Key Points
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Lymphoid neogenesis that is induced during highly destructive, chronic inflammatory processes, such as autoimmunity and infection, leads to the formation of ectopic germinal centres (GCs) and T-cell areas. Tertiary lymphoid organs (TLOs) are embedded in the target tissue and lack afferent lymph vessels.
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The direct access to antigen and the microarchitectural differences between secondary lymphoid organs (SLOs) and TLOs might determine whether the immune responses induced in TLOs are qualitatively different from those that are induced in canonical SLOs.
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The molecular mechanisms that underlie the formation and maintenance of SLOs and TLOs are remarkably similar. In both processes, lymphotoxin-α1β2 (LTα1β2) and lymphoid chemokines, such as CC-chemokine ligand 19 (CCL19), CCL21, CXC-chemokine ligand 12 (CXCL12) and CXCL13, that regulate lymphocyte homing and compartmentalization have a key role.
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In addition to the lymphotoxin-driven chemokine loop, antigenic stimulation is required to induce and maintain TLO formation.
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There are marked differences in the degree of permissiveness of different tissues in supporting TLO formation, indicating that the host tissue actively contributes to this process.
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In some autoimmune diseases, TLOs fulfil many of the criteria for having a pathological role in the disease process. These include: features of an active GC reaction, presence of plasma cells that produce autoantibodies and correlation with circulating antibody titres.
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TLOs that form in infected tissues most probably have a protective role and function to contain local infection, but they might enhance the risk of autoimmunity.
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Several tools are available that inhibit lymphoid tissue formation by interfering with adhesion molecules, LTα1β2 or lymphoid chemokines. Suppression of lymphoid neogenesis could be a useful strategy to block chronic inflammation, particularly in autoimmune diseases.
Abstract
The frequent observation of organized lymphoid structures that resemble secondary lymphoid organs in tissues that are targeted by chronic inflammatory processes, such as autoimmunity and infection, has indicated that lymphoid neogenesis might have a role in maintaining immune responses against persistent antigens. In this Review, we discuss recent progress in several aspects of lymphoid neogenesis, focusing on the similarities with lymphoid tissue development, the mechanisms of induction, functional competence and pathophysiological significance. As more information on these issues becomes available, a better understanding of the role of lymphoid neogenesis in promoting chronic inflammation might eventually lead to new strategies to target immunopathological processes.
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References
Söderström, N. & Biörklund, A. Organization of the invading lymphoid tissue in human lymphoid thyroiditis. Scand. J. Immunol. 3, 295–301 (1974).
Levine, G. D. & Rosai, J. Thymic hyperplasia and neoplasia: a review of current concepts. Hum. Pathol. 9, 495–515 (1978).
Prineas, J. W. Multiple sclerosis: Presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord. Science 103, 1123–1125 (1979).
Knecht, H., Saremaslani, P. & Hedinger, C. Immunohistological findings in Hashimoto's thyroiditis, focal lymphocytic thyroiditis and thyroiditis de Quervain. Virchows Arch. 393, 251–231 (1981).
Thomas, J. A., Willcox, H. N. & Newsom-Davis, J. Immunohistological studies of the thymus in myasthenia gravis. Correlation with clinical state and thymocyte culture responses. J. Neuroimmunol. 3, 319–335 (1982).
Young, C. L. & Adamson, T. C., Vaughan, J. H., Fox, R. I. Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum. 27, 32–39 (1984).
Ruddle, N. Lymphoid neo-organogenesis: lymphotoxin's role in inflammation and development. Immunol. Res. 19, 119–125 (1999).
Hjelmström, P. Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J. Leukoc. Biol. 69, 331–339 (2001).
Ansel, K. M. & Cyster, J. G. Chemokines in lymphopoiesis and lymphoid organ development. Curr. Opin. Immunol. 13, 172–179 (2001).
Muller, G., Hopken, U. E. & Lipp, M. The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol. Rev. 195, 117–135 (2003).
Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).
Nishikawa, S., Honda, K., Vieira, P. & Yoshida, H. Organogenesis of peripheral lymphoid organs. Immunol. Rev. 195, 72–80 (2003).
Cupedo, T. & Mebius, R. E. Role of chemokines in the development of secondary and tertiary lymphoid tissue. Semin. Immunol. 15, 243–248 (2003).
Magalhães, R., Stiehl, P., Morawietz, L. & Berek, C. Morphological and molecular pathology of the B cell response in synovitis of rheumatoid arthritis. Virchows Arch. 441, 415–427 (2002).
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). This paper provides the first evidence of functionally competent germinal centres that produce pathogenic autoantibodies in the thyroid during autoimmune disease.
Salomonsson, S. et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome. Arthritis Rheum. 48, 3187–3201 (2003).
Manzo, A. et al. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur. J. Immunol. 35, 1347–1359 (2005).
Takemura, S. et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).
MacLennan, I. C. M. Germinal centers. Ann. Rev. Immunol. 12, 117–139 (1994).
Park, C. S. & Choi, Y. S. How do follicular dendritic cells interact intimately with B cells in the germinal center? Immunology 114, 2–10 (2005).
Corcione, A. et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc. Natl Acad. Sci. USA 101, 11064–11069 (2004).
Moser, B. & Eberl, L. Lymphocyte traffic control by chemokines: follicular B helper T cells. Immunol. Lett. 22, 105–112 (2003).
Brandtzaeg, P. & Pabst R. Let's go mucosal: communication on slippery ground. Trends Immunol. 25, 570–577 (2004).
von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph node. Nature Rev. Immunol. 3, 867–878 (2003).
Fu, Y. & Chaplin, D. D. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17, 399–433 (1999).
Gommerman, J. L. & Browning, J. L. Lymphotoxin/LIGHT, lymphoid microenvironments and autoimmune disease. Nature Rev. Immunol. 3, 642–655 (2003).
Ware, C. F. Network communications: lymphotoxins, LIGHT and TNF. Annu. Rev. Immunol. 23, 787–819 (2005).
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). This paper was the first to show that expression of LTα in a non-lymphoid tissue induces inflammation with lymphoid neogenesis.
Cuff C. A. et al. Lymphotoxin α3 induces chemokines and adhesion molecules: insight into the role of LTα in inflammation and lymphoid organ development. J. Immunol. 161, 6853–6860 (1998).
Hjelmström, P. et al. Lymphoid tissue homing chemokines are expressed in chronic inflammation. Am. J. Pathol. 156, 1133–1138 (2000).
Drayton, D. L. et al. 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).
Schrama, D. et al. Targeting of lymphotoxin-α to the tumour elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14, 111–121 (2001). This paper shows that delivery of LTα into an experimental tumour leads to the formation of ectopic lymphoid tissue, which sustains an antitumour immune response.
Kim, H. -J. et al. Establishment of early lymphoid infrastructure in transplanted tumours mediated by local production of lymphotoxin α in the combined absence of functional B and T cells. J. Immunol. 172, 4037–4047 (2004).
Yu, P. et al. Priming of naive T cells inside tumours leads to eradication of established tumours. Nature Immunol. 5, 141–149 (2004).
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).
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). This study highlights the influence of tissue-specific microenvironments on the induction of lymphoid neogenesis.
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). This paper shows that ectopically expressed CXCL13 is sufficient to induce lymphoid neogenesis.
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).
Martin, A. P. et al. A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. J. Immunol. 173, 4791–4798 (2004).
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). This paper was the first to show that lymphoid chemokine expression is associated with lymphoid neogenesis in an infectious disease.
Shi, K. 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. 166, 650–655 (2001).
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).
Armengol, M. P. et al. Chemokines determine local lymphoneogenesis and a reduction of circulating CXCR4+ T and CCR7 B and T lymphocytes in thyroid autoimmune diseases. J. Immunol. 170, 6320–6328 (2003).
Aust, G. et al. The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases. Eur. J. Endocrinol. 150, 225–234 (2004).
Page, G. & Miossec, P. Paired synovium and lymph nodes from rheumatoid arthritis patients differ in dendritic cell and chemokine expression. J. Pathol. 204, 28–38 (2004).
Serafini, B., Rosicarelli, B., Magliozzi, R. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004). This paper was the first to describe fully developed B-cell follicles in the meninges of patients with multiple sclerosis.
Faveeuw, C., Gagnerault, M. C. & Lepault, F. Expression of homing and adhesion molecules in infiltrated islets of Langerhans and salivary glands of nonobese diabetic mice. J. Immunol. 152, 5969–5978 (1994).
Yoneyama, H. et al. Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease. J. Exp. Med. 193, 35–49 (2001).
Katakai, T., Hara, T., Sugai, M., Gonda, H. & Shimizu, A. Th1-biased tertiary lymphoid tissue supported by CXC chemokine ligand-13-producing stromal network in chronic lesions of autoimmune gastritis. J. Immunol. 171, 4359–4368 (2003).
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).
Magliozzi, R., Columba-Cabezas, S., Serafini, B. & Aloisi, F. 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. 148, 11–23 (2004).
Bistrup, A. et al. Detection of a sulfontranserase (HEC-GlcNac6ST) in high endothelial venules of lymph nodes and in high endothelial venule-like vessels within ectopic lymphoid aggregates: relationship to the MECA-79 epitope. Am. J. Pathol. 164, 1635–1644 (2004).
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).
Carlsen, H. S., Baekkevold, E. S., Morton, H. C., Haraldsen, G. & Brandtzaeg, P. Monocyte-like and mature macrophages produce CXCL13 (B cell-attracting chemokine 1) in inflammatory lesions with lymphoid neogenesis. Blood 104, 3021–3027 (2004).
Amft, N. 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 Sjogren's syndrome. Arthritis Rheum. 44, 2633–2641 (2001).
Grant, A. J., Lalor, P., Hubscher, S. G., Briskin, M. & Adams, D. H. MAdCAM-1 expression is increased in primary sclerosing cholangitis and supports lymphocyte adhesion to hepatic endothelium: a mechanism to explain the recruitment of mucosal lymphocytes to the liver in inflammatory liver disease. Hepatology 33, 1065–1073 (2001).
Kobayashi, M. et al. Induction of peripheral lymph node addressin in human gastric mucosa infected by Helicobacter pylori. Proc. Natl Acad. Sci. USA 101, 17807–17812 (2004).
Barone, F. et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren's syndrome. Arthritis Rheum. 52, 1773–1784 (2005).
Wyatt, J. I. & Rathbone, B. J. Immune response of the gastric mucosa to Campylobacter pylori. Scand. J. Gastroenterol. Suppl. 142, 44–49 (1988).
Schröder, A. E., Greiner, A., Seyfert, C. & Berek, C. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 93, 221–225 (1996). This study provides the first evidence for antigen-driven B-cell responses in an autoimmune lesion.
Sims, G. P., Shiono, H., Willcox, N. & Stott, D. I. Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J. Immunol. 167, 1935–1944 (2001).
Camacho, S. A., Kosco-Vilbois, M. H. & Berek, C. The dynamic structure of the germinal center. Immunol. Today 19, 511–514 (1998).
Genta, R. M., Hammer, H. W. & Graham, D. Y. Gastric lymphoid follicles in Helicobacter pylori infection: frequency, distribution, and response to triple therapy. Hum. Pathol. 24, 577–583 (1993).
Kang, Y. M. et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J. Exp. Med. 195, 1325–1336 (2002). This paper highlights the importance of B-cell–T-cell interactions in the induction of ectopic germinal centres.
Manser, T. Textbook germinal centers? J. Immunol. 172, 3369–3375 (2004).
Cupedo T., Jansen, W., Krall, G. & Mebius, R. E. Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21, 655–667 (2004). This study provides evidence that immune activation is required for complete organization of ectopic lymphoid tissue.
Ludewig, B., Odermatt, B., Landmann, S., Hentgartner, 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).
Moyron-Quiroz, J. E. et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nature Med. 10, 927–934 (2004). This study shows that an infectious challenge can induce lymphoid neogenesis in LTα-deficient mice, which lack SLOs.
Perrier, P. et al. Distinct transcriptional programs activated by interleukin-10 with or without lipopolysaccharide in dendritic cells: induction of the B cell-activating chemokine, CXC chemokine ligand 13. J. Immunol. 172, 7031–7042 (2004).
Christopherson, K. W., Hood, A. F., Travers, J. B., Ramsey, H. & Hromas, R. A. Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases. Blood 101, 801–806 (2003).
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).
Chen, S. C. et al. Central nervous system inflammation and neurological disease in transgenic mice expressing the CC chemokine CCL21 in oligodendrocytes. J. Immunol. 168, 1009–1017 (2002).
Burman A. et al. A chemokine-dependent stromal induction mechanism for aberrant lymphocyte accumulation and compromised lymphatic return in rheumatoid arthritis. J. Immunol. 174, 1693–1700 (2005).
Carlsen, H. S., Haraldsen, G., Brandtzaeg, P. & Baekkevold, E. S. Disparate lymphoid chemokine expression in mice and men: no evidence of CCL21 synthesis by human high endothelial venules. Blood 106, 444–446 (2005).
Lindhout, E. et al. Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells. J. Immunol. 162, 5949–5956 (1999).
Parsonage, G. et al. A stromal address code defined by fibroblasts. Trends Immunol. 26, 150–156 (2005).
Ambrosini, E. et al. Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 64, 706–715 (2005).
Bofill, M. et al. Microenvironments in the normal thymus and the thymus in myasthenia gravis. Am. J. Pathol. 119, 462–473 (1985).
Roxanis, I., Micklem, K., McConville, J., Newsom-Davis, J. & Willcox, N. Thymic myoid cells and germinal center formation in myasthenia gravis; possible roles in pathogenesis. J. Neuroimmunol. 125, 185–197 (2002).
Randen, I., Mellbye, O. J., Forre, O. & Natvig, J. B. The identification of germinal centers and follicular dendritic cell networks in rheumatoid synovial tissue. Scand. J. Immunol. 41, 481–486 (1995).
Aziz, K. E., McCluskey, P. J. & Wakefield, D. Characterization of follicular dendritic cells in labial salivary glands of patients with primary Sjögren's syndrome: comparison with tonsillar lymphoid follicles. Ann. Rheum. Dis. 56, 140–143 (1997).
Uccelli, A., Aloisi, F. & Pistoia, V. Unveiling the enigma of the CNS as a B-cell fostering environment. Trends Immunol. 26, 254–259 (2005).
Campbell, D. A., Poulter, L. W., Janossy, G. & du Bois, R. M. Immunohistological analysis of lung tissue from patients with cryptogenic fibrosing alveolitis suggesting local expression of immune hypersensitivity. Thorax 40, 405–411 (1985).
Wallace, W. The immunological architecture of B-lymphocyte aggregates in cryptogenic fibrosing alveolitis. J. Pathol. 178, 323–329 (1996).
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 sindrome. J. Clin. Invest. 102, 938–946 (1998).
Kim, H. -J., Krenn, V., Steinhauser, G. & Berek, C. Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J. Immunol. 162, 3053–3062 (1999).
Qin, Y. et al. Clonal expansion and somatic hypermutation of VH genes of B cells from cerebrospinal fluid in multiple sclerosis. J. Clin. Invest. 102, 1045–1050 (1998).
Itoh, K et al. Immunoglobulin heavy chain variable region gene replacement as a mechanism for receptor revision in rheumatoid arthritis synovial tissue B lymphocytes. J. Exp. Med. 192, 1151–1164 (2000).
Zhang, Z., Wu, X., Limbaugh, B. H. & Bridges, S. L. Jr Expression of recombination-activating genes and terminal deoxynucleotidyl transferase and secondary rearrangement of immunoglobulin κ light chains in rheumatoid arthritis synovial tissue. Arthritis Rheum. 44, 2275–2284 (2001). This study shows that B-cell-receptor revision occurs in an autoimmune lesion, which indicates that there is a risk of generating new autoreactive B cells.
Szodoray P., Jellestad, P., Teague, M. & Jonsson, R. Attenuated apoptosis of B cell activating factor-expressing cells in primary Sjogren's syndrome. Lab. Invest. 83, 357–365 (2003).
Ohata, J. et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J. Immunol. 174, 864–870 (2005).
Krumbholz, M. et al. BAFF is produced by astrocytes and upregulated in multiple sclerosis lesions and primary central nervous system lymphoma. J. Exp. Med. 201, 195–200 (2005).
Shiono, H. et al. Failure to downregulate Bcl-2 protein in thymic germinal center B cells in myasthenia gravis. Eur. J. Immunol. 27, 805–809 (1997).
Takemura, S., Klimiuk, P. A., Braun, A., Goronzy, J. J. & Weyand, C. M. T cell activation in rheumatoid synovium is B cell dependent. J. Immunol. 167, 4710–4718 (2001).
Holmoy, T. et al. Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells. Eur. J. Immunol. 35, 1786–1794 (2005).
McMahon, E. J., Bailey, S. L., Vanderlugt Castenada, C., Waldner, H. & Miller, S. D. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Med. 11, 335–349 (2005).
Stolte, M. & Eidt, S. Lymphoid follicles in antral mucosa: immune response to Campylobacter pylori? J. Clin. Pathol. 42, 1269–1271 (1989).
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).
Murakami, J. et al. Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C. Hepatology 30, 143–150 (1999).
Sansonno, D. et al. Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur. J. Immunol. 34, 126–136 (2004).
Matsumoto, M. et al. Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-β receptor. J. Virol. 71, 1301–1309 (1997).
Steere, A. C., Duray, P. H. & Butcher, E. C. Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Arthritis Rheum. 31, 487–495 (1988).
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).
Slavin, R. G. et al. Localization of IgE to lung germinal lymphoid follicles in a patient with allergic bronchopulmonary aspergillosis. J. Allergy Clin. Immunol. 90, 1006–1008 (1992).
Chvatchko, Y., Kosco-Vilbois, M. H., Herren, S., Lefort, J. & Bonnefoy, J. -Y. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J. Exp. Med. 184, 2353–2360 (1996).
Ramshaw, A. L. & Parums, D. V. Immunohistochemical characterization of inflammatory cells associated with advanced atherosclerosis. Histopathology 17, 543–552 (1990).
Houtkamp, M. A. et al. Adventitial infiltrates associated with advanced atherosclerotic plaques: structural organization suggests generation of local humoral immune responses. J. Pathol. 193, 263–269 (2001).
Coronella, J. A. et al. Antigen-driven oligoclonal expansion of tumour-infiltrating B cells in infiltrating ductal carcinoma of the breast. J. Immunol. 169, 1829–1836 (2002).
Nzula, S., Going, J. J. & Stott, D. I. Antigen-driven clonal proliferation, somatic hypermutation, and selection of B lymphocytes infiltrating human ductal breast carcinoma. Cancer Res. 63, 3275–3280 (2003).
Baddoura, F. K. et al. Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection. Am. J. Transplant. 5, 510–516 (2005).
Zinkernagel, R. M. Localization dose and time of antigen determine immune reactivity. Semin. Immunol. 12, 163–171 (2000).
Matzinger, P. The danger model: A renewed sense of self. Science 296, 301–305 (2002).
Von Herrath, M. G., Fujinami, R. S. & Whitton, J. L. Microorganisms and autoimmunity: making the barren field fertile? Nature Rev. Microbiol. 1, 151–157 (2003).
Mattsson, A., Lönroth, H., Quiding-Järbrink, M. & Svennerholm, A. M. Induction of B cell responses in the stomach of Helicobacter pylori-infected subjects after oral cholera vaccination. J. Clin. Invest. 102, 51–56 (1998).
Buljevac, D. et al. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 125, 952–960 (2002).
Wu, Q. et al. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J. Exp. Med. 193, 1327–1332 (2001). This paper shows that treatment of NOD mice with an inhibitor of the lymphotoxin pathway reverses insulitis and causes disruption of pancreatic lymphoid aggregates.
Zheng, B. et al. CXCL13 neutralization reduces the severity of collagen-induced arthritis. Arthritis Rheum. 52, 620–626 (2005).
Gross, J. A. et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease: impaired B cell maturation in mice lacking BLyS. Immunity 15, 289–302 (2001).
Gommerman, J. L. et al. Manipulation of lymphoid microenvironments in nonhuman primates by an inhibitor of the lymphotoxin pathway. J. Clin. Invest. 110, 1359–1369 (2002).
Monson, N. L. et al. Effect of Rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch. Neurol. 62, 258–264 (2005).
Saccardi R. et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 105, 2601–2607 (2005).
Vissers, J. L. M., Hartgers, F. C., Lindhout, E., Figdor, C. G. & Adema, G. J. BLC (CXCL13) is expressed by different dendritic cell subsets in vitro and in vivo. Eur. J. Immunol. 31, 1544–1549 (2001).
Surawicz, C. M. & Belic L. Rectal biopsy helps to distinguish acute self-limiting colitis from idiopathic inflammatory bowel disease. Gastroenterology 86, 104–113 (1984).
Kaiserling, E. Newly formed lymph nodes in the submucosa in chronic inflammatory bowel disease. Lymphology 34, 22–29 (2001).
Mooij, P., de Wit, H. J. & Drexhage, H. A. An excess of dietary iodine accelerates the development of a thyroid-associated lymphoid tissue in autoimmune prone BB rats. Clin. Immunol. Immunopathol. 69, 189–198 (1993).
Oshima, C. et al. Induction of follicular gastritis following postthymectomy autoimmune gastritis in Helicobacter-pylori-infected BALB/c mice. Infect. Immun. 68, 100–106 (2000).
Acknowledgements
We thank M. P. Armengol for critically reading the manuscript and for useful suggestions. The work in the laboratory of F.A. is supported by the Italian Ministry of Health and Program of Collaboration between Istituto Superiore di Sanità and National Institutes of Health, and Sixth Framework Programme of the European Union (NeuroproMiSe). The work of the laboratory of R.P.-B. is supported by the Spanish Ministry of Health, Instituto de Salud Carlos III, Ministry of Education and Science (Interministerial de Ciencia y Tecnología (CICYT) Plan Nacional), the Department of Universities and Information Society (DURSI) of the Generalitat de Catalunya, Fundació la Marató de TV3 (Barcelona) and Sixth Framework Programme of the European Community (EURO-THYMAIDE).
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Glossary
- Somatic hypermutation
-
An accumulation of point mutations in the variable-region genes of immunoglobulin heavy and light chains that gives rise to high-affinity antibodies specific for a given antigen in a process known as affinity maturation. B cells that express high-affinity immunoglobulins on their surface are selected by limited amounts of the antigen and competition for survival factors.
- Immunoglobulin class switching
-
DNA rearrangement of the variable, diversity and junction (VDJ) regions from IgM to any of the IgG, IgA and IgE constant genes at the heavy-chain locus. Recombination occurs in repetitive sequences of DNA that are located upstream of each constant gene.
- Receptor revision
-
A molecular process, also known as editing, that involves secondary variable-region gene rearrangements (either in the heavy- or light-chain loci) that generate a new B-cell receptor with altered specificity.
- Canalicular system
-
A network of channels lined by fibroblastic reticular cells in the lymph-node cortex and paracortex. Conduits drain lymph (which consists mainly of water and low-molecular-weight molecules) from the subcapsular sinus to high endothelial venules (HEVs). Corridors are broad spaces around HEVs where emigrating lymphocytes are retained.
- Germinal centre
-
A highly specialized and dynamic microenvironment that gives rise to secondary B-cell follicles during an immune response. It is the principal site of B-cell maturation, which leads to the generation of memory B cells and plasma cells that produce high-affinity antibodies.
- High endothelial venule
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(HEV). A specialized venule that occurs in secondary lymphoid organs, except the spleen. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.
- Follicular dendritic cells
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(FDCs). Specialized reticular fibroblasts located in the germinal centre that present antigen to B cells through antigen–antibody complexes and promote B-cell survival and proliferation.
- Mucosa-associated lymphoid tissue
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(MALT). Lymphoid tissue that enables antigen sampling from the mucosal surfaces and stimulation of cognate naive B and T cells. Its function is to ensure a rapid protective response to invading pathogens and the induction of tolerance to innocuous soluble antigens and commensal bacteria.
- CD3−CD4+CD45+ haematopoietic inducer cells
-
A population of haematopoietic precursors that colonize lymphoid tissues early in development and can differentiate into dendritic cells and natural killer cells, but not B or T cells. They are essential components of lymphoid organogenesis, owing to their ability to express LTα1β2, interact with stromal cells and induce expression of adhesion molecules and chemokines that regulate lymphocyte migration and segregation in the lymphoid tissue.
- Stromal organizer cells
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Cells of mesenchymal origin that are activated by lymphoid cells through the lymphotoxin-β receptor to express adhesion molecules and chemokines that regulate lymphoid tissue development.
- Immune-privileged site
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Areas in the body with a decreased immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and uterus.
- Meninges
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Fibroblastic layers that ensheath the brain and spinal cord and line the subarachnoid space where the cerebrospinal fluid circulates. The meninges contain a resident population of macrophages and dendritic cells and are a less immune-privileged central-nervous-system compartment compared with the neural parenchyma.
- Anti-idiotypic network
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A peripheral immunoregulatory mechanism by which anti-idiotypic T cells and antibodies recognize idiotypic determinants residing within the variable or hypervariable regions (CDR2 and CDR3) of T-cell receptors or antibodies. Such a regulatory network is thought to have an important role in the regulation of autoimmune responses.
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Aloisi, F., Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6, 205–217 (2006). https://doi.org/10.1038/nri1786
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DOI: https://doi.org/10.1038/nri1786
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