihan,et al.  Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis , 2005, European journal of immunology.

[137]  C. Ware,et al.  LTβR Signaling Induces Cytokine Expression and Up-Regulates Lymphangiogenic Factors in Lymph Node Anlagen1 , 2009, The Journal of Immunology.

[138]  S. Perrin,et al.  Lymphotoxin-β Receptor Signaling Is Required for the Homeostatic Control of HEV Differentiation and Function , 2005 .

[139]  Frank Emmrich,et al.  Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture — primary culture cells markedly differ from fourth-passage cells , 2000, Arthritis research.

[140]  A. Manzo,et al.  Secondary and ectopic lymphoid tissue responses in rheumatoid arthritis: from inflammation to autoimmunity and tissue damage/remodeling , 2010, Immunological reviews.

[141]  Kim L Kusser,et al.  Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. , 2009, Immunity.

[142]  M. Rescigno,et al.  Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning , 2009, Mucosal Immunology.

[143]  M. Ramos-Casals The B-lymphocyte stimulator connection in Sjogren's syndrome. , 2013, Rheumatology.

[144]  T. Randall,et al.  Ectopic lymphoid tissues and local immunity. , 2008, Seminars in immunology.

[145]  S. Lira,et al.  Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. , 2006, The Journal of clinical investigation.

[146]  Ulrich Wagner,et al.  Follicular Dendritic Cells Emerge from Ubiquitous Perivascular Precursors , 2012, Cell.

[147]  B. Hinz,et al.  Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells , 2007, Nature Immunology.

[148]  N. Söderström,et al.  Organization of the Invading Lymphoid Tissue in Human Lymphoid Thyroiditis , 1974, Scandinavian journal of immunology.

[149]  Manuel A. González,et al.  Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. , 2009, Arthritis and rheumatism.

[150]  James O. Jones,et al.  Suppression of Antitumor Immunity by Stromal Cells Expressing , 2022 .

[151]  J. Buckner Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases , 2010, Nature Reviews Immunology.

[152]  A. Tzioufas,et al.  "Lymphoid" chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: possible participation in lymphoid structure formation. , 2001, Arthritis and rheumatism.

[153]  R. Harvey,et al.  Nkx2-5(+)islet1(+) mesenchymal precursors generate distinct spleen stromal cell subsets and participate in restoring stromal network integrity. , 2013, Immunity.

[154]  Thomas Hawighorst,et al.  Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis , 2001, Nature Medicine.

[155]  H. Kelchtermans,et al.  Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis , 2010, Arthritis research & therapy.

[156]  E. Akirav,et al.  Secondary Lymphoid Organs: Responding to Genetic and Environmental Cues in Ontogeny and the Immune Response1 , 2009, The Journal of Immunology.

[157]  B. Hunt,et al.  Endothelial cell activation , 1998, BMJ.

[158]  R. Caporali,et al.  Serum levels of CXCL13 are associated with ultrasonographic synovitis and predict power Doppler persistence in early rheumatoid arthritis treated with non-biological disease-modifying anti-rheumatic drugs , 2012, Arthritis Research & Therapy.

[159]  J. Fjell,et al.  Lymphoid tissue homing chemokines are expressed in chronic inflammation. , 2000, The American journal of pathology.

[160]  M. Willart,et al.  Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus–infected mice , 2009, The Journal of experimental medicine.

[161]  R. Roozendaal,et al.  Stromal cell-immune cell interactions. , 2011, Annual review of immunology.

[162]  C. Orosz,et al.  Can graft endothelial cells initiate a host anti-graft immune response? , 1996, Transplantation.

[163]  M. Salmon,et al.  A stromal address code defined by fibroblasts. , 2005, Trends in immunology.

[164]  A. Ostman,et al.  Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? , 2004, Lung cancer.

[165]  M. Peakman,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 , 2010, The Journal of Immunology.

[166]  Keiichiro Suzuki,et al.  Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. , 2008, Immunity.

[167]  T. Junt,et al.  Restoration of lymphoid organ integrity through the interaction of lymphoid tissue–inducer cells with stroma of the T cell zone , 2008, Nature Immunology.

[168]  Antonio Alcami,et al.  The chemokine receptor D6 limits the inflammatory response in vivo , 2005, Nature Immunology.

[169]  R. Strieter,et al.  Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. , 1991, Journal of immunology.

[170]  Kozo Nakamura,et al.  Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[171]  L. Wilkinson,et al.  Demonstration of lymphatics in human synovial tissue , 2004, Rheumatology International.

[172]  C. Thiemermann,et al.  Mesenchymal Stromal Cells: Current Understanding and Clinical Status , 2009, Stem cells.

[173]  F. Aloisi,et al.  Lymphoid neogenesis in chronic inflammatory diseases , 2006, Nature Reviews Immunology.

[174]  Richard A. Martin,et al.  Lymphoid Aggregates That Resemble Tertiary Lymphoid Organs Define a Specific Pathological Subset in Metal-on-Metal Hip Replacements , 2013, PloS one.

[175]  W. Dougall,et al.  RANK is essential for osteoclast and lymph node development. , 1999, Genes & development.

[176]  U. Müller-Ladner,et al.  MMPs and rheumatoid synovial fibroblasts: Siamese twins in joint destruction? , 2002, Annals of the rheumatic diseases.

[177]  Youjin Lee,et al.  Priming of naive T cells inside tumors leads to eradication of established tumors , 2004, Nature Immunology.

[178]  J. Smolen,et al.  Cadherin 11 promotes invasive behavior of fibroblast-like synoviocytes. , 2009, Arthritis and rheumatism.

[179]  M. McGurk,et al.  Activation-Induced Cytidine Deaminase Expression in Follicular Dendritic Cell Networks and Interfollicular Large B Cells Supports Functionality of Ectopic Lymphoid Neogenesis in Autoimmune Sialoadenitis and MALT Lymphoma in Sjögren’s Syndrome1 , 2007, The Journal of Immunology.

[180]  Howard Y. Chang,et al.  Deletional Tolerance Mediated by Extrathymic Aire-Expressing Cells , 2008, Science.

[181]  W. Lesslauer,et al.  Ectopic LTαβ Directs Lymphoid Organ Neogenesis with Concomitant Expression of Peripheral Node Addressin and a HEV-restricted Sulfotransferase , 2003, The Journal of experimental medicine.

[182]  Francesco Dazzi,et al.  Mesenchymal stem cells: the fibroblasts’ new clothes? , 2009, Haematologica.

[183]  M. Salmon,et al.  A Chemokine-Dependent Stromal Induction Mechanism for Aberrant Lymphocyte Accumulation and Compromised Lymphatic Return in Rheumatoid Arthritis , 2005, The Journal of Immunology.

[184]  P. Hjelmström Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines , 2001, Journal of leukocyte biology.

[185]  Jason G. Cyster,et al.  Overlapping Roles of CXCL13, Interleukin 7 Receptor α, and CCR7 Ligands in Lymph Node Development , 2003, The Journal of experimental medicine.

[186]  G. Aust,et al.  The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases. , 2004, European journal of endocrinology.

[187]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[188]  F. Breedveld,et al.  Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. , 2005, Arthritis and rheumatism.

[189]  Jenna M. Sullivan,et al.  Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. , 2011, Immunity.

[190]  S. Liao,et al.  Lymphoid organ development: from ontogeny to neogenesis , 2006, Nature Immunology.

[191]  H. Schwarz,et al.  Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules , 2006, Journal of Cell Science.

[192]  S. Segerer,et al.  The role of lymphatics in renal inflammation. , 2012, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[193]  R. Jain,et al.  Lymphotoxin-alpha contributes to lymphangiogenesis. , 2010, Blood.

[194]  W. O'Fallon,et al.  Lymphoid Neogenesis in Rheumatoid Synovitis1 , 2001, The Journal of Immunology.

[195]  P. Robbins,et al.  Synovial fibroblasts spread rheumatoid arthritis to unaffected joints , 2009, Nature Medicine.

[196]  M. Boes,et al.  Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation , 2014, eLife.

[197]  P. von der Weid,et al.  Role of the lymphatic system in the pathogenesis of Crohn's disease , 2011, Current opinion in gastroenterology.

[198]  Simon A. Jones,et al.  Ectopic lymphoid-like structures in infection, cancer and autoimmunity , 2014, Nature Reviews Immunology.

[199]  Jingtai Cao,et al.  VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. , 2004, The Journal of clinical investigation.

[200]  M. Salmon,et al.  Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. , 2003, Arthritis and rheumatism.

[201]  K. Matsushima,et al.  Lymph Node Stromal Cells Negatively Regulate Antigen-Specific CD4+ T Cell Responses , 2014, The Journal of Immunology.

[202]  S. Turley,et al.  Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self , 2007, Nature Immunology.

[203]  W. Reith,et al.  Lymph node stromal cells acquire peptide–MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance , 2014, The Journal of experimental medicine.

[204]  T. Rülicke,et al.  The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes , 2014, Nature Immunology.

[205]  M. Brenner,et al.  Fibroblast‐like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin‐11 , 2010, Immunological reviews.

[206]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[207]  C. Beltrami,et al.  Resistance to Rituximab Therapy and Local BAFF Overexpression in Sjögren’s Syndrome-Related Myoepithelial Sialadenitis and Low-Grade Parotid B-Cell Lymphoma , 2008, The open rheumatology journal.

[208]  F. Lafeber,et al.  Increased interleukin (IL)-7Rα expression in salivary glands of patients with primary Sjögren's syndrome is restricted to T cells and correlates with IL-7 expression, lymphocyte numbers and activity , 2012, Annals of the rheumatic diseases.

[209]  J. Caamaño,et al.  A Stroma-Derived Defect in NF-κB2−/− Mice Causes Impaired Lymph Node Development and Lymphocyte Recruitment1 , 2004, The Journal of Immunology.

[210]  Jordan S. Pober,et al.  Evolving functions of endothelial cells in inflammation , 2007, Nature Reviews Immunology.

[211]  Ronald N Germain,et al.  Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. , 2006, Immunity.

[212]  D. Adams,et al.  Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans , 2011, The American journal of pathology.

[213]  Scott N. Mueller,et al.  Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection , 2007, Proceedings of the National Academy of Sciences.

[214]  S. Abramson,et al.  The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. , 2005, Clinical immunology.

[215]  Tsutomu Takeuchi,et al.  Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells , 2009, Nature.

[216]  T. Cupedo,et al.  The role of CD45+CD4+CD3– cells in lymphoid organ development , 2002, Immunological reviews.

[217]  R. Flavell,et al.  Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. , 1993, Journal of immunology.

[218]  T. Cupedo,et al.  Cellular Interactions in Lymph Node Development , 2005, The Journal of Immunology.

[219]  Jason G. Cyster,et al.  A chemokine-driven positive feedback loop organizes lymphoid follicles , 2000, Nature.

[220]  M. Juan,et al.  Chemokines Determine Local Lymphoneogenesis and a Reduction of Circulating CXCR4+ T and CCR7 B and T Lymphocytes in Thyroid Autoimmune Diseases1 , 2003, The Journal of Immunology.

[221]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[222]  M. Juan,et al.  Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. , 2001, The American journal of pathology.

[223]  D. Zawieja,et al.  Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. , 2010, Blood.

[224]  E. Kremmer,et al.  Lymph node T cell homeostasis relies on steady state homing of dendritic cells. , 2011, Immunity.