Homing chemokines in rheumatoid arthritis
© BioMed Central Ltd 2002
Received: 17 December 2001
Accepted: 15 January 2002
Published: 31 January 2002
In about 20% of patients with rheumatoid arthritis, B and T lymphocytes recruited into the inflamed synovium are organized into complex microstructures, which resemble secondary lymphoid organs. The development of such lymphoid aggregates with germinal centers appears to contribute to the pathogenesis of the disease. Growing evidence indicates that chemokines and their receptors control the recruitment and positioning of leukocytes as well as their organization into node-like lymphoid structures. Here, we comment on recent studies highlighting the importance of chemokines in rheumatoid arthritis, in particular of B-cell-activating chemokine-1 in lymphoid neogenesis in the inflamed synovium.
KeywordsBCA-1 chemokine receptors chemokines CXCR5 ectopic follicles
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of the cartilage and bone in the joints . Despite the large research effort, neither the initiating event nor the perpetuating factors are clearly understood. The characteristic features of the disease are synovial lining hyperplasia and chronic infiltration of inflammatory cells including T lymphocytes, B lymphocytes, monocytes/macrophages and granulocytes. The hyperplastic lining layer is mainly composed of highly activated macrophage-like cells and proliferating fibroblast-like cells. The infiltrating lymphocytes are localized in the sublining tissue and are found around the blood vessels and in the stroma. Frequently, lymph-node-like aggregates are observed. Today, it is generally accepted that chemokines and their receptors are critical for the recruitment and positioning of cells in the inflamed synovium .
The human chemokine system comprises about 50 chemokines and 18 receptors [3–6]. Depending on the number and spacing of cysteine residues in the NH2-terminal region, chemokines are partitioned into four structural families (CXC, CC, CX3C and C), and depending on the their function in inflammation and immunity, they have recently been grouped into inflammatory (also called inducible) and homing (also called constitutive, lymphoid or housekeeping) chemokines. Inflammatory chemokines are expressed by many different tissue cells and by immigrating leukocytes on stimulation with proinflammatory cytokines and pathogens. The main function of these chemokines is to recruit effector cells of the innate and adaptive immune systems, including granulocytes, monocytes, natural killer cells and effector lymphocytes. Homing chemokines, by contrast, are constitutively expressed in discrete areas within lymphoid and non-lymphoid tissues. Such chemokines control the physiological traffic and homing of leukocytes, which mainly belong to the adaptive immune system. All chemokines act via seven transmembrane domain receptors that are coupled to guanosine-triphosphate-binding proteins .
Chemokines and their receptors in RA
Since it is well known that proinflammatory cytokines including tumour necrosis factor-α and IL-1β play a crucial role in the pathogenesis of RA, it is not surprising that inflammatory chemokines are found to be abundantly expressed in the inflamed RA synovium [8, 9]. Numerous studies have demonstrated that activated synovial fibroblasts and monocytes/macrophages are the main producers of chemokines, such as IL-8 (recently designated CXCL8 ), epithelial-neutrophil activating protein-78 (ENA-78 or CXCL5), monocyte-chemoattractant protein-1 (MCP-1 or CCL2), RANTES (regulated upon activation, normal T-cell expressed and secreted or CCL5) and macrophage inflammatory protein-1α (MIP-1α or CCL3) in RA synovial tissue, and that elevated levels of these chemokines are also detected in RA synovial fluids . IL-8 and ENA-78, which act on granulocytes, and MCP-1, RANTES and MIP-1α, which act primarily on monocytes and lymphocytes, are involved in the selective recruitment and activation of these cells. Recent studies have focused on the analysis of chemokine receptor expression in RA synovial T lymphocytes. The marked expression of the chemokine receptors CXCR3, CXCR6 and CCR5 on memory CD4+ T lymphocytes, which represent the predominant infiltrate the inflamed synovium, is consistent with their highly differentiated state [11–16]. These inflammatory chemokine receptors are prominently expressed on effector T lymphocytes (Th1 cells) that mediate a type 1 inflammation such as RA. Interestingly, it has also been demonstrated that the RA synovial memory CD4+ T lymphocytes express high levels of the chemokine receptor CXCR4, and that the ligand stromal cell-derived factor 1 (SDF-1 or CXCL12) is produced by synovial fibroblasts and endothelial cells [17, 18]. Since CXCR4 expression is enhanced by IL-15 and transforming growth factor-β, which are present in the inflamed joint, CXCR4 and SDF-1 have been suggested to be important in retaining the cells at this site [17, 18].
In about 20% of patients with RA, infiltrating T and B lymphocytes accumulate underneath the synovial lining layer and organize into lymphocyte aggregates with germinal centres (GCs) [19–21]. These ectopic lymphoid structures share many features with secondary lymphoid tissue and are thought to contribute to the pathogenesis of the disease . Some homing chemokines, which are mainly expressed in lymphoid tissues, have been implicated in the formation of lymphoid structures [5, 23]. The first indication of their involvement came from studies of CXCR5 (formerly known as Burkitt's lymphoma receptor-1 ), which is highly selective for the single chemokine B-cell-activating chemokine-1 (BCA-1) [25, 26]. The chemokine receptor CXCR5 is expressed in all circulating mature B lymphocytes and a subset of memory CD4+ T lymphocytes, whereas the expression of its ligand, BCA-1, is mainly confined to B-cell follicles [27–30]. Mice deficient in CXCR5 or B-lymphocyte chemoattractant (the murine homologue of human BCA-1) have a profound disturbance of follicle and GC formation in the spleen and Peyer's patches [31, 32]. Transgenic expression of BCA-1 in pancreatic islets, on the other hand, was shown to promote the development of lymph-node-like structures suggesting that BCA-1 can induce extranodal formation of organized lymphoid tissue . Lymphoid neogenesis is not only observed in RA, but also in several other chronic inflammatory diseases including Helicobacter pylori gastritis, Sjögren's syndrome, Hashimoto's thyroiditis and chronic hepatitis C . It is interesting to note that BCA-1 expression has been detected in all instances where extranodal lymphoid structures were examined, including H. pylori-induced, gastric-mucosa-associated lymphoid tissue and gastric lymphomas  as well as Sjögren's syndrome [35, 36]. Evidence for the critical involvement of BCA-1 in the formation of RA-associated follicular aggregates is summarized below.
BCA-1 in RA lymphoid follicle formation
Shi et al. and Takemura et al.  have reported that BCA-1 is expressed in the RA synovium. In both studies, BCA-1 mRNA was detected in all RA samples by reverse-transcriptase-mediated (RT)-PCR, but the transcript level was markedly higher in tissues with GC-positive lymphoid follicles than in tissues with GC-negative lymphoid follicles or with a diffuse lymphoid infiltrate. Immunohistochemical analysis showed that BCA-1 was mainly expressed within the GC, and the follicular dendritic cells (FDCs) were identified as cellular source [37, 38]. In addition, Takemura et al. report that endothelial cells lining small arterioles and capillaries, and synovial fibroblasts in the lining and sublining tissue stained positive for BCA-1 in samples either with or without GC-positive follicles. The presence on the endothelial cells suggests that BCA-1 may also be involved in transendothelial migration of CXCR5-positive cells . Evidence for a role of other homing chemokines in RA-associated lymphoid structure formation is less clear. For instance, ectopic lymphoid tissues were readily observed in mice carrying a transgene for secondary lymphoid tissue chemokine (SLC) . In RA synovial tissue, Takemura et al. detected SLC mRNA by RT-PCR, while Shi et al. did not confirm these findings by immunohistochemical analysis of SLC protein expression. Further research is required to determine whether SLC is important in leukocyte aggregation within the RA synovium.
Intriguingly, a perfect correlation was found between the occurrence of FDCs and GC-positive follicles in rheumatoid synovitis . GCs were observed only when FDCs, which produce BCA-1, were present in the follicle. Whether the FDCs develop locally from precursors or whether they are recruited to this area is not known. In either case, they are critical for lymphoid neogenesis in the synovium. Furthermore, the strict requirement of FDCs suggests that antigen recognition events play a major role.
Clearly, we do not yet understand the mechanisms of extranodal lymphoid follicle formation in RA. Recent studies provide evidence that chemokines have an inductive function in establishing these microstructures. The induction of BCA-1 and other lymphoid-tissue-inducing chemokines may convert the synovial lesion from an acute to a chronic state by amplifying antigen-specific responses. Blocking chemokine activity by means of chemokine receptor antagonists may thus have significant therapeutic value.
= B cell-activating chemokine-1 (CXCL13)
= CC-chemokine receptor
= CXC-chemokine receptor
= epithelial-neutrophil activating protein-78 (CXCL5)
= follicular dendritic cell
= germinal centre
= monocyte-chemoattractant protein-1 (CCL2)
= macrophage inflammatory protein-1α (CCL3)
= rheumatoid arthritis
- RANTES = regulated upon activation:
normal T cell expressed and secreted (CCL5)
= reverse-transcriptase-mediated polymerase chain reaction
= stromal cell-derived factor 1 (CXCL12)
= secondary lymphoid tissue chemokine (CCL21)
= T helper cell.
This work was supported by grant 31-55996.98 of the Swiss National Science Foundation. We thank Marco Baggiolini for critical reading of the manuscript.
- Harris ED: Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990, 322: 1277-1289.PubMedView ArticleGoogle Scholar
- Godessart N, Kunkel SL: Chemokines in autoimmune disease. Curr Opin Immunol. 2001, 13: 670-675. 10.1016/S0952-7915(01)00277-1.PubMedView ArticleGoogle Scholar
- Loetscher P, Moser B, Baggiolini M: Chemokines and their receptors in lymphocyte traffic and HIV infection. Adv Immunol. 2000, 74: 127-180.PubMedView ArticleGoogle Scholar
- Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA: International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev. 2000, 52: 145-176.PubMedGoogle Scholar
- Moser B, Loetscher P: Lymphocyte traffic control by chemokines. Nat Immunol. 2001, 2: 123-128. 10.1038/84219.PubMedView ArticleGoogle Scholar
- Mackay CR: Chemokines: immunology's high impact factors. Nat Immunol. 2001, 2: 95-101. 10.1038/84298.PubMedView ArticleGoogle Scholar
- Thelen M: Dancing to the tune of chemokines. Nat Immunol. 2001, 2: 129-134. 10.1038/84224.PubMedView ArticleGoogle Scholar
- Kunkel SL, Lukacs N, Kasama T, Strieter RM: The role of chemokines in inflammatory joint disease. J Leukocyte Biol. 1996, 59: 6-12.PubMedGoogle Scholar
- Szekanecz Z, Koch AE: Update on synovitis. Curr Rheumatol Rep. 2001, 3: 53-63.PubMedView ArticleGoogle Scholar
- Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity. 2000, 12: 121-127.PubMedView ArticleGoogle Scholar
- Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998, 101: 746-754.PubMedPubMed CentralView ArticleGoogle Scholar
- Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer J-M: CCR5 is characteristic of Th1 lymphocytes. Nature. 1998, 391: 344-345. 10.1038/34814.PubMedView ArticleGoogle Scholar
- Mack M, Brühl H, Gruber R, Jaeger C, Cihak J, Eiter V, Plachy J, Stangassinger M, Uhlig K, Schattenkirchner M, Schlöndorff D: Predominance of mononuclear cells expressing the chemokine receptor CCR5 in synovial effusions of patients with different forms of arthritis. Arthritis Rheum. 1999, 42: 981-988. 10.1002/1529-0131(199905)42:5<981::AID-ANR17>3.0.CO;2-4.PubMedView ArticleGoogle Scholar
- Suzuki N, Nakajima A, Yoshino S, Matsushima K, Yagita H, Okumura K: Selective accumulation of CCR5+ T lymphocytes into inflamed joints of rheumatoid arthritis. Int Immunol. 1999, 11: 553-559. 10.1093/intimm/11.4.553.PubMedView ArticleGoogle Scholar
- Kim CH, Kunkel EJ, Boisvert J, Johnston B, Campbell JJ, Genovese MC, Greenberg HB, Butcher EC: Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Invest. 2001, 107: 595-601.PubMedPubMed CentralView ArticleGoogle Scholar
- Patel DD, Zachariah JP, Whichard LP: CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol. 2001, 98: 39-45. 10.1006/clim.2000.4957.PubMedView ArticleGoogle Scholar
- Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana-Seisdedos F, Amara A, Curnow SJ, Lord JM, Scheel-Toellner D, Salmon M: Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol. 2000, 165: 3423-3429.PubMedView ArticleGoogle Scholar
- Nanki T, Hayashida K, El Gabalawy HS, Suson S, Shi K, Girschick HJ, Yavuz S, Lipsky PE: Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol. 2000, 165: 6590-6598.PubMedView ArticleGoogle Scholar
- Young CL, Adamson TC, Vaughan JH, Fox RI: Immunohistologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum. 1984, 27: 32-39.PubMedView ArticleGoogle Scholar
- Wagner UG, Kurtin PJ, Wahner A, Brackertz M, Berry DJ, Goronzy JJ, Weyand CM: The role of CD8+ CD40L+ T cells in the formation of germinal centers in rheumatoid synovitis. J Immunol. 1998, 161: 6390-6397.PubMedGoogle Scholar
- Hjelmstrom P: Lymphoid neogenesis: de novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukocyte Biol. 2001, 69: 331-339.PubMedGoogle Scholar
- Weyand CM, Goronzy JJ, Takemura S, Kurtin PJ: Cell-cell interactions in synovitis. Interactions between T cells and B cells in rheumatoid arthritis. Arthritis Res. 2000, 2: 457-463. 10.1186/ar128.PubMedPubMed CentralView ArticleGoogle Scholar
- Cyster JG: Chemokines and cell migration in secondary lymphoid organs. Science. 1999, 286: 2098-2102. 10.1126/science.286.5447.2098.PubMedView ArticleGoogle Scholar
- Dobner T, Wolf I, Emrich T, Lipp M: Differentiation-specific expression of a novel G protein-coupled receptor from Burkitt's lymphoma. Eur J Immunol. 1992, 22: 2795-2799.PubMedView ArticleGoogle Scholar
- Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B: B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med. 1998, 187: 655-660. 10.1084/jem.187.4.655.PubMedPubMed CentralView ArticleGoogle Scholar
- Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT: A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature. 1998, 391: 799-803. 10.1038/35876.PubMedView ArticleGoogle Scholar
- Förster R, Emrich T, Kremmer E, Lipp M: Expression of the G-protein-coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells. Blood. 1994, 84: 830-840.PubMedGoogle Scholar
- Cyster JG, Ngo VN, Ekland EH, Gunn MD, Sedgwick JD, Ansel KM: Chemokines and B-cell homing to follicles. Curr Top Microbiol Immunol. 1999, 246: 87-92.PubMedGoogle Scholar
- Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B: CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med. 2000, 192: 1553-1562. 10.1084/jem.192.11.1553.PubMedPubMed CentralView ArticleGoogle Scholar
- Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, Forster R: Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med. 2000, 192: 1545-1552. 10.1084/jem.192.11.1545.PubMedPubMed CentralView ArticleGoogle Scholar
- Förster R, Mattis AE, Kremmer E, Wolf E, Brem G, Lipp M: A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 1996, 87: 1037-1047.PubMedView ArticleGoogle Scholar
- Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG: A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature. 2000, 406: 309-314. 10.1016/S0370-2693(97)00683-7.PubMedView ArticleGoogle Scholar
- Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG: BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity. 2000, 12: 471-481.PubMedView ArticleGoogle Scholar
- Mazzucchelli L, Blaser A, Kappeler A, Schärli P, Laissue JA, Bag-giolini M, Uguccioni M: BCA-1 is highly expressed in Helicobacter pylori-induced mucosa-associated lymphoid tissue and gastric lymphoma. J Clin Invest. 1999, 104: R49-R54.PubMedPubMed CentralView ArticleGoogle Scholar
- Amft N, Curnow SJ, Scheel-Toellner D, Devadas A, Oates J, Crocker J, Hamburger J, Ainsworth J, Mathews J, Salmon M, Bowman SJ, Buckley CD: 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. 2001, 44: 2633-2641. 10.1002/1529-0131(200111)44:11<2633::AID-ART443>3.0.CO;2-9.PubMedView ArticleGoogle Scholar
- Xanthou G, Polihronis M, Tzioufas AG, Paikos S, Sideras P, Mout-sopoulos HM: "Lymphoid" chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjogren's syndrome patients: possible participation in lymphoid structure formation. Arthritis Rheum. 2001, 44: 408-418. 10.1002/1529-0131(200102)44:2<408::AID-ANR60>3.3.CO;2-S.PubMedView ArticleGoogle Scholar
- Shi K, Hayashida K, Kaneko M, Hashimoto J, Tomita T, Lipsky PE, Yoshikawa H, Ochi T: Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol. 2001, 166: 650-655.PubMedView ArticleGoogle Scholar
- Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O'Fallon WM, Goronzy JJ, Weyand CM: Lymphoid neogenesis in rheumatoid synovitis. J Immunol. 2001, 167: 1072-1080.PubMedView ArticleGoogle Scholar
- Schaerli P, Loetscher P, Moser B: Cutting edge: induction of follicular homing precedes effector th cell development. J Immunol. 2001, 167: 6082-6086.PubMedView ArticleGoogle Scholar
- Fan L, Reilly CR, Luo Y, Dorf ME, Lo D: Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol. 2000, 164: 3955-3959.PubMedView ArticleGoogle Scholar