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Chemokines in autoimmune disease
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Chemokines in autoimmune disease Nuria Godessart* and Steven L Kunkel† Growing evidence indicates that structural cells play a crucial role in the chronic inflammation of autoimmunity by their recruitment of chemokine-dependent cells. Members of the two functional classes of chemokines, inflammatory and homeostatic, seem to be involved in lymphocyte recruitment and survival, and in establishing ectopic lymphoid structures in the target organs of autoimmune diseases. Results from animal models suggest that chemokines are reasonable therapeutic targets in autoimmunity. Addresses *Department of Pharmacology, Almirall Prodesfarma Research Center, Cardener 68–74, 08028 Barcelona, Spain; e-mail: [email protected] † Department of Pathology, The University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA; e-mail: [email protected] Correspondence: Steven L Kunkel Current Opinion in Immunology 2001, 13:670–675 0952-7915/01/$ — see front matter © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations CNS central nervous system EAE experimental autoimmune encephalomyelitis MS multiple sclerosis RA rheumatoid arthritis
Introduction The clinical manifestations of various autoimmune diseases are usually the consequence of an initial strong immune response to a particular self-antigen, which leads to significant leukocyte activation/accumulation in the tissue of the target organ and subsequent pathology. The management of these disorders is frequently difficult, requiring the use of potent, often cytotoxic, immunosuppressive therapies. These treatment strategies reflect, in part, our limited understanding of the mechanisms that allow leukocytes to initiate and maintain the inflammatory response associated with autoimmune disorders. Recent evidence supports the concept that leukocyte activation and elicitation through cytokine-driven networks is one of the key processes that ‘sets the stage’ for the pathology associated with the autoimmune response. Clearly, one of the families of effector molecules under the cytokine network rubric is the large group of mediators known as chemokines (Table 1). These polypeptide mediators provide the mechanism to elicit the appropriate subpopulation of leukocytes that are required to participate in an inflammatory response [1]. This review focuses on the most recent findings describing the role of chemokines in clinical multiple sclerosis (MS) and rheumatoid arthritis (RA) and their surrogate experimental models. In addition, we provide an overview of the
chemokines reported to be involved in the pathology of various autoimmune diseases (Table 2).
Multiple sclerosis and experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS and can be studied as either an acute or relapsing cell-mediated immune response. The immunologic mechanism responsible for initiating and maintaining EAE operates through the sensitization of T lymphocytes to myelin basic protein. The subsequent pathology of this immune response is a direct result of the demyelination that occurs as the inflammatory response progresses in the central nervous system (CNS). Even though many therapeutic approaches have been applied to ameliorating the disease, such as hormone therapy [2], interferon-β [3] and antigen-specific immunotherapy [4•], MS remains an enigmatic disease that is difficult to treat. Recent data suggest, however, that targeting specific chemokines that support leukocyte trafficking into the CNS may provide a useful therapeutic approach to the management of this disease. Clinical studies have demonstrated that the expression of chemokines and chemokine receptors is altered significantly during the evolution of human MS [5–8]. In these studies, the CC chemokine ligands CCL3, CCL4 and CCL5, and the receptors CCR2, CCR3 and CCR5 were found to be elevated in CNS tissue recovered from MS patients. Interestingly, the levels of the CC chemokine CCL2 and the CXC chemokine CXCL10 were found to vary inversely in the cerebrospinal fluid of patients with acute MS: CCL2 levels were much lower than controls, whereas CXCL10 chemokines were markedly increased. The latter finding is of interest, as CXCL10 is induced by interferon-γ — a type-1 cytokine that has been identified as an important cytokine in the progression of both MS and EAE. Additional studies in humans have focused on the participation of CCR5 — one of the receptors for CCL3, CCL4 and CCL5 — as a key receptor in T-cell trafficking into the CNS. The likelihood that CCR5 participates in directed migration of T cells in this disease process is underscored by investigations demonstrating that the chemotactic response of T cells to CCL5 and CCL3, but not other to chemokines, is enhanced significantly in cells recovered from MS patients [7]. Further evidence that CCR5 may have a role in this disease is provided by immunohistochemical investigations of post-mortem CNS tissue, which show that CCR5 is localized in invading T cells, foamy macrophages and microglial cells [8]. Although these data are of interest, they must be viewed in perspective of a recent study that has assessed the occurrence
Chemokines in autoimmune disease Godessart and Kunkel
of MS in patients who are positive for ‘CCR5 ∆32’ — a human mutation in CCR5 that results in a non-functional receptor [9•]. These patients, who basically are CCR5 knockouts, do not possess a significant level of protection from the initial phases of this autoimmune disease, but are associated with a lower risk of recurrent clinical disease [9•]. Further sets of studies have been directed at determining whether therapeutic treatment of patients with interferon-β can ameliorate the disease by reducing the CCR5-related activity [3,10]. In these studies, humans treated with interferon showed a reduction in levels of T-cell CCR5, which correlated with a decrease in T-cell migration to CCL5 and CCL3. The hypothesis that chemokines might potentially serve as a mechanism for the delivery of T-cell populations that target the CNS in MS has provided the impetus to study this process closely in in vivo models, especially in models of EAE. Much of the current information suggesting that chemokines are important in human MS has resulted from data using an EAE system in knockout mice [11•,12••,13••]. In these studies, mice genetically deficient in either CCR1 or CCR2 are resistant to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide. The CCR2 knockout mice failed to develop a significant Tcell response to the CNS and failed to increase levels of CCL5 and CCL2, as well as to develop a significant expression pattern for CCR1 and CCR5. Interestingly, T cells for the CCR2 knockout animals exhibited a decrease in antigen-induced proliferation and showed reduced levels of interferon-γ. The data assessing the role of CCR1 and CCR2 knockout mice in EAE support previous studies demonstrating the induction of the ligands for those receptors, CCL2 and CCL3, in the course of the disease [14,15].
Rheumatoid arthritis RA is a chronic inflammatory autoimmune disease of unknown etiology that affects diarthroidal joints. Synovial tissue in RA is characterized by hyperplasia of resident synoviocytes and the presence of a cellular infiltrate comprising myeloid and lymphoid cells. Interactions between resident and migratory cells cause cellular activation, leading to perpetuation of the chronic synovitis and eventually to destruction of cartilage and bone (reviewed in [16•]). The inflamed synovium displays inappropriate recruitment and reduced apoptosis of infiltrating cells, angiogenesis, and the presence of lymphoid structures. Recent evidence suggests that chemokines have important roles in many of these processes. Recently, elevated levels of CC chemokines (CCL2, CCL3, CCL4 and CCL5) and CXC chemokines (CXCL5, CXCL8, CXCL9 and CXCL10) have been reported for biological samples from RA patients [17–21]. These chemokines may control cell trafficking directly by interacting with their cognate receptors present on inflammatory cells and also by modulating angiogenesis [22]. CXC chemokines containing an ELR amino acid motif, such as CXCL5 and CXCL8, promote neovascularization [23], which allows sustained cell migration and the supply of oxygen and nutrients for the
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Table 1 Representative chemokines belonging to the four supergene families and their receptors. Family
Funtional classification* Chemokines†
Receptors
C
Inflammatory
XCL1 (lymphotactin)
XCR1
CC
Inflammatory
CCL2 (MCP-1) CCL3 (MIP-1α) CCL4 (MIP-1β) CCL5 (RANTES) CCL11 (eotaxin)
CCR2 CCR1, CCR5 CCR5 CCR1, CCR3, CCR5 CCR3
Inflammatory and homeostatic
CCL17 (TARC) CCL22 (MDC)
CCR4 CCR4
Homeostatic
CCL18 (PARC) CCL19 (ELC) CCL21 (SLC)
Unknown CCR7 CCR7
CXC
Inflammatory, angiogenic CXCL1 (GRO-α) CXCR2, CXCR1 CXCL2 (GRO-β) CXCR2 CXCL3 (GRO-γ ) CXCR2 CXCL5 (ENA-78) CXCR2 CXCL7 (NAP-2) CXCR2 CXCL8 (IL-8) CXCR1, CXCR2 Inflammatory, angiostatic CXCL9 (MIG) CXCL10 (IP-10) CXCL4 (PF-4)
CXCR3 CXCR3 Unknown
Inflammatory
CXCR6
CXCL16
Homeostatic, angiogenic CXCL12 (SDF-1) CXCR4 Homeostatic CXXXC Inflammatory
CXCL13 (BCA-1) CXCR5 CX3CL1 (fractalkine)
CX3CR1
*Inflammatory chemokines have also been described as inducible chemokines, whereas homeostatic chemokines are also known as lymphoid or constitutive chemokines. † Chemokine names are denoted by the new nomenclature system [41], with the common names given in parentheses. This is by no means a complete account for the 60+ members of these different family members.
developing invasive ‘pannus’ (i.e. the inflammatory synovial tissue). The angiostatic chemokines CXCL9 and CXCL10 are also abundantly present in RA joints and may counteract the effects of the pro-angiogenic mediators. Studies on chemokine receptor expression have focused mainly on expression in monocytes and T cells — the predominant cells that migrate to arthritic joints. Peripheral blood monocytes express a variety of CC and CXC receptors [20,24] that may be able to bind most of the pro-inflammatory chemokines mentioned above. In RA patients, circulating monocytes were found to express mainly CCR1, CCR2, and CCR4, whereas synovial fluid was enriched in CCR3+ and CCR5+ cells [24]. Different laboratories have reported that CD4+ memory T cells from synovium express CCR5, CXCR2, CXCR3, CXCR4 and/or CXCR6 [17,25–27,28••,29••] at higher levels than expressed by circulating T cells.
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Table 2 Overview of the main chemokines involved in different autoimmune diseases. Disease
Chemokine
Samples
References
Type I diabetes
CXCL12 CCL3, CCL5, CXCL10
Humans NOD mouse pancreas
[42] [43,44]
Graves’ disease
CCL3, CCL4, CCL5
Human thyroid glands
[45,46]
MS
CCL2, CCL5, CXCL10 CCL3, CCL4, CCL5 CCL2, CCL3
Human serum and CSF Human brain tissue EAE mice
[3,5] [6] [14,15]
RA
CCL2, CCL4, CXCL8, CXCL9, CXCL10, CXCL12 CXCL12, CXCL13 CCL3,CXCL8 CCL2, CXCL10
SF and ST SF and ST Ectopic lymph nodes Lymph Blood
[17,18,20] [28••,29••] [32•,33•] [21] [17,19]
Sjögren’s syndrome
CCL17, CCL18, CCL19, CCL22,CXCL13 CCL3, CCL4, CCL5, CXCL8
Human salivary glands
[47] [48]
Systemic lupus erythematosus
CCL2, CCL5 CXCL10
Serum
[49] [50]
CSF, cerebrospinal fluid; NOD, non-obese diabetic; SF, synovial fluid; ST, synovial tissue.
Differences in the receptor expression pattern of cells from blood and synovium would suggest that cells expressing a particular receptor are selectively recruited from blood, and/or the receptor is upregulated after the cells enter into the joint. The expression of CXCR4 on T cells illustrates the latter situation. Two independent groups have reported that CD4+ memory T cells from synovial tissue and synovial fluid express high levels of CXCR4 [28••,29••]. Only a small percentage of circulating CD4+ T cells from RA patients express this receptor, suggesting that some factors present in the joint microenvironment are responsible for the local induction of CXCR4. Interestingly, cytokines such as TGF-β1 [28••] and, to a lesser extent, IL-15 [28••,29••], have been found to upregulate CXCR4 on T cells in vitro. Endothelial cells [28••] and synovial fibroblasts [29••] are potential sources of CXCL12 — the only known ligand for CXCR4. CD40 engagement enhances the synthesis of the chemokine in cultured synovial fibroblasts. Thus, memory T cells expressing CD154 (the CD40 ligand) can stimulate expression of CXCL12, creating a positive feedback loop [29••]. Furthermore, CXCL12 reduces the apoptosis of T cells in vitro, suggesting that this chemokine may have a role in the sustained survival of T cells in the joint [29••]. Lymphoid structures have been found in the target organs of many autoimmune diseases (reviewed in [30•]). In RA, the synovial membrane of some patients contains ectopic de novo lymph nodes with germinal centers, plasma cells and deposits of immune complexes. Synovial B cells are postulated to be important for the synthesis of antibodies (rheumatoid factor) and also for T-cell activation and cytokine synthesis (reviewed in [31••]). Studies on the
chemokines involved in lymphoid neogenesis revealed that elevated amounts of CXCL13 are present only in the synovium of patients containing those structures and that follicular dendritic cells were the main cellular source of the chemokine [32•]. CXCL13 is the ligand of CXCR5 — a receptor expressed on naive B cells and presumably involved in local B-cell accumulation. Other researchers have reported that CXCR4 [29••,33•] and CXCL12 are involved in the homing and also the sustained survival of B cells in the synovium [33•]. Recently, the presumed relevance of B cells in the pathology of RA has been proved in the clinic. The depletion of B lymphocytes by the administration of Rituxan (a monoclonal antibody against CD20) markedly improved arthritis in five patients with refractory arthritis without causing clinically relevant immunosuppresion (JC Edwards, C Cambridge, abstract 1950, Annual Scientific Meeting of the American College of Rheumatology, Philadelphia, 28 October to 2 November 2000).
Chemokines as therapeutic targets in arthritis The chemokine system is a potential target for the clinical management of RA. The efficacy of some successful anti-arthritic therapies such as the anti-TNF antibody, infliximab, might be related, in part, to a reduction in synthesis of CCL2 and CXCL8 [34]. This is consistent with the fact that these chemokines have been postulated to be markers of clinical manifestations in RA [18,19]. Nevertheless, the levels of chemokines in plasma and synovial fluid determined by different laboratories are often contradictory. Differences in the patients’ therapy or the clinical stage of the disease at the time of sample collection might account for these discrepancies.
Chemokines in autoimmune disease Godessart and Kunkel
Strategies to target chemokines could include inhibitors of chemokine synthesis, receptor antagonists, chemokine toxins [35] and DNA vaccines [36]. Given the inherent redundancy in the system, it seems unlikely that targeting a single chemokine or receptor could be of benefit. The results from studies of CCR5 ∆32 in RA are conflicting, but suggest that a lack of functional CCR5 may delay clinical progression [37,38]. The efficacy of blocking the chemokine system in experimental models of arthritis has been demonstrated previously using truncated CC chemokines (functional receptor antagonists) and anti-chemokine antibodies. Recently, the effect of DNA vaccination with CC chemokines in the rat adjuvant arthritis model has been reported [39]. Administering DNA constructs encoding CCL2, CCL3 or CCL5 inhibited the development and progression of arthritis; the most potent of these was the CCL2-encoding DNA vaccine [39]. Several companies have disclosed potent small-molecule receptor antagonists, but positive results from tests in rodent models of RA are lacking. Species specificity could account for this fact, because most compounds reported only bind human receptors. A CCR1 antagonist that is active in both human and mouse receptors has been described recently [40], and will provide a tool to assess the role of CCR1 in different experimental models in mice.
continues to explore the biology of chemokines, new avenues of target validation will become apparent. The ability to capitalize on these new advances in the chemokine field will be beneficial to a number of immunology disciplines, including the area of autoimmune diseases.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest •• of outstanding interest 1.
Szekanecz Z, Halloran MM, Volin MV, Woods JM, Strieter RM, Haines GK, Kunkel SL, Burdick MD, Koch AW: Temporal expression of inflammatory cytokines and chemokines in rat adjuvantinduced arthritis. Arthritis Rheum 2000, 43:1266-1277.
2.
Bebo BF, Fyfe-Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H: Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol 2001, 166:2080-2089.
3.
Iarlori C, Reale M, Lugaresi A, DeLuca G, Bonanni L, Di Iorio A, Feliciani C, Conti P, Gambi D: RANTES production and expression is reduced in relapsing-remitting multiple sclerosis patients β1b. J Neuroimmunol 2000, 107:100-107. treated with interferon-β
4. •
McFarland HI, Lobito AA, Johnson MM, Palardy GR, Yee CSK, Jordan EK, Frank JA, Tresser N, Genain CP, Mueller LM et al.: Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis. J Immunol 2001, 166:2116-2121. This article is important because it demonstrates for the first time in a primate model that immunotherapy has the potential to be an effective means to treat MS specifically. In this study, the investigators successfully eliminated reactive T cells by administering large amounts of myelin antigen. 5.
Franciotta D, Martino G, Zardin E, Furlan R, Bergamaschi R, Andreoni L, Cosi V: Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies. Neuroimmunol 2001, 115:192-198.
6.
Boven LA, Montagne L, Nottet HS, De Groot CJ: Macrophage α, MIP-1β β, and RANTES mRNA inflammatory protein-1α semiquantificaiton and protein expression in active demyelinating multiple sclerosis lesions. Clin Exp Immunol 2000, 122:257-263.
7.
Zang YC, Samanta AK, Halder JB, Hong J, Tejada-Simon MV, Rivera VM, Zhang JZ: Aberrant T cell migration toward RANTES and MIP-1 apha in patients with multiple sclerosis. Over-expression of chemokine receptor CCR5. Brain 2000, 123:1874-1882.
8.
Simpson J, Rezaie P, Newcombe J, Cuzner ML, Male D, Woodroofe MN: Expression of the β-chemokine receptor CCR2, CCR3, CCR5 in multiple sclerosis central nervous system tissue. J Neuroimmunol 2000, 108:192-200.
Conclusions The initiation and maintenance of autoimmune diseases depend on many different mechanisms, which often activate preset inflammatory processes of the host. For example, leukocyte recruitment is one of these processes that is fundamental to the pathology of both normal immune responses to a foreign challenge, as well as the host response to a self-antigen. Investigations published in the past year support the concept that chemokine-directed leukocyte activation and elicitation are fundamental to the tissue injury associated with the evolution of autoimmune diseases. Of particular importance are the studies that demonstrate that chemokines are important in establishing ectopic lymphoid tissue during the development of RA, and those that underscore a role for chemokines as homing signals for specific leukocyte subpopulations during the inflammatory process. Furthermore, recent advances have defined the role of chemokines derived from structural cells, for example, fibroblasts and endothelial cells, as possessing important effector activity in supporting the continued recruitment process in autoimmune diseases. The global interest in chemokine biology has provided the impetus to assess the occurrence of autoimmune disease in patients that are essentially CCR5 knockouts. Multiple sclerosis patients with the ∆32 mutation, which causes non-functioning CCR5, can still mount a significant immune response and support the inflammation normally found associated with the disease. As the scientific community
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Sellebjerg F, Madsen HO, Jensen CV, Jensen J, Garred P: CCR5 δ32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J Neuroimmunol 2000, 102:98-106. This article addresses the influence of the human mutation in CCR5 on the development of MS. Although the human CCR5 knockout does not confer resistance to the disease, it is associated with a lower risk of recurring disease. 9. •
10. Zang YC, Halder JB, Samanta AK, Hong J, Rivera VM, Zhang JZ: Regulation of chemokine receptor CCR5 and production of α by interferon-β β. J Neuroimmunol 2001, RANTES and MIP-1α 112:174-180. 11. Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, • Hancock WW: Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol 2000, 30:2372-2377. This article demonstrates the importance of the chemokine receptor CCR1 in the development of EAE, as CCR1 knockout mice had less severe disease, as compared with control mice, and did not show induction of systemic immunosuppression. 12. Izikson L, Klein RS, Charo IF, Weiner HL, Luster A: Resistance to •• experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR2). J Exp Med 2000, 192:1075-1080. An important contribution to the EAE literature, this article demonstrates that CCR2 knockout mice are resistant to the development of EAE. Numerous mechanisms may be responsible for the resistant state, including the lack of
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mononuclear cells infiltrating the CNS, the reduction in chemokine expression, and the lack of T-cell antigen-induced proliferation. 13. Fife BT, Huffnagle GB, Kuziel WA, Karpus WJ: CC chemokine •• receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J Exp Med 2000, 192:899-905. An article that further substantiates the findings in [12••]. 14. Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD: An important role for the chemokine macrophage α in the pathogenesis of the T cellinflammatory protein-1α mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 1995, 155:5003-5010. 15. Kennedy KJ, Strieter RM, Kunkel SL, Lukacs NW, Karpus WJ: Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines α and monocyte chemotactic macrophage inflammatory protein-1α protein-1. J Neuroimmunol 1998, 92:98-108. 16. Szekanecz Z, Koch AE: Update on synovitis. Curr Rheumatol Rep • 2001, 3:53-63. This article provides a comprehensive overview of the cells and mediators involved in the key mechanisms underlying the inflammatory process in RA synovium. The authors address the role of adhesion molecules, cytokines, growth factors and chemokines at the different stages of the pathology. 17.
Patel DD, Zachariah JP, Whichard LP: CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol 2001, 98:39-45.
18. Kraan MC, Patel DD, Haringman JJ, Smith MD, Weedon H, Ahern MJ, Breedveld FC, Tak PP: The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res 2001, 3:65-71. 19. Ellingsen T, Buus A, Stengaard-Pedersen K: Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis. J Rheumatol 2001, 28:41-46. 20. Hayashida K, Nanki T, Girschick H, Yavuz S, Ochi T, Lipsky PE: Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8. Arthritis Res 2001, 3:118-126. 21. Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE: Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes. Arthritis Rheum 2001, 44:541-549. 22. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RM: CXC chemokines in angiogenesis. J Leukoc Biol 2000, 68:1-8. 23. Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, Woodruff DC, Burdick MD, Strieter RM: Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum 2001, 44:31-40. 24. Katschke KJ Jr, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE: Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 2001, 44:1022-1032. 25. Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM, Mellado M, Acevedo A, Garcia MI, Albar JP, Martinez C, Marazuela M: CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest 2001, 81:409-418. 26. 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. 27.
Nanki T, Lipsky PE: Cytokine, activation marker, and chemokine receptor expression by individual CD4+ memory T cells in rheumatoid arthritis synovium. Arthritis Res 2000, 5:415-423.
28. 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 β1 on synovial T cells contributes to their accumulation by TGF-β within the rheumatoid synovium. J Immunol 2000, 165:3423-3429. This article is the first to suggest that the receptor–ligand pair CXCR4–CXCL12 is involved in T-cell migration to the RA synovium. The
authors demonstrate that, among the different cytokines that can induce CXCR4 expression in T-cell lines, TGF-β1 is not only the most potent but also the more relevant cytokine in vivo. 29. 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. This article supports the results presented in [28••], and also reports two interesting findings: the enhancement of CXCL12 synthesis by resident cells upon cell-to-cell contact (via engagement of CD40), and the role of this chemokine in preventing T-cell apoptosis. 30. Hjelmstrom P: Lymphoid neogenesis: de novo formation of • lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukoc Biol 2001, 69:331-339. This recent review summarizes the factors underlying the generation of ectopic lymph nodes in chronic inflammation driven by autoimmune and infectious diseases. Intriguingly, lymphoid neogenesis is shown to be associated with neoplastic transformation of lymphocytes from ectopic germinal centers. 31. 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. A very interesting article reviewing the factors involved in aberrant lymphoid neogenesis in arthritis. The role of chemokines in the compartmentalization of lymphocytes and dendritic cells into lymph nodes is summarized. The authors review recent data suggesting that synovial B cells are involved in the disease process, independently of their ability to synthesize antibodies. They also postulate that B cells play a role in T-cell activation via synthesis of mediators (cytokines or chemokines) and, more likely, by acting as antigenpresenting cells. 32. 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 centers of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol 2001, 166:650-655. This article suggests that CXCL13 is involved in the formation of germinal centers in the ectopic lymph nodes in RA synovium by means of attracting CXCR5+ B cells. Immunohistochemistry studies revealed that CXCL13 is produced by follicular dendritic cells located in B-cell-rich areas. The lack of CCL21, a CCR7 ligand normally found in the T-cell-rich areas in lymph nodes, suggest that other chemokines control the recruitment of T cells. 33. Burger JA, Zvaifler NJ, Tsukada N, Firestein GS, Kipps TJ: Fibroblast • like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J Clin Invest 2001, 107:305-315. This paper suggests that fibroblast-like synoviocytes from RA joints may support the development of lymphoid structures by attracting B cells in a chemokine-dependent process. B cells expressing CXCR4 can migrate toward CXCL12 produced by fibroblasts. Both the synthesis of CXCL12 and the expression of the integrin VCAM-1 by fibroblasts are necessary to support cell attraction via CXCR4 and VLA-4 expressed on B cells. These studies also suggest that fibroblasts can synthesize CXCL12, but only those properly stimulated to express VCAM-1 will be able to support B-cell migration. α therapy of rheumatoid arthritis: 34. Feldmann M, Maini RN: Anti-TNFα what have we learned? Annu Rev Immunol 2001, 19:163-196. 35. Bruhl H, Cihak J, Stangassinger M, Schlondorff D, Mack M: Depletion of CCR5-expressing cells with bispecific antibodies and chemokine toxins: a new strategy in the treatment of chronic inflammatory diseases and HIV. J Immunol 2001, 166:2420-2426. 36. Karin N: Gene therapy for T cell-mediated autoimmunity: teaching the immune system how to restrain its own harmful activities by targeted DNA vaccines. Isr Med Assoc J 2000, 2:63-68. 37.
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Xanthou G, Polihronis M, Tzioufas AG, Paikos S, Sideras P, Moutsopoulos 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.
48. Cuello C, Palladinetti P, Tedla N, Di Girolamo N, Lloyd AR, McCluskey PJ, Wakefield D: Chemokine expression and leucocyte infiltration in Sjogren’s syndrome. Br J Rheumatol 1998, 37:779-783. 49. Kaneko H, Ogasawara H, Naito T, Akimoto H, Lee S, Hishikawa T, Sekigawa I, Tokano Y, Takasaki Y, Hirose SI, Hashimoto H: Circulating levels of β-chemokines in systemic lupus erythematosus. J Rheumatol 1999, 26:568-573. 50. Narumi S, Takeuchi T, Kobayashi Y, Konishi K: Serum levels of IFN-inducible protein-10 relating to the activity of systemic lupus erythematosus. Cytokine 2000, 12:1561-1565.
Chemokines in autoimmune disease Nuria Godessart* and Steven L Kunkel† Growing evidence indicates that structural cells play a crucial role in the chronic inflammation of autoimmunity by their recruitment of chemokine-dependent cells. Members of the two functional classes of chemokines, inflammatory and homeostatic, seem to be involved in lymphocyte recruitment and survival, and in establishing ectopic lymphoid structures in the target organs of autoimmune diseases. Results from animal models suggest that chemokines are reasonable therapeutic targets in autoimmunity. Addresses *Department of Pharmacology, Almirall Prodesfarma Research Center, Cardener 68–74, 08028 Barcelona, Spain; e-mail: [email protected] † Department of Pathology, The University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109-0602, USA; e-mail: [email protected] Correspondence: Steven L Kunkel Current Opinion in Immunology 2001, 13:670–675 0952-7915/01/$ — see front matter © 2001 Elsevier Science Ltd. All rights reserved. Abbreviations CNS central nervous system EAE experimental autoimmune encephalomyelitis MS multiple sclerosis RA rheumatoid arthritis
Introduction The clinical manifestations of various autoimmune diseases are usually the consequence of an initial strong immune response to a particular self-antigen, which leads to significant leukocyte activation/accumulation in the tissue of the target organ and subsequent pathology. The management of these disorders is frequently difficult, requiring the use of potent, often cytotoxic, immunosuppressive therapies. These treatment strategies reflect, in part, our limited understanding of the mechanisms that allow leukocytes to initiate and maintain the inflammatory response associated with autoimmune disorders. Recent evidence supports the concept that leukocyte activation and elicitation through cytokine-driven networks is one of the key processes that ‘sets the stage’ for the pathology associated with the autoimmune response. Clearly, one of the families of effector molecules under the cytokine network rubric is the large group of mediators known as chemokines (Table 1). These polypeptide mediators provide the mechanism to elicit the appropriate subpopulation of leukocytes that are required to participate in an inflammatory response [1]. This review focuses on the most recent findings describing the role of chemokines in clinical multiple sclerosis (MS) and rheumatoid arthritis (RA) and their surrogate experimental models. In addition, we provide an overview of the
chemokines reported to be involved in the pathology of various autoimmune diseases (Table 2).
Multiple sclerosis and experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS and can be studied as either an acute or relapsing cell-mediated immune response. The immunologic mechanism responsible for initiating and maintaining EAE operates through the sensitization of T lymphocytes to myelin basic protein. The subsequent pathology of this immune response is a direct result of the demyelination that occurs as the inflammatory response progresses in the central nervous system (CNS). Even though many therapeutic approaches have been applied to ameliorating the disease, such as hormone therapy [2], interferon-β [3] and antigen-specific immunotherapy [4•], MS remains an enigmatic disease that is difficult to treat. Recent data suggest, however, that targeting specific chemokines that support leukocyte trafficking into the CNS may provide a useful therapeutic approach to the management of this disease. Clinical studies have demonstrated that the expression of chemokines and chemokine receptors is altered significantly during the evolution of human MS [5–8]. In these studies, the CC chemokine ligands CCL3, CCL4 and CCL5, and the receptors CCR2, CCR3 and CCR5 were found to be elevated in CNS tissue recovered from MS patients. Interestingly, the levels of the CC chemokine CCL2 and the CXC chemokine CXCL10 were found to vary inversely in the cerebrospinal fluid of patients with acute MS: CCL2 levels were much lower than controls, whereas CXCL10 chemokines were markedly increased. The latter finding is of interest, as CXCL10 is induced by interferon-γ — a type-1 cytokine that has been identified as an important cytokine in the progression of both MS and EAE. Additional studies in humans have focused on the participation of CCR5 — one of the receptors for CCL3, CCL4 and CCL5 — as a key receptor in T-cell trafficking into the CNS. The likelihood that CCR5 participates in directed migration of T cells in this disease process is underscored by investigations demonstrating that the chemotactic response of T cells to CCL5 and CCL3, but not other to chemokines, is enhanced significantly in cells recovered from MS patients [7]. Further evidence that CCR5 may have a role in this disease is provided by immunohistochemical investigations of post-mortem CNS tissue, which show that CCR5 is localized in invading T cells, foamy macrophages and microglial cells [8]. Although these data are of interest, they must be viewed in perspective of a recent study that has assessed the occurrence
Chemokines in autoimmune disease Godessart and Kunkel
of MS in patients who are positive for ‘CCR5 ∆32’ — a human mutation in CCR5 that results in a non-functional receptor [9•]. These patients, who basically are CCR5 knockouts, do not possess a significant level of protection from the initial phases of this autoimmune disease, but are associated with a lower risk of recurrent clinical disease [9•]. Further sets of studies have been directed at determining whether therapeutic treatment of patients with interferon-β can ameliorate the disease by reducing the CCR5-related activity [3,10]. In these studies, humans treated with interferon showed a reduction in levels of T-cell CCR5, which correlated with a decrease in T-cell migration to CCL5 and CCL3. The hypothesis that chemokines might potentially serve as a mechanism for the delivery of T-cell populations that target the CNS in MS has provided the impetus to study this process closely in in vivo models, especially in models of EAE. Much of the current information suggesting that chemokines are important in human MS has resulted from data using an EAE system in knockout mice [11•,12••,13••]. In these studies, mice genetically deficient in either CCR1 or CCR2 are resistant to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide. The CCR2 knockout mice failed to develop a significant Tcell response to the CNS and failed to increase levels of CCL5 and CCL2, as well as to develop a significant expression pattern for CCR1 and CCR5. Interestingly, T cells for the CCR2 knockout animals exhibited a decrease in antigen-induced proliferation and showed reduced levels of interferon-γ. The data assessing the role of CCR1 and CCR2 knockout mice in EAE support previous studies demonstrating the induction of the ligands for those receptors, CCL2 and CCL3, in the course of the disease [14,15].
Rheumatoid arthritis RA is a chronic inflammatory autoimmune disease of unknown etiology that affects diarthroidal joints. Synovial tissue in RA is characterized by hyperplasia of resident synoviocytes and the presence of a cellular infiltrate comprising myeloid and lymphoid cells. Interactions between resident and migratory cells cause cellular activation, leading to perpetuation of the chronic synovitis and eventually to destruction of cartilage and bone (reviewed in [16•]). The inflamed synovium displays inappropriate recruitment and reduced apoptosis of infiltrating cells, angiogenesis, and the presence of lymphoid structures. Recent evidence suggests that chemokines have important roles in many of these processes. Recently, elevated levels of CC chemokines (CCL2, CCL3, CCL4 and CCL5) and CXC chemokines (CXCL5, CXCL8, CXCL9 and CXCL10) have been reported for biological samples from RA patients [17–21]. These chemokines may control cell trafficking directly by interacting with their cognate receptors present on inflammatory cells and also by modulating angiogenesis [22]. CXC chemokines containing an ELR amino acid motif, such as CXCL5 and CXCL8, promote neovascularization [23], which allows sustained cell migration and the supply of oxygen and nutrients for the
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Table 1 Representative chemokines belonging to the four supergene families and their receptors. Family
Funtional classification* Chemokines†
Receptors
C
Inflammatory
XCL1 (lymphotactin)
XCR1
CC
Inflammatory
CCL2 (MCP-1) CCL3 (MIP-1α) CCL4 (MIP-1β) CCL5 (RANTES) CCL11 (eotaxin)
CCR2 CCR1, CCR5 CCR5 CCR1, CCR3, CCR5 CCR3
Inflammatory and homeostatic
CCL17 (TARC) CCL22 (MDC)
CCR4 CCR4
Homeostatic
CCL18 (PARC) CCL19 (ELC) CCL21 (SLC)
Unknown CCR7 CCR7
CXC
Inflammatory, angiogenic CXCL1 (GRO-α) CXCR2, CXCR1 CXCL2 (GRO-β) CXCR2 CXCL3 (GRO-γ ) CXCR2 CXCL5 (ENA-78) CXCR2 CXCL7 (NAP-2) CXCR2 CXCL8 (IL-8) CXCR1, CXCR2 Inflammatory, angiostatic CXCL9 (MIG) CXCL10 (IP-10) CXCL4 (PF-4)
CXCR3 CXCR3 Unknown
Inflammatory
CXCR6
CXCL16
Homeostatic, angiogenic CXCL12 (SDF-1) CXCR4 Homeostatic CXXXC Inflammatory
CXCL13 (BCA-1) CXCR5 CX3CL1 (fractalkine)
CX3CR1
*Inflammatory chemokines have also been described as inducible chemokines, whereas homeostatic chemokines are also known as lymphoid or constitutive chemokines. † Chemokine names are denoted by the new nomenclature system [41], with the common names given in parentheses. This is by no means a complete account for the 60+ members of these different family members.
developing invasive ‘pannus’ (i.e. the inflammatory synovial tissue). The angiostatic chemokines CXCL9 and CXCL10 are also abundantly present in RA joints and may counteract the effects of the pro-angiogenic mediators. Studies on chemokine receptor expression have focused mainly on expression in monocytes and T cells — the predominant cells that migrate to arthritic joints. Peripheral blood monocytes express a variety of CC and CXC receptors [20,24] that may be able to bind most of the pro-inflammatory chemokines mentioned above. In RA patients, circulating monocytes were found to express mainly CCR1, CCR2, and CCR4, whereas synovial fluid was enriched in CCR3+ and CCR5+ cells [24]. Different laboratories have reported that CD4+ memory T cells from synovium express CCR5, CXCR2, CXCR3, CXCR4 and/or CXCR6 [17,25–27,28••,29••] at higher levels than expressed by circulating T cells.
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Table 2 Overview of the main chemokines involved in different autoimmune diseases. Disease
Chemokine
Samples
References
Type I diabetes
CXCL12 CCL3, CCL5, CXCL10
Humans NOD mouse pancreas
[42] [43,44]
Graves’ disease
CCL3, CCL4, CCL5
Human thyroid glands
[45,46]
MS
CCL2, CCL5, CXCL10 CCL3, CCL4, CCL5 CCL2, CCL3
Human serum and CSF Human brain tissue EAE mice
[3,5] [6] [14,15]
RA
CCL2, CCL4, CXCL8, CXCL9, CXCL10, CXCL12 CXCL12, CXCL13 CCL3,CXCL8 CCL2, CXCL10
SF and ST SF and ST Ectopic lymph nodes Lymph Blood
[17,18,20] [28••,29••] [32•,33•] [21] [17,19]
Sjögren’s syndrome
CCL17, CCL18, CCL19, CCL22,CXCL13 CCL3, CCL4, CCL5, CXCL8
Human salivary glands
[47] [48]
Systemic lupus erythematosus
CCL2, CCL5 CXCL10
Serum
[49] [50]
CSF, cerebrospinal fluid; NOD, non-obese diabetic; SF, synovial fluid; ST, synovial tissue.
Differences in the receptor expression pattern of cells from blood and synovium would suggest that cells expressing a particular receptor are selectively recruited from blood, and/or the receptor is upregulated after the cells enter into the joint. The expression of CXCR4 on T cells illustrates the latter situation. Two independent groups have reported that CD4+ memory T cells from synovial tissue and synovial fluid express high levels of CXCR4 [28••,29••]. Only a small percentage of circulating CD4+ T cells from RA patients express this receptor, suggesting that some factors present in the joint microenvironment are responsible for the local induction of CXCR4. Interestingly, cytokines such as TGF-β1 [28••] and, to a lesser extent, IL-15 [28••,29••], have been found to upregulate CXCR4 on T cells in vitro. Endothelial cells [28••] and synovial fibroblasts [29••] are potential sources of CXCL12 — the only known ligand for CXCR4. CD40 engagement enhances the synthesis of the chemokine in cultured synovial fibroblasts. Thus, memory T cells expressing CD154 (the CD40 ligand) can stimulate expression of CXCL12, creating a positive feedback loop [29••]. Furthermore, CXCL12 reduces the apoptosis of T cells in vitro, suggesting that this chemokine may have a role in the sustained survival of T cells in the joint [29••]. Lymphoid structures have been found in the target organs of many autoimmune diseases (reviewed in [30•]). In RA, the synovial membrane of some patients contains ectopic de novo lymph nodes with germinal centers, plasma cells and deposits of immune complexes. Synovial B cells are postulated to be important for the synthesis of antibodies (rheumatoid factor) and also for T-cell activation and cytokine synthesis (reviewed in [31••]). Studies on the
chemokines involved in lymphoid neogenesis revealed that elevated amounts of CXCL13 are present only in the synovium of patients containing those structures and that follicular dendritic cells were the main cellular source of the chemokine [32•]. CXCL13 is the ligand of CXCR5 — a receptor expressed on naive B cells and presumably involved in local B-cell accumulation. Other researchers have reported that CXCR4 [29••,33•] and CXCL12 are involved in the homing and also the sustained survival of B cells in the synovium [33•]. Recently, the presumed relevance of B cells in the pathology of RA has been proved in the clinic. The depletion of B lymphocytes by the administration of Rituxan (a monoclonal antibody against CD20) markedly improved arthritis in five patients with refractory arthritis without causing clinically relevant immunosuppresion (JC Edwards, C Cambridge, abstract 1950, Annual Scientific Meeting of the American College of Rheumatology, Philadelphia, 28 October to 2 November 2000).
Chemokines as therapeutic targets in arthritis The chemokine system is a potential target for the clinical management of RA. The efficacy of some successful anti-arthritic therapies such as the anti-TNF antibody, infliximab, might be related, in part, to a reduction in synthesis of CCL2 and CXCL8 [34]. This is consistent with the fact that these chemokines have been postulated to be markers of clinical manifestations in RA [18,19]. Nevertheless, the levels of chemokines in plasma and synovial fluid determined by different laboratories are often contradictory. Differences in the patients’ therapy or the clinical stage of the disease at the time of sample collection might account for these discrepancies.
Chemokines in autoimmune disease Godessart and Kunkel
Strategies to target chemokines could include inhibitors of chemokine synthesis, receptor antagonists, chemokine toxins [35] and DNA vaccines [36]. Given the inherent redundancy in the system, it seems unlikely that targeting a single chemokine or receptor could be of benefit. The results from studies of CCR5 ∆32 in RA are conflicting, but suggest that a lack of functional CCR5 may delay clinical progression [37,38]. The efficacy of blocking the chemokine system in experimental models of arthritis has been demonstrated previously using truncated CC chemokines (functional receptor antagonists) and anti-chemokine antibodies. Recently, the effect of DNA vaccination with CC chemokines in the rat adjuvant arthritis model has been reported [39]. Administering DNA constructs encoding CCL2, CCL3 or CCL5 inhibited the development and progression of arthritis; the most potent of these was the CCL2-encoding DNA vaccine [39]. Several companies have disclosed potent small-molecule receptor antagonists, but positive results from tests in rodent models of RA are lacking. Species specificity could account for this fact, because most compounds reported only bind human receptors. A CCR1 antagonist that is active in both human and mouse receptors has been described recently [40], and will provide a tool to assess the role of CCR1 in different experimental models in mice.
continues to explore the biology of chemokines, new avenues of target validation will become apparent. The ability to capitalize on these new advances in the chemokine field will be beneficial to a number of immunology disciplines, including the area of autoimmune diseases.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest •• of outstanding interest 1.
Szekanecz Z, Halloran MM, Volin MV, Woods JM, Strieter RM, Haines GK, Kunkel SL, Burdick MD, Koch AW: Temporal expression of inflammatory cytokines and chemokines in rat adjuvantinduced arthritis. Arthritis Rheum 2000, 43:1266-1277.
2.
Bebo BF, Fyfe-Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H: Low-dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol 2001, 166:2080-2089.
3.
Iarlori C, Reale M, Lugaresi A, DeLuca G, Bonanni L, Di Iorio A, Feliciani C, Conti P, Gambi D: RANTES production and expression is reduced in relapsing-remitting multiple sclerosis patients β1b. J Neuroimmunol 2000, 107:100-107. treated with interferon-β
4. •
McFarland HI, Lobito AA, Johnson MM, Palardy GR, Yee CSK, Jordan EK, Frank JA, Tresser N, Genain CP, Mueller LM et al.: Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis. J Immunol 2001, 166:2116-2121. This article is important because it demonstrates for the first time in a primate model that immunotherapy has the potential to be an effective means to treat MS specifically. In this study, the investigators successfully eliminated reactive T cells by administering large amounts of myelin antigen. 5.
Franciotta D, Martino G, Zardin E, Furlan R, Bergamaschi R, Andreoni L, Cosi V: Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies. Neuroimmunol 2001, 115:192-198.
6.
Boven LA, Montagne L, Nottet HS, De Groot CJ: Macrophage α, MIP-1β β, and RANTES mRNA inflammatory protein-1α semiquantificaiton and protein expression in active demyelinating multiple sclerosis lesions. Clin Exp Immunol 2000, 122:257-263.
7.
Zang YC, Samanta AK, Halder JB, Hong J, Tejada-Simon MV, Rivera VM, Zhang JZ: Aberrant T cell migration toward RANTES and MIP-1 apha in patients with multiple sclerosis. Over-expression of chemokine receptor CCR5. Brain 2000, 123:1874-1882.
8.
Simpson J, Rezaie P, Newcombe J, Cuzner ML, Male D, Woodroofe MN: Expression of the β-chemokine receptor CCR2, CCR3, CCR5 in multiple sclerosis central nervous system tissue. J Neuroimmunol 2000, 108:192-200.
Conclusions The initiation and maintenance of autoimmune diseases depend on many different mechanisms, which often activate preset inflammatory processes of the host. For example, leukocyte recruitment is one of these processes that is fundamental to the pathology of both normal immune responses to a foreign challenge, as well as the host response to a self-antigen. Investigations published in the past year support the concept that chemokine-directed leukocyte activation and elicitation are fundamental to the tissue injury associated with the evolution of autoimmune diseases. Of particular importance are the studies that demonstrate that chemokines are important in establishing ectopic lymphoid tissue during the development of RA, and those that underscore a role for chemokines as homing signals for specific leukocyte subpopulations during the inflammatory process. Furthermore, recent advances have defined the role of chemokines derived from structural cells, for example, fibroblasts and endothelial cells, as possessing important effector activity in supporting the continued recruitment process in autoimmune diseases. The global interest in chemokine biology has provided the impetus to assess the occurrence of autoimmune disease in patients that are essentially CCR5 knockouts. Multiple sclerosis patients with the ∆32 mutation, which causes non-functioning CCR5, can still mount a significant immune response and support the inflammation normally found associated with the disease. As the scientific community
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Sellebjerg F, Madsen HO, Jensen CV, Jensen J, Garred P: CCR5 δ32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J Neuroimmunol 2000, 102:98-106. This article addresses the influence of the human mutation in CCR5 on the development of MS. Although the human CCR5 knockout does not confer resistance to the disease, it is associated with a lower risk of recurring disease. 9. •
10. Zang YC, Halder JB, Samanta AK, Hong J, Rivera VM, Zhang JZ: Regulation of chemokine receptor CCR5 and production of α by interferon-β β. J Neuroimmunol 2001, RANTES and MIP-1α 112:174-180. 11. Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, • Hancock WW: Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol 2000, 30:2372-2377. This article demonstrates the importance of the chemokine receptor CCR1 in the development of EAE, as CCR1 knockout mice had less severe disease, as compared with control mice, and did not show induction of systemic immunosuppression. 12. Izikson L, Klein RS, Charo IF, Weiner HL, Luster A: Resistance to •• experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR2). J Exp Med 2000, 192:1075-1080. An important contribution to the EAE literature, this article demonstrates that CCR2 knockout mice are resistant to the development of EAE. Numerous mechanisms may be responsible for the resistant state, including the lack of
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mononuclear cells infiltrating the CNS, the reduction in chemokine expression, and the lack of T-cell antigen-induced proliferation. 13. Fife BT, Huffnagle GB, Kuziel WA, Karpus WJ: CC chemokine •• receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J Exp Med 2000, 192:899-905. An article that further substantiates the findings in [12••]. 14. Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD: An important role for the chemokine macrophage α in the pathogenesis of the T cellinflammatory protein-1α mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 1995, 155:5003-5010. 15. Kennedy KJ, Strieter RM, Kunkel SL, Lukacs NW, Karpus WJ: Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines α and monocyte chemotactic macrophage inflammatory protein-1α protein-1. J Neuroimmunol 1998, 92:98-108. 16. Szekanecz Z, Koch AE: Update on synovitis. Curr Rheumatol Rep • 2001, 3:53-63. This article provides a comprehensive overview of the cells and mediators involved in the key mechanisms underlying the inflammatory process in RA synovium. The authors address the role of adhesion molecules, cytokines, growth factors and chemokines at the different stages of the pathology. 17.
Patel DD, Zachariah JP, Whichard LP: CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol 2001, 98:39-45.
18. Kraan MC, Patel DD, Haringman JJ, Smith MD, Weedon H, Ahern MJ, Breedveld FC, Tak PP: The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res 2001, 3:65-71. 19. Ellingsen T, Buus A, Stengaard-Pedersen K: Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis. J Rheumatol 2001, 28:41-46. 20. Hayashida K, Nanki T, Girschick H, Yavuz S, Ochi T, Lipsky PE: Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8. Arthritis Res 2001, 3:118-126. 21. Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE: Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes. Arthritis Rheum 2001, 44:541-549. 22. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RM: CXC chemokines in angiogenesis. J Leukoc Biol 2000, 68:1-8. 23. Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, Woodruff DC, Burdick MD, Strieter RM: Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint. Arthritis Rheum 2001, 44:31-40. 24. Katschke KJ Jr, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE: Differential expression of chemokine receptors on peripheral blood, synovial fluid, and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 2001, 44:1022-1032. 25. Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM, Mellado M, Acevedo A, Garcia MI, Albar JP, Martinez C, Marazuela M: CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab Invest 2001, 81:409-418. 26. 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. 27.
Nanki T, Lipsky PE: Cytokine, activation marker, and chemokine receptor expression by individual CD4+ memory T cells in rheumatoid arthritis synovium. Arthritis Res 2000, 5:415-423.
28. 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 β1 on synovial T cells contributes to their accumulation by TGF-β within the rheumatoid synovium. J Immunol 2000, 165:3423-3429. This article is the first to suggest that the receptor–ligand pair CXCR4–CXCL12 is involved in T-cell migration to the RA synovium. The
authors demonstrate that, among the different cytokines that can induce CXCR4 expression in T-cell lines, TGF-β1 is not only the most potent but also the more relevant cytokine in vivo. 29. 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. This article supports the results presented in [28••], and also reports two interesting findings: the enhancement of CXCL12 synthesis by resident cells upon cell-to-cell contact (via engagement of CD40), and the role of this chemokine in preventing T-cell apoptosis. 30. Hjelmstrom P: Lymphoid neogenesis: de novo formation of • lymphoid tissue in chronic inflammation through expression of homing chemokines. J Leukoc Biol 2001, 69:331-339. This recent review summarizes the factors underlying the generation of ectopic lymph nodes in chronic inflammation driven by autoimmune and infectious diseases. Intriguingly, lymphoid neogenesis is shown to be associated with neoplastic transformation of lymphocytes from ectopic germinal centers. 31. 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. A very interesting article reviewing the factors involved in aberrant lymphoid neogenesis in arthritis. The role of chemokines in the compartmentalization of lymphocytes and dendritic cells into lymph nodes is summarized. The authors review recent data suggesting that synovial B cells are involved in the disease process, independently of their ability to synthesize antibodies. They also postulate that B cells play a role in T-cell activation via synthesis of mediators (cytokines or chemokines) and, more likely, by acting as antigenpresenting cells. 32. 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 centers of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol 2001, 166:650-655. This article suggests that CXCL13 is involved in the formation of germinal centers in the ectopic lymph nodes in RA synovium by means of attracting CXCR5+ B cells. Immunohistochemistry studies revealed that CXCL13 is produced by follicular dendritic cells located in B-cell-rich areas. The lack of CCL21, a CCR7 ligand normally found in the T-cell-rich areas in lymph nodes, suggest that other chemokines control the recruitment of T cells. 33. Burger JA, Zvaifler NJ, Tsukada N, Firestein GS, Kipps TJ: Fibroblast • like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J Clin Invest 2001, 107:305-315. This paper suggests that fibroblast-like synoviocytes from RA joints may support the development of lymphoid structures by attracting B cells in a chemokine-dependent process. B cells expressing CXCR4 can migrate toward CXCL12 produced by fibroblasts. Both the synthesis of CXCL12 and the expression of the integrin VCAM-1 by fibroblasts are necessary to support cell attraction via CXCR4 and VLA-4 expressed on B cells. These studies also suggest that fibroblasts can synthesize CXCL12, but only those properly stimulated to express VCAM-1 will be able to support B-cell migration. α therapy of rheumatoid arthritis: 34. Feldmann M, Maini RN: Anti-TNFα what have we learned? Annu Rev Immunol 2001, 19:163-196. 35. Bruhl H, Cihak J, Stangassinger M, Schlondorff D, Mack M: Depletion of CCR5-expressing cells with bispecific antibodies and chemokine toxins: a new strategy in the treatment of chronic inflammatory diseases and HIV. J Immunol 2001, 166:2420-2426. 36. Karin N: Gene therapy for T cell-mediated autoimmunity: teaching the immune system how to restrain its own harmful activities by targeted DNA vaccines. Isr Med Assoc J 2000, 2:63-68. 37.
Gomez-Reino JJ, Pablos JL, Carreira PE, Santiago B, Serrano L, Vicario JL, Balsa A, Figueroa M, de Juan MD: Association of rheumatoid arthritis with a functional chemokine receptor, CCR5. Arthritis Rheum 1999, 42:989-992.
38. Garred P, Madsen HO, Petersen J, Marquart H, Hansen TM, Freiesleben Sorensen S, Volck B, Svejgaard A, Andersen V: CC chemokine receptor 5 polymorphism in rheumatoid arthritis. J Rheumatol 1998, 25:1462-1465. 39. Youssef S, Maor G, Wildbaum G, Grabie N, Gour-Lavie A, Karin N: C-C chemokine-encoding DNA vaccines enhance breakdown of tolerance to their gene products and treat ongoing adjuvant arthritis. J Clin Invest 2000, 106:361-371.
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40. Naya A, Sagara Y, Ohwaki K, Saeki T, Ichikawa D, Iwasawa Y, Noguchi K, Ohtake N: Design, synthesis, and discovery of a novel CCR1 antagonist. J Med Chem 2001, 44:1429-1435. 41. Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity 2000, 12:121-127. 42. Dubois-Laforgue D, Hendel H, Caillat-Zucman S, Zagury JF, Winkler C, Boitard C, Timsit J: A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes. Diabetes 2001, 50:1211-1213. 43. Cameron MJ, Arreaza GA, Grattan M, Meagher C, Sharif S, Burdick MD, Strieter RM, Cook DN, Delovitch TL: Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes. J Immunol 2000, 165:1102-1110. 44. Arimilli S, Ferlin W, Solvason N, Deshpande S, Howard M, Mocci S: Chemokines in autoimmune diseases. Immunol Rev 2000, 177:43-51. 45. Ashhab Y, Dominguez O, Sospedra M, Roura-Mir C, Lucas-Martin A, Pujol-Borrell R: A one-tube polymerase chain reaction protocol demonstrates CC chemokine overexpression in Graves’ disease glands. J Clin Endocrinol Metab 1999, 84:2873-2882.
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