Ectopic lymphoid-like structures in infection, cancer and autoimmunity (original) (raw)

• Jones, S. A. Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175, 3463–3468 (2005).
  Article CAS PubMed Google Scholar
• Buckley, C. D. Why does chronic inflammation persist: An unexpected role for fibroblasts. Immunol. Lett. 138, 12–14 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Rev. Immunol. 7, 429–442 (2007).
  Article CAS Google Scholar
• Choy, E. H., Kavanaugh, A. F. & Jones, S. A. The problem of choice: current biologic agents and future prospects in RA. Nature Rev. Rheumatol. 9, 154–163 (2013).
  Article CAS Google Scholar
• Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 121, 3375–3383 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Raza, K. The Michael Mason prize: early rheumatoid arthritis—the window narrows. Rheumatology 49, 406–410 (2010).
  Article PubMed Google Scholar
• Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nature Rev. Immunol. 6, 205–217 (2006). This is an excellent commentary on the development of lymphoid structures in disease.
  Article CAS Google Scholar
• Neyt, K., Perros, F., GeurtsvanKessel, C. H., Hammad, H. & Lambrecht, B. N. Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33, 297–305 (2012).
  Article CAS PubMed Google Scholar
• Cañete, J. D. et al. Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor-α therapy in rheumatoid arthritis. Ann. Rheum. Dis. 68, 751–756 (2009). This study provides an example of how distinct synovial histopathology may influence the response to biological therapy. The presence of ELSs was associated with an inferior response to anti-TNF therapy.
  Article CAS PubMed Google Scholar
• Coppola, D. et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am. J. Pathol. 179, 37–45 (2011).
  Article PubMed PubMed Central Google Scholar
• Drayton, D. L., Liao, S., Mounzer, R. H. & Ruddle, N. H. Lymphoid organ development: from ontogeny to neogenesis. Nature Immunol. 7, 344–353 (2006). This is an excellent review about the mechanisms controlling lymphoid neogenesis.
  Article CAS Google Scholar
• De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).
  Article CAS PubMed Google Scholar
• Kratz, A., Campos-Neto, A., Hanson, M. S. & Ruddle, N. H. Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J. Exp. Med. 183, 1461–1472 (1996).
  Article CAS PubMed Google Scholar
• Drayton, D. L., Ying, X., Lee, J., Lesslauer, W. & Ruddle, N. H. Ectopic LTαβ directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J. Exp. Med. 197, 1153–1163 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Ruddle, N. H. Lymphatic vessels and tertiary lymphoid organs. J. Clin. Invest. 124, 953–959 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Meier, D. et al. Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26, 643–654 (2007). This is an early report on the role of IL-7 and LTi cells in lymphoid neogenesis.
  Article CAS PubMed Google Scholar
• Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).
  Article CAS PubMed Google Scholar
• Schmutz, S. et al. Cutting edge: IL-7 regulates the peripheral pool of adult RORγ+ lymphoid tissue inducer cells. J. Immunol. 183, 2217–2221 (2009). The study describes the role of RORγt in LTi cells and provides a potential link to the involvement of T H 17-like cells in lymphoid neogenesis.
  Article CAS PubMed Google Scholar
• Luther, S. A., Ansel, K. M. & Cyster, J. G. Overlapping roles of CXCL13, interleukin 7 receptor-α, and CCR7 ligands in lymph node development. J. Exp. Med. 197, 1191–1198 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Yoshida, H. et al. Different cytokines induce surface lymphotoxin-αβ on IL-7 receptor-α cells that differentially engender lymph nodes and Peyer's patches. Immunity 17, 823–833 (2002). This study suggests that unique cellular and molecular mechanisms contribute to lymphoid neogenesis in distinct anatomical sites.
  Article CAS PubMed Google Scholar
• Sato, M. et al. Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction. Transplantation 91, 1398–1405 (2011).
  Article CAS PubMed Google Scholar
• Rangel-Moreno, J., Moyron-Quiroz, J. E., Hartson, L., Kusser, K. & Randall, T. D. Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza. Proc. Natl Acad. Sci. USA 104, 10577–10582 (2007). This study demonstrates the importance of homeostatic chemokines in the organization of lymphoid structures.
  Article CAS PubMed Google Scholar
• Braun, A., Takemura, S., Vallejo, A. N., Goronzy, J. J. & Weyand, C. M. Lymphotoxin β-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum. 50, 2140–2150 (2004).
  Article CAS PubMed Google Scholar
• Takemura, S. et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).
  Article CAS PubMed Google Scholar
• Timmer, T. C. et al. Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum. 56, 2492–2502 (2007). This is an investigative study of ELS development in the context of human disease.
  Article CAS PubMed Google Scholar
• Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Deteix, C. et al. Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection. J. Immunol. 184, 5344–5351 (2010).
  Article CAS PubMed Google Scholar
• Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nature Immunol. 12, 639–646 (2011). References 29 and 30 suggest a role of IL-17 and T H 17-like cells in ELS development.
  Article CAS Google Scholar
• Link, A. et al. Association of T-zone reticular networks and conduits with ectopic lymphoid tissues in mice and humans. Am. J. Pathol. 178, 1662–1675 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Furtado, G. C. et al. TNFα-dependent development of lymphoid tissue in the absence of RORγt lymphoid tissue inducer cells. Mucosal Immunol. 7, 602–614 (2013). This study supports a role for resident myeloid cells and stromal cells in lymphoid neogenesis.
  Article CAS PubMed PubMed Central Google Scholar
• Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208, 125–134 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424–433 (2002).
  Article CAS PubMed Google Scholar
• Luther, S. A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J. G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000).
  Article CAS PubMed Google Scholar
• Chen, S. C. et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J. Immunol. 168, 1001–1008 (2002).
  Article CAS PubMed Google Scholar
• Fan, L., Reilly, C. R., Luo, Y., Dorf, M. E. & Lo, D. Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J. Immunol. 164, 3955–3959 (2000).
  Article CAS PubMed Google Scholar
• Slight, S. R. et al. CXCR5+ T helper cells mediate protective immunity against tuberculosis. J. Clin. Invest. 123, 712–726 (2013).
  CAS PubMed PubMed Central Google Scholar
• Bombardieri, M. et al. Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice. J. Immunol. 189, 3767–3776 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Gu-Trantien, C. et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873–2892 (2013). This study uses imaging to correlate the infiltration of T FH cells with clinical outcome in patients with breast cancer.
  Article CAS PubMed PubMed Central Google Scholar
• Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000). This study describes the original identification and functional characterization of T FH cells.
  Article CAS PubMed PubMed Central Google Scholar
• Nakayamada, S. et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35, 919–931 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, K. T. et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of _in vitro_-generated and _in vivo_-derived follicular T helper cells. Immunity 35, 622–632 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Fahey, L. M. et al. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J. Exp. Med. 208, 987–999 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• King, I. L. & Mohrs, M. IL-4–producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206, 1001–1007 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Glatman Zaretsky, A. et al. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206, 991–999 (2009).
  Article CAS PubMed Google Scholar
• Bauquet, A. T. et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH17 cells. Nature Immunol. 10, 167–175 (2009).
  Article CAS Google Scholar
• Huber, M. et al. IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc. Natl Acad. Sci. USA 105, 20846–20851 (2008).
  Article PubMed Google Scholar
• Ma, C. S. et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119, 3997–4008 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, C. S. et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205, 1551–1557 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mitsdoerffer, M. et al. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc. Natl Acad. Sci. USA 107, 14292–14297 (2010).
  Article PubMed Google Scholar
• Nurieva, R. I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Manzo, A. et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum. 58, 3377–3387 (2008).
  Article CAS PubMed Google Scholar
• Tokoyoda, K. et al. Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity 30, 721–730 (2009).
  Article CAS PubMed Google Scholar
• Odegard, J. M. et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J. Exp. Med. 205, 2873–2886 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Marinkovic, T. et al. Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J. Clin. Invest. 116, 2622–2632 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Muniz, L. R., Pacer, M. E., Lira, S. A. & Furtado, G. C. A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. J. Immunol. 187, 828–834 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• GeurtsvanKessel, C. H. et al. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J. Exp. Med. 206, 2339–2349 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Halle, S. 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. 206, 2593–2601 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Manser, T. Textbook germinal centers? J. Immunol. 172, 3369–3375 (2004).
  Article CAS PubMed Google Scholar
• Teng, G. & Papavasiliou, F. N. Immunoglobulin somatic hypermutation. Annu. Rev. Genet. 41, 107–120 (2007).
  Article CAS PubMed Google Scholar
• Stavnezer, J., Guikema, J. E. & Schrader, C. E. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26, 261–292 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).
  Article CAS PubMed Google Scholar
• Barreto, V., Reina-San-Martin, B., Ramiro, A. R., McBride, K. M. & Nussenzweig, M. C. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol. Cell 12, 501–508 (2003).
  Article CAS PubMed Google Scholar
• Bombardieri, M. 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 Sjogren's syndrome. J. Immunol. 179, 4929–4938 (2007).
  Article CAS PubMed Google Scholar
• Humby, F. et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 6, e1 (2009). This study describes the functional properties of ELSs in patients with rheumatoid arthritis.
  Article PubMed PubMed Central Google Scholar
• Nacionales, D. C. et al. B cell proliferation, somatic hypermutation, class switch recombination, and autoantibody production in ectopic lymphoid tissue in murine lupus. J. Immunol. 182, 4226–4236 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Serafini, B. et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Takahashi, E. et al. Oral clarithromycin enhances airway immunoglobulin A (IgA) immunity through induction of IgA class switching recombination and B-cell-activating factor of the tumor necrosis factor family molecule on mucosal dendritic cells in mice infected with influenza A virus. J. Virol. 86, 10924–10934 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Cheng, J. et al. Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal. Proc. Natl Acad. Sci. USA 108, 5560–5565 (2011).
  Article PubMed Google Scholar
• Scheel, T., Gursche, A., Zacher, J., Haupl, T. & Berek, C. V-region gene analysis of locally defined synovial B and plasma cells reveals selected B cell expansion and accumulation of plasma cell clones in rheumatoid arthritis. Arthritis Rheum. 63, 63–72 (2011). This study provides a functional evaluation of ELSs in patients with rheumatoid arthritis.
  Article CAS PubMed Google Scholar
• Stott, D. I., Hiepe, F., Hummel, M., Steinhauser, G. & Berek, C. Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren's syndrome. J. Clin. Invest. 102, 938–946 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Grewal, J. S. et al. Salivary glands act as mucosal inductive sites via the formation of ectopic germinal centers after site-restricted MCMV infection. FASEB J. 25, 1680–1696 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Khader, S. A. et al. In a murine tuberculosis model, the absence of homeostatic chemokines delays granuloma formation and protective immunity. J. Immunol. 183, 8004–8014 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Mazzucchelli, L. et al. BCA-1 is highly expressed in _Helicobacter pylori_-induced mucosa-associated lymphoid tissue and gastric lymphoma. J. Clin. Invest. 104, R49–R54 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Mosnier, J. F. et al. The intraportal lymphoid nodule and its environment in chronic active hepatitis C: an immunohistochemical study. Hepatology 17, 366–371 (1993).
  Article CAS PubMed Google Scholar
• Ulrichs, T. et al. Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J. Pathol. 204, 217–228 (2004).
  Article PubMed Google Scholar
• Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nature Med. 10, 927–934 (2004).
  Article CAS PubMed Google Scholar
• Xu, B. et al. Lymphocyte homing to bronchus-associated lymphoid tissue (BALT) is mediated by L-selectin/PNAd, α4β1 integrin/VCAM-1, and LFA-1 adhesion pathways. J. Exp. Med. 197, 1255–1267 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Moyron-Quiroz, J. E. et al. Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25, 643–654 (2006).
  Article CAS PubMed Google Scholar
• Manzo, A., Bombardieri, M., Humby, F. & Pitzalis, C. Secondary and ectopic lymphoid tissue responses in rheumatoid arthritis: from inflammation to autoimmunity and tissue damage/remodeling. Immunol. Rev. 233, 267–285 (2010).
  Article CAS PubMed Google Scholar
• Bombardieri, M. & Pitzalis, C. Ectopic lymphoid neogenesis and lymphoid chemokines in Sjogren's syndrome: at the interplay between chronic inflammation, autoimmunity and lymphomagenesis. Curr. Pharm. Biotechnol. 13, 1989–1996 (2012).
  Article CAS PubMed Google Scholar
• Berrih-Aknin, S., Ragheb, S., Le Panse, R. & Lisak, R. P. Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. Autoimmun Rev. 12, 885–893 (2013).
  Article CAS PubMed Google Scholar
• Armengol, M. P. et al. Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am. J. Pathol. 159, 861–873 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Ekland, E. H., Forster, R., Lipp, M. & Cyster, J. G. Requirements for follicular exclusion and competitive elimination of autoantigen-binding B cells. J. Immunol. 172, 4700–4708 (2004).
  Article CAS PubMed Google Scholar
• Le Pottier, L. et al. Ectopic germinal centers are rare in Sjogren's syndrome salivary glands and do not exclude autoreactive B cells. J. Immunol. 182, 3540–3547 (2009).
  Article CAS PubMed Google Scholar
• Salomonsson, S. et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum. 48, 3187–3201 (2003).
  Article CAS PubMed Google Scholar
• Shimaoka, Y. et al. Nurse-like cells from bone marrow and synovium of patients with rheumatoid arthritis promote survival and enhance function of human B cells. J. Clin. Invest. 102, 606–618 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Pender, M. P. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 24, 584–588 (2003).
  Article CAS PubMed Google Scholar
• Cavalcante, P. et al. Epstein–Barr virus persistence and reactivation in myasthenia gravis thymus. Ann. Neurol. 67, 726–738 (2010).
  PubMed Google Scholar
• Croia, C. et al. Epstein–Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis. Ann. Rheum. Dis. 72, 1559–1568 (2013). This study provides an example of how viral infection may influence the development and functional properties of ELSs in autoimmune disease.
  Article CAS PubMed Google Scholar
• Croia, C. et al. Implication of Epstein–Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjogren's syndrome. Arthritis Rheum. http://dx.doi.org/10.1002/art.38726 (2014).
• Schonbeck, S., Padberg, F., Hohlfeld, R. & Wekerle, H. Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis. J. Clin. Invest. 90, 245–250 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Thaunat, O. Pathophysiologic significance of B-cell clusters in chronically rejected grafts. Transplantation 92, 121–126 (2011).
  Article PubMed Google Scholar
• Thaunat, O. et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J. Immunol. 185, 717–728 (2010). This study provides an example of how the development of severe inflammation following chronic transplant rejection is accompanied by lymphoid neogenesis.
  Article CAS PubMed Google Scholar
• Brown, K., Sacks, S. H. & Wong, W. Tertiary lymphoid organs in renal allografts can be associated with donor-specific tolerance rather than rejection. Eur. J. Immunol. 41, 89–96 (2011).
  Article CAS PubMed Google Scholar
• Le Texier, L. et al. Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile. Am. J. Transplant. 11, 429–438 (2011).
  Article CAS PubMed Google Scholar
• Dieu-Nosjean, M. C. et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26, 4410–4417 (2008).
  Article CAS PubMed Google Scholar
• de Chaisemartin, L. et al. Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res. 71, 6391–6399 (2011).
  Article CAS PubMed Google Scholar
• Bergomas, F. et al. Tertiary intratumor lymphoid tissue in colo-rectal cancer. Cancers 4, 1–10 (2011).
  Article PubMed PubMed Central Google Scholar
• Nzula, S., Going, J. J. & Stott, D. I. Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinomas. Cancer Res. 63, 3275–3280 (2003).
  CAS PubMed Google Scholar
• Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).
  Article CAS PubMed Google Scholar
• Goc, J., Fridman, W. H., Sautes-Fridman, C. & Dieu-Nosjean, M. C. Characteristics of tertiary lymphoid structures in primary cancers. Oncoimmunology 2, e26836 (2013).
  Article PubMed PubMed Central Google Scholar
• Hamanishi, J. et al. Activated local immunity by CC chemokine ligand 19-transduced embryonic endothelial progenitor cells suppresses metastasis of murine ovarian cancer. Stem Cells 28, 164–173 (2010).
  CAS PubMed Google Scholar
• Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Maiti, A. K. et al. Confirmation of an association between rs6822844 at the Il2–Il21 region and multiple autoimmune diseases: evidence of a general susceptibility locus. Arthritis Rheum. 62, 323–329 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• van Heel, D. A. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genet. 39, 827–829 (2007).
  Article CAS PubMed Google Scholar
• Jones, J. L. et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 119, 2052–2061 (2009). This study provides an example of how clinical intervention aids the mechanistic understanding of ELS development in the context of disease.
  CAS PubMed PubMed Central Google Scholar
• Mells, G. F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nature Genet. 43, 329–332 (2011).
  Article CAS PubMed Google Scholar
• Lessard, C. J. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome. Nature Genet. 45, 1284–1292 (2013).
  Article CAS PubMed Google Scholar
• Zhang, J. et al. Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians. Hum. Mol. Genet. 23, 524–533 (2014).
  Article CAS PubMed Google Scholar
• Lill, C. M. et al. MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. Brain 136, 1778–1782 (2013).
  Article PubMed PubMed Central Google Scholar
• Hislop, A. D., Taylor, G. S., Sauce, D. & Rickinson, A. B. Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annu. Rev. Immunol. 25, 587–617 (2007).
  Article CAS PubMed Google Scholar
• Thorley-Lawson, D. A. Epstein–Barr virus: exploiting the immune system. Nature Rev. Immunol. 1, 75–82 (2001).
  Article CAS Google Scholar
• Pitzalis, C., Kelly, S. & Humby, F. New learnings on the pathophysiology of RA from synovial biopsies. Curr. Opin. Rheumatol. 25, 334–344 (2013).
  Article PubMed Google Scholar
• van de Sande, M. G. et al. Presence of lymphocyte aggregates in the synovium of patients with early arthritis in relationship to diagnosis and outcome: is it a constant feature over time? Ann. Rheum. Dis. 70, 700–703 (2011).
  Article PubMed Google Scholar
• Ulrichs, T. et al. Differential organization of the local immune response in patients with active cavitary tuberculosis or with nonprogressive tuberculoma. J. Infect. Dis. 192, 89–97 (2005).
  Article PubMed Google Scholar
• Shoenfeld, Y. & Isenberg, D. A. Mycobacteria and autoimmunity. Immunol. Today 9, 178–182 (1988).
  Article CAS PubMed Google Scholar
• Sansonno, D. et al. Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis. Blood 112, 1620–1627 (2008).
  Article CAS PubMed Google Scholar
• Sansonno, D. et al. Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J. Immunol. 160, 3594–3601 (1998).
  CAS PubMed Google Scholar
• Ramos-Casals, M., De Vita, S. & Tzioufas, A. G. Hepatitis C virus, Sjogren's syndrome and B-cell lymphoma: linking infection, autoimmunity and cancer. Autoimmun Rev. 4, 8–15 (2005).
  Article PubMed Google Scholar
• Deutsch, A. J. et al. MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation. Blood 109, 3500–3504 (2007).
  Article CAS PubMed Google Scholar
• Hussell, T., Isaacson, P. G., Crabtree, J. E. & Spencer, J. _Helicobacter pylori_-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J. Pathol. 178, 122–127 (1996).
  Article CAS PubMed Google Scholar
• Wohrer, S., Troch, M. & Raderer, M. Therapy of gastric mucosa-associated lymphoid tissue lymphoma. Expert Opin. Pharmacother. 8, 1263–1273 (2007).
  Article PubMed Google Scholar
• Bende, R. J. et al. Among B cell non-Hodgkin's lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity. J. Exp. Med. 201, 1229–1241 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Klimiuk, P. A. et al. Circulating tumour necrosis factor-α and soluble tumour necrosis factor receptors in patients with different patterns of rheumatoid synovitis. Ann. Rheum. Dis. 62, 472–475 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kotake, S. et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum. 44, 1003–1012 (2001).
  Article CAS PubMed Google Scholar
• Dharmapatni, A. A. et al. TWEAK and Fn14 expression in the pathogenesis of joint inflammation and bone erosion in rheumatoid arthritis. Arthritis Res. Ther. 13, R51 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, A. et al. In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J. Immunol. 186, 1849–1860 (2011).
  Article CAS PubMed Google Scholar
• Magliozzi, R. et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann. Neurol. 68, 477–493 (2010).
  Article CAS PubMed Google Scholar
• Coronella-Wood, J. A. & Hersh, E. M. Naturally occurring B-cell responses to breast cancer. Cancer Immunol. Immunother. 52, 715–738 (2003).
  Article PubMed Google Scholar
• Denkert, C. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28, 105–113 (2010).
  Article CAS PubMed Google Scholar
• Krell, J., Frampton, A. E. & Stebbing, J. The clinical significance of tumor infiltrating lymphoctyes in breast cancer: does subtype matter? BMC Cancer 12, 135 (2012).
  Article PubMed PubMed Central Google Scholar
• Liu, W., Peng, Y. & Tobin, D. J. A new 12-gene diagnostic biomarker signature of melanoma revealed by integrated microarray analysis. PeerJ 1, e49 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Jonsson, G. et al. Gene expression profiling-based identification of molecular subtypes in stage IV melanomas with different clinical outcome. Clin. Cancer Res. 16, 3356–3367 (2010).
  Article PubMed Google Scholar
• DiLillo, D. J., Yanaba, K. & Tedder, T. F. B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J. Immunol. 184, 4006–4016 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Shiao, S. L., Ganesan, A. P., Rugo, H. S. & Coussens, L. M. Immune microenvironments in solid tumors: new targets for therapy. Genes Dev. 25, 2559–2572 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Chiavolini, D. et al. Bronchus-associated lymphoid tissue (BALT) and survival in a vaccine mouse model of tularemia. PLoS ONE 5, e11156 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Thaunat, O. et al. B cell survival in intragraft tertiary lymphoid organs after rituximab therapy. Transplantation 85, 1648–1653 (2008).
  Article CAS PubMed Google Scholar
• Badot, V. et al. Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis. Arthritis Res. Ther. 11, R57 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Fava, R. A. et al. A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis. J. Immunol. 171, 115–126 (2003).
  Article CAS PubMed Google Scholar
• Gatumu, M. K. et al. Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjogren's syndrome in salivary glands of non-obese diabetic mice. Arthritis Res. Ther. 11, R24 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, Y. et al. Recruitment and activation of naive T cells in the islets by lymphotoxin-β receptor-dependent tertiary lymphoid structure. Immunity 25, 499–509 (2006).
  Article CAS PubMed Google Scholar
• Emu, B. et al. Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin-α: results of a phase I randomized, placebo-controlled trial. Arthritis Res. Ther. 14, R6 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Zheng, B. et al. CXCL13 neutralization reduces the severity of collagen-induced arthritis. Arthritis Rheum. 52, 620–626 (2005).
  Article CAS PubMed Google Scholar
• Kramer, J. M., Klimatcheva, E. & Rothstein, T. L. CXCL13 is elevated in Sjogren's syndrome in mice and humans and is implicated in disease pathogenesis. J. Leukoc. Biol. 94, 1079–1089 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Henry, R. A. & Kendall, P. L. 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. 185, 1460–1465 (2010).
  Article CAS PubMed Google Scholar
• Pelletier, D. & Hafler, D. A. Fingolimod for multiple sclerosis. N. Engl. J. Med. 366, 339–347 (2012).
  Article CAS PubMed Google Scholar
• Mehling, M. et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71, 1261–1267 (2008).
  Article CAS PubMed Google Scholar
• Young, D. A. et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum. 56, 1152–1163 (2007).
  Article CAS PubMed Google Scholar
• Herber, D. et al. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J. Immunol. 178, 3822–3830 (2007).
  Article CAS PubMed Google Scholar
• Frey, O. et al. Inducible costimulator (ICOS) blockade inhibits accumulation of polyfunctional T helper 1/T helper 17 cells and mitigates autoimmune arthritis. Ann. Rheum. Dis. 69, 1495–1501 (2010).
  Article CAS PubMed Google Scholar
• Hu, Y. L., Metz, D. P., Chung, J., Siu, G. & Zhang, M. B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J. Immunol. 182, 1421–1428 (2009).
  Article CAS PubMed Google Scholar
• Nanji, S. A. et al. Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse. Diabetes 55, 27–33 (2006).
  Article CAS PubMed Google Scholar
• Wengner, A. M. et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 56, 3271–3283 (2007).
  Article CAS PubMed Google Scholar
• Lee, B. H., Carcamo, W. C., Chiorini, J. A., Peck, A. B. & Nguyen, C. Q. Gene therapy using IL-27 ameliorates Sjogren's syndrome-like autoimmune exocrinopathy. Arthritis Res. Ther. 14, R172 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).
  Article PubMed Google Scholar
• Ludewig, B., Odermatt, B., Landmann, S., Hengartner, H. & Zinkernagel, R. M. Dendritic cells induce autoimmune diabetes and maintain disease via de novo formation of local lymphoid tissue. J. Exp. Med. 188, 1493–1501 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Astorri, E. 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. 185, 3359–3368 (2010).
  Article CAS PubMed Google Scholar
• Sharifi, S., Murphy, M., Loda, M., Pinkus, G. S. & Khettry, U. Nodular lymphoid lesion of the liver: an immune-mediated disorder mimicking low-grade malignant lymphoma. Am. J. Surg. Pathol. 23, 302–308 (1999).
  Article CAS PubMed Google Scholar
• Grant, A. J., Lalor, P. F., Hubscher, S. G., Briskin, M. & Adams, D. H. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33, 1065–1072 (2001).
  Article CAS PubMed Google Scholar
• Grant, A. J. et al. Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am. J. Pathol. 160, 1445–1455 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Hill, M. E., Shiono, H., Newsom-Davis, J. & Willcox, N. The myasthenia gravis thymus: a rare source of human autoantibody-secreting plasma cells for testing potential therapeutics. J. Neuroimmunol. 201–202, 50–56 (2008).
• Nacionales, D. C. et al. Type I interferon production by tertiary lymphoid tissue developing in response to 2,6,10,14-tetramethyl-pentadecane (pristane). Am. J. Pathol. 168, 1227–1240 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Houtkamp, M. A., de Boer, O. J., van der Loos, C. M., van der Wal, A. C. & Becker, A. E. Adventitial infiltrates associated with advanced atherosclerotic plaques: structural organization suggests generation of local humoral immune responses. J. Pathol. 193, 263–269 (2001).
  Article CAS PubMed Google Scholar
• Grabner, R. et al. Lymphotoxin-β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged _ApoE_−/− mice. J. Exp. Med. 206, 233–248 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Carlsen, H. S., Baekkevold, E. S., Johansen, F. E., Haraldsen, G. & Brandtzaeg, P. B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue. Gut 51, 364–371 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Weninger, W. et al. Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis. J. Immunol. 170, 4638–4648 (2003).
  Article CAS PubMed Google Scholar
• Surawicz, C. M. & Belic, L. Rectal biopsy helps to distinguish acute self-limited colitis from idiopathic inflammatory bowel disease. Gastroenterology 86, 104–113 (1984).
  Article CAS PubMed Google Scholar
• Kaiserling, E. Newly-formed lymph nodes in the submucosa in chronic inflammatory bowel disease. Lymphology 34, 22–29 (2001).
  CAS PubMed Google Scholar
• McNamee, E. N. et al. Ectopic lymphoid tissue alters the chemokine gradient, increases lymphocyte retention and exacerbates murine ileitis. Gut 62, 53–62 (2013).
  Article CAS PubMed Google Scholar
• Demoor, T. et al. Role of lymphotoxin-α in cigarette smoke-induced inflammation and lymphoid neogenesis. Eur. Respir. J. 34, 405–416 (2009).
  Article CAS PubMed Google Scholar
• Hogg, J. C. et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 2645–2653 (2004).
  Article CAS PubMed Google Scholar
• Van Pottelberge, G. R. et al. Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD. Eur. Respir. J. 36, 781–791 (2010).
  Article CAS PubMed Google Scholar
• Nielsen, J. S. et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27− memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 18, 3281–3292 (2012).
  Article CAS PubMed Google Scholar
• Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).
  Article CAS PubMed Google Scholar
• Eisenthal, A. et al. Expression of dendritic cells in ovarian tumors correlates with clinical outcome in patients with ovarian cancer. Hum. Pathol. 32, 803–807 (2001).
  Article CAS PubMed Google Scholar
• Yeung, M. M. et al. Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-γδ expression. Gut 47, 215–227 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Winter, S. et al. The chemokine receptor CXCR5 is pivotal for ectopic mucosa-associated lymphoid tissue neogenesis in chronic _Helicobacter pylori_-induced inflammation. J. Mol. Med. 88, 1169–1180 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Shomer, N. H., Fox, J. G., Juedes, A. E. & Ruddle, N. H. _Helicobacter_-induced chronic active lymphoid aggregates have characteristics of tertiary lymphoid tissue. Infect. Immun. 71, 3572–3577 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ghosh, S., Steere, A. C., Stollar, B. D. & Huber, B. T. In situ diversification of the antibody repertoire in chronic Lyme arthritis synovium. J. Immunol. 174, 2860–2869 (2005).
  Article CAS PubMed Google Scholar
• Rangel-Moreno, J. et al. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30, 731–743 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Beelen, R. H., Oosterling, S. J., van Egmond, M., van den Born, J. & Zareie, M. Omental milky spots in peritoneal pathophysiology (spots before your eyes). Perit. Dial. Int. 25, 30–32 (2005).
  PubMed Google Scholar
• Di Paolo, N. et al. Omental milky spots and peritoneal dialysis — review and personal experience. Perit. Dial. Int. 25, 48–57 (2005).
  PubMed Google Scholar
• Hiramatsu, K. et al. Inhalation of diesel exhaust for three months affects major cytokine expression and induces bronchus-associated lymphoid tissue formation in murine lungs. Exp. Lung Res. 29, 607–622 (2003).
  Article CAS PubMed Google Scholar
• Mahendra, G. et al. Necrotic and inflammatory changes in metal-on-metal resurfacing hip arthroplasties. Acta Orthop. 80, 653–659 (2009).
  Article PubMed PubMed Central Google Scholar
• Perros, F. et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 185, 311–321 (2012).
  Article PubMed Google Scholar